GLIMMER: A 6-week Dose Ranging Study of CHF 5259 pMDI in Subjects With Chronic Obstructive Pulmonary Disease

• Sponsor: Chiesi Farmaceutici S.p.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03084796
• Collaborator: (none)
• Enrollment: 733
• Locations: 112
• Arms: 6
• Actual Duration (Months): 10.3
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the dose-response of different doses of CHF 5259 pMDI on lung function and other clinical outcomes, to identify the optimal dose(s) in terms of benefit/ risk ratio for further development in the target subject population.

Condition or Disease	Intervention/Treatment	Phase
COPD; Chronic Obstructive Pulmonary Disease	Drug: CHF 5259; Drug: Placebo; Drug: Tiotropium Bromide 18 µg Inhalation Capsule	Phase 2

Detailed Description

This is a phase II, multicenter, randomized, double-blind, placebo and active controlled dose-ranging 6-arm parallel group study to identify the optimal dose of CHF 5259 pMDI (pressurized metered dose inhaler) with respect to lung function as well as other clinical efficacy and safety outcomes.

After a 2 week run-in period under rescue albuterol and background inhaled corticosteroid (ICS) as needed, patients were randomized to one of the 6 study treatment groups. Following randomization, subjects were assessed after 3 weeks and 6 weeks of study treatment at the study center. A follow-up phone was performed a week after the last visit.

During the study, daily symptoms, rescue and background medication use and compliance with the study drug were recorded in a subject diary. Treatment-Emergent Adverse Events (TEAEs) were assessed and recorded throughout the study. At screening and subsequent visits, subjects underwent physical and vital signs examinations, spirometry measurements, and 12-lead electrocardiogram (ECG). Symptoms and chronic obstructive pulmonary disease (COPD) health status were assessed through validated questionnaires. Routine hematology, blood chemistry, and pregnancy testing were performed before enrollment and at end of study. 24-hour (24-H) digital recording of ECGs (Holter) was performed before and after the first dose and just before the last dose of study treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 733 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: A 6-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 5259 pMDI (HFA Glycopyrronium Bromide Via Pressurized Metered Dose Inhaler) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
• Actual Study Start Date: Jul 28, 2017
• Actual Primary Completion Date: May 23, 2018
• Actual Study Completion Date: Jun 6, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment A CHF 5259 pMDI 6.25 μg, 1 inhalation twice daily (bid); (total daily dose [TDD] of CHF 5259 12.5 μg)	Drug: CHF 5259; Dose Response: Test one of four different doses of CHF 5259
Experimental: Treatment B CHF 5259 pMDI 12.5 μg, 1 inhalation bid; (TDD of CHF 5259: 25 μg)	Drug: CHF 5259; Dose Response: Test one of four different doses of CHF 5259
Experimental: Treatment C CHF 5259 pMDI 12.5 μg, 2 inhalations bid; (TDD of CHF 5259: 50 μg)	Drug: CHF 5259; Dose Response: Test one of four different doses of CHF 5259
Experimental: Treatment D CHF 5259 pMDI 25 μg, 2 inhalations bid; (TDD of CHF 5259: 100 μg)	Drug: CHF 5259; Dose Response: Test one of four different doses of CHF 5259
Placebo Comparator: Treatment E Placebo, 2 inhalations of CHF 5259 pMDI-matched Placebo bid;	Drug: Placebo; Placebo Control
Active Comparator: Treatment F Tiotropium (TIO) 18 μg, SPIRIVA® HandiHaler®, 2 inhalations once daily (od) of the content of 1 capsule; (TDD of TIO: 18 μg)	Drug: Tiotropium Bromide 18 µg Inhalation Capsule; Active Control; Other Names: SPIRIVA® HANDIHALER®

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6 [Baseline, Week 6]

   Change from baseline in FEV1 AUC(0-12h), normalized by time, at the end of treatment (Week 6). Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;

Secondary Outcome Measures

1. Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1 [Baseline, Day 1]

   Change from baseline in FEV1 AUC(0-12h), normalized by time, on Day 1. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;

2. Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6 [Baseline, Day 1, Week 6]

   Change from baseline in FEV1 AUC(0-4h), normalized by time on Day 1 of treatment (Week 0). Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 and at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-4h)=Mean FEV1 after inhalation, measured at prespecified times for up to 4-h observation period (0-4h), normalized by time;

3. Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6 [Baseline, Day 1, Week 6]

   Change from baseline in FEV1 peak(0-4h) (L) on Day 1 and at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.

4. Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6 [Baseline, Day 1, Week 6]

   Change from baseline in FVC AUC(0-12h), normalized by time, on Day 1 and at the end of treatment (Week 6). Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-12h)=Mean FVC after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;

5. Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6 [Baseline, Day 1, Week 6]

   Change from baseline in FVC AUC(0-4h), normalized by time, on Day 1 and at the end of treatment (Week 6). Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-4)=Mean FVC after inhalation, measured at prespecified times for up to 4-h observation period (0-4 h), normalized by time;

6. Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6 [Baseline, Day 1, Week 6]

   Change from baseline in FVC peak(0-4h) (L) on Day 1 and at the end of treatment at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.

7. Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1 [Day 1]

   Time to onset of action is defined as the time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥100 mL.

8. Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1 [Day 1]

   Number of patients achieving onset of action was defined as a change from baseline in post-dose FEV1 ≥100 mL on Day 1. These are the patients who contributed to the results, reported as median and 95% CI for 'time to onset of action' presented in Outcome Measure 8, above.

9. Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6 [Baseline, Week 3, Week 6]

   Change from baseline in FEV1 at treatment visit 3 (Week 3) and treatment visit 4 (Week 6) of treatment. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second;

10. Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6 [Baseline, Week 3, Week 6]

    Change from baseline in IC at treatment Visit 3 (Week 3) and treatment Visit 4 (Week 6). Spirometry was used to measure IC and was performed according to internationally accepted standards. Definitions: Baseline: value of the measurement recorded at 45 mins pre-dose at Visit 2 (Week 0); IC=Inspiratory capacity;

11. Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6 [Baseline, Week 3, Week 6]

    Number of subjects achieving TDI focal score ≥1, at treatment visit 3 (Week 3) and at treatment visit 4 (Week 6). TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement); total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important. Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;

12. Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6 [Baseline, Week 3, Week 6]

    Transitional Dyspnea Index (TDI) focal score at treatment visit 3 (Week 3) and treatment visit 4 (Week 6). TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement), with a total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important. Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;

13. Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period [Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period]

    Evaluate the number of rescue medication-free days compared with baseline. Results are shown as percentage (%) of rescue medication-free days; an increased value indicates improvement from baseline. Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3, Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0).

14. Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period [Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period]

    Evaluate the change from baseline in average use of rescue medication (number of puffs/day) during the inter-visit periods and the entire treatment period. Results are shown as number of puffs/day; a decrease (implies improvement) from baseline in average use of rescue medication. Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3 (Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0);

15. Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period [Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period]

    Change from baseline in average EXACT-Respiratory Symptom (E-RS) total score during inter-visit periods and the entire treatment period E-RS in COPD uses 11 respiratory symptom items from the 14-item EXAcerbations of COPD tool (EXACT). E-RS total score quantifies respiratory symptom severity on a scale ranging from 0 to 40. Higher E-RS total scores indicate more severe symptoms and a declining total score indicates health improvement. E-RS questionnaire was completed by the patient each evening (e-diary). Definitions: For details on baseline, inter-visit periods, and the entire treatment period, please refer to outcome measure #15.

16. Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) [Baseline, Day 1, Week 6]

    Vital signs -- Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were measured at prespecified times, using a 12-Lead single ECGs were recorded at all study visits (pre-dose at V1 (Week -2) and V3 (Week 3), as well as at pre-dose and 1.5 hours post-dose at Visit 2 (Week 0) and Visit 4 (Week 6). Results are shown by treatment group, as change from baseline (in mmHg) for representative timepoints. Definitions: Baseline=Values recorded pre-dose (Visit 2, Week 0); Day 1=Day of the first dose of randomized study drug (Visit 2, Week 0);

17. Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR) [Baseline, Day 1, Week 6]

    Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Heart rate (HR) Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5m, +55m, and at +2.5 h.

18. Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval [Baseline, Day 1, Week 6]

    Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - PR Interval Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

19. Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval [Baseline, Day 1, Week 6]

    Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - QRS Interval Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

20. Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF) [Baseline, Day 1, Week 6]

    Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Fridericia-corrected QT interval (QTcF). Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

21. 24-hour Holter ECG - Prolonged QTcF - Male Subjects [Baseline, Day 1, Week 6]

    24-hour Holter ECG - Prolonged QTcF - Male subjects. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

22. 24-hour Holter ECG - Prolonged QTcF - Female Subjects [Baseline, Day 1, Week 6]

    24-hour Holter ECG - Prolonged QTcF - Female subjects. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

23. 24-hour Holter ECG - Prolonged QTcF - Change From Baseline [Baseline, Day 1, Week 6]

    24-hour Holter ECG - Prolonged QTcF - Change from baseline. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h. Results are presented as the number of subjects who had a change from baseline in QTcF of: > 30 msec, > 60 msec, and no prolongation (by > 30 msec or > 60 msec).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female subjects aged ≥ 40 who have signed an Informed Consent Form prior to initiation of any study-related procedure.

• Subjects with a diagnosis of COPD (according to GOLD 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD Report) at least 12 months before the screening visit.

• Current smokers or ex-smokers who quit smoking at least 6 months prior to screening visit, with a smoking history of at least 10 pack years

• A post-bronchodilator forced expiratory volume in the 1st second (FEV1) ≥50% and <80% of the predicted normal value and,

• a post-bronchodilator FEV1/ Forced Vital Capacity (FVC) < 0.7 at screening and

• a demonstrated reversibility to ipratropium defined as ΔFEV1 ≥ 5% over baseline 30-45 minutes after inhaling 4 puffs of ipratropium

• Subjects under regular COPD therapy for at least 2 months prior to screening with either inhaled long-acting muscarinic antagonist (LAMA), inhaled ICS/ long-acting β2-agonist (LABA), inhaled ICS + LAMA

• Symptomatic subjects at screening with a CAT score ≥10. This criterion must be confirmed at randomization

• Symptomatic subjects with a BDI focal score ≤ 10. This criterion must be confirmed at randomization

• A cooperative attitude and ability to demonstrate correct use of the inhalers and e-diary.

Exclusion Criteria:

• Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS they are willing to use highly effective birth control methods

• Diagnosis of asthma or Asthma-COPD Overlap Syndrome (ACOS) as described in global initiative for asthma (GINA) Report 2016, history of allergic rhinitis or atopy (atopy which may raise contra-indications or impact the efficacy of the study treatment according to Investigator's judgment)

• COPD Exacerbations: a moderate or severe COPD exacerbation that has not resolved ≤14 days prior to screening and ≤30 days following the last dose of any oral/systemic corticosteroid or antibiotic (whichever comes last). A Moderate or Severe COPD exacerbation during the run-in period

• Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screening or during run-in

• Subjects treated with non-cardio-selective β-blockers in the month preceding screening or during the run-in period

• Subjects treated with long-acting anti-histamines unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study, or if taken as needed

• Subjects requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia

• Known respiratory disorders other than COPD which may impact the efficacy of the study treatment according the Investigator's judgment.

• Subjects who have clinically significant cardiovascular condition

• Subjects who have a clinically significant abnormal 12-lead ECG that results in active medical problem which may impact the safety of the subject according to Investigator's judgement

• Subjects whose 12-lead ECG shows Fridericia corrected QT interval (QTcF) >450 ms for males or QTcF >470 ms for females at screening visit

• Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that in the opinion of the Investigator would prevent use of anticholinergic agents

• History of hypersensitivity to M3 receptor antagonists, β2-adrenergic receptor agonist, corticosteroids or any of the excipients contained in any of the formulations used in the study which may raise contra-indications or impact the efficacy of the study treatment according to the Investigator's judgement

• Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study treatment according to Investigator's judgement

• Subjects with serum potassium levels <3.5 mEq/L (or 3.5 mmol/L) at screening

• Use of potent cytochrome P450 2D6 and 3A4 inhibitors within 4 weeks prior to screening

• Unstable or uncontrolled concurrent disease; fever, endocrine disease, gastrointestinal disease; neurological disease; hematological disease; autoimmune disorders, or other which may impact the feasibility of the results of the study according to Investigator's judgment

• History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening

• Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.

• Subjects who are mentally or legally incapacitated, or subjects accommodated in an establishment as a result of an official or judicial order.

• Subjects who have undergone major surgery in the 3 months prior to screening visit or have a planned surgery during the trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chiesi Investigational Site	Birmingham	Alabama	United States	35244
2	Chiesi Investigational Site	Dothan	Alabama	United States	36305
3	Chiesi Investigational Site	Montgomery	Alabama	United States	36106
4	Chiesi Investigational Site	Flagstaff	Arizona	United States	86001
5	Chiesi Investigational Site	Glendale	Arizona	United States	85306
6	Chiesi Investigational Site	Phoenix	Arizona	United States	85006
7	Chiesi Investigational Site	Phoenix	Arizona	United States	85014
8	Chiesi Investigational Site	Phoenix	Arizona	United States	85018
9	Chiesi Investigational Site	Surprise	Arizona	United States	85374
10	Chiesi Investigational Site	Tempe	Arizona	United States	85283
11	Chiesi Investigational Site	Tucson	Arizona	United States	85710
12	Chiesi Investigational Site	Anaheim	California	United States	92801
13	Chiesi Investigational Site	Escondido	California	United States	92025
14	Chiesi Investigational Site	Fullerton	California	United States	92835
15	Clinical Trials Research	Lincoln	California	United States	95648
16	Chiesi Investigational Site	Long Beach	California	United States	90806
17	Chiesi Investigational Site	Los Angeles	California	United States	90017
18	Chiesi Investigational Site	Los Angeles	California	United States	90036
19	Chiesi Investigational Site	Los Angeles	California	United States	90048
20	Chiesi Investigational Site	Newport Beach	California	United States	92663
21	Chiesi Investigational Site	San Diego	California	United States	92120
22	Chiesi Investigational Site	Tustin	California	United States	92780
23	Chiesi Investigational Site	Westminster	California	United States	92683
24	Chiesi Investigational Site	Boulder	Colorado	United States	80301
25	Chiesi Investigational Site	Centennial	Colorado	United States	80112
26	Chiesi Investigational Site	Denver	Colorado	United States	80230
27	Chiesi Investigational Site	Lafayette	Colorado	United States	80026
28	Chiesi Investigational Site	Brandon	Florida	United States	33511
29	Chiesi Investigational Site	Clearwater	Florida	United States	33765
30	Chiesi Investigational Site	Daytona Beach	Florida	United States	32117
31	Chiesi Investigational Site	Edgewater	Florida	United States	32132
32	Chiesi Investigational Site	Hialeah	Florida	United States	33012
33	Chiesi Investigational Site	Kissimmee	Florida	United States	34741
34	Chiesi Investigational Site	Miami	Florida	United States	33144
35	Chiesi Investigational Site	Miami	Florida	United States	33165
36	Chiesi Investigational Site	Miami	Florida	United States	33176
37	Chiesi Investigational Site	Miami	Florida	United States	33186
38	Chiesi Investigational Site	Orlando	Florida	United States	32825
39	Chiesi Investigational Site	Panama City	Florida	United States	32405
40	Chiesi Investigational Site	Blue Ridge	Georgia	United States	30513
41	Chiesi Investigational Site	Dacula	Georgia	United States	30019
42	Chiesi Investigational Site	Duluth	Georgia	United States	30096
43	Chiesi Investigational Site	Lawrenceville	Georgia	United States	30046
44	Chiesi Investigational Site	Marietta	Georgia	United States	30060
45	Chiesi Investigational Site	Savannah	Georgia	United States	31405
46	Chiesi Investigational Site	Chicago	Illinois	United States	60607
47	Chiesi Investigational Site	Evansville	Indiana	United States	47714
48	Chiesi Investigational Site	Valparaiso	Indiana	United States	46383
49	Chiesi Investigational Site	Louisville	Kentucky	United States	40215
50	Chiesi Investigational Site	Louisville	Kentucky	United States	40218
51	Chiesi Investigational Site	Crowley	Louisiana	United States	70526
52	Chiesi Investigational Site	Lake Charles	Louisiana	United States	70601
53	Chiesi Investigational Site	Lutherville	Maryland	United States	21093
54	Chiesi Investigational Site	Fall River	Massachusetts	United States	02720
55	Chiesi Investigational Site	Fall River	Massachusetts	United States	02721
56	Chiesi Investigational Site	Ann Arbor	Michigan	United States	48106
57	Chiesi Investigational Site	Farmington Hills	Michigan	United States	48336
58	Chiesi Investigational Site	Minneapolis	Minnesota	United States	55402
59	Chiesi Investigational Site	Saint Charles	Missouri	United States	63301
60	Chiesi Investigational Site	Saint Louis	Missouri	United States	63141
61	Chiesi Investigational Site	Missoula	Montana	United States	59808
62	Chiesi Investigational Site	Omaha	Nebraska	United States	68114
63	Chiesi Investigational Site	Las Vegas	Nevada	United States	89119
64	Chiesi Investigational Site	Summit	New Jersey	United States	07901
65	Chiesi Investigational Site	Albuquerque	New Mexico	United States	87108
66	Chiesi Investigational Site	Bronx	New York	United States	10455
67	Chiesi Investigational Site	Charlotte	North Carolina	United States	28207
68	Chiesi Investigational Site	Gastonia	North Carolina	United States	28054
69	Chiesi Investigational Site	Hendersonville	North Carolina	United States	28739
70	Chiesi Investigational Site	Mooresville	North Carolina	United States	28117
71	Chiesi Investigational Site	Raleigh	North Carolina	United States	27607
72	Chiesi Investigational Site	Shelby	North Carolina	United States	28150
73	Chiesi Investigational Site	Wilmington	North Carolina	United States	28401
74	Chiesi Investigational Site	Winston-Salem	North Carolina	United States	27103
75	Chiesi Investigational Site	Cincinnati	Ohio	United States	45242
76	Chiesi Investigational Site	Columbus	Ohio	United States	43213
77	Chiesi Investigational Site	Columbus	Ohio	United States	43215
78	Clinical Research Solutions	Dayton	Ohio	United States	45409
79	Chiesi Investigational Site	Grove City	Ohio	United States	43123
80	Chiesi Investigational Site	Edmond	Oklahoma	United States	73034
81	Chiesi Investigational Site	Oklahoma City	Oklahoma	United States	73103
82	Chiesi Investigational Site	Medford	Oregon	United States	97504
83	Chiesi Investigational Site	Portland	Oregon	United States	97202
84	Chiesi Investigational Site	Philadelphia	Pennsylvania	United States	19140
85	Chiesi Investigational Site	East Providence	Rhode Island	United States	02914
86	Chiesi Investigational Site	Anderson	South Carolina	United States	29621
87	Chiesi Investigational Site	Charleston	South Carolina	United States	29406
88	Chiesi Investigational Site	Easley	South Carolina	United States	29640
89	Chiesi Investigational Site	Fort Mill	South Carolina	United States	29707
90	Chiesi Investigational Site	Gaffney	South Carolina	United States	29340
91	Chiesi Investigational Site	Greenville	South Carolina	United States	29615
92	Chiesi Investigational Site	Mount Pleasant	South Carolina	United States	29464
93	Chiesi Investigational Site	Orangeburg	South Carolina	United States	29118
94	Chiesi Investigational Site	Rock Hill	South Carolina	United States	29732
95	Chiesi Investigational Site	Seneca	South Carolina	United States	29678
96	Chiesi Investigational Site	Spartanburg	South Carolina	United States	29303
97	Chiesi Investigational Site	Union	South Carolina	United States	29379
98	Chiesi Investigational Site	Rapid City	South Dakota	United States	57702
99	Chiesi Investigational Site	Franklin	Tennessee	United States	37067
100	Chiesi Investigational Site	Jackson	Tennessee	United States	38305
101	Chiesi Investigational Site	Knoxville	Tennessee	United States	37909
102	Chiesi Investigational Site	Tullahoma	Tennessee	United States	37388
103	Chiesi Investigational Site	Boerne	Texas	United States	78006
104	Chiesi Investigational Site	Cypress	Texas	United States	77429
105	Chiesi Investigational Site	New Braunfels	Texas	United States	78130
106	Chiesi Investigational Site	Sherman	Texas	United States	75092
107	Chiesi Investigational Site	Tomball	Texas	United States	77375
108	Chiesi Investigational Site	South Burlington	Vermont	United States	05403
109	Chiesi Investigational Site	Richmond	Virginia	United States	23225
110	Chiesi Investigational Site	Everett	Washington	United States	98208
111	Chiesi Investigational Site	Richland	Washington	United States	99352
112	Chiesi Investigational Site	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• Chiesi Farmaceutici S.p.A.

Investigators

• Principal Investigator: Edward Kerwin, MD, Crisor LLC c/o Clinical Research Institute of Southern Oregon, Inc.

Study Documents (Full-Text)

• Study Protocol - Jan 9, 2018
• Statistical Analysis Plan - Sep 20, 2018

More Information

Additional Information:

• From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017.
• Chiesi Respiratory
• Chiesi Farmaceutici is the first company to submit a marketing authorisation application to the European Medicine Agency for a Triple Combination for the treatment of COPD
• Glycopyrronium bromide
• American Thoracic Society: Baseline Dyspnea Index (BDI) & Transition Dyspnea Index (TDI).
• American Thoracic Society: COPD Assessment Test (CAT).

Publications

• Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O'Donnell D, McIvor A, Sharma S, Bishop G, Anthony J, Cowie R, Field S, Hirsch A, Hernandez P, Rivington R, Road J, Hoffstein V, Hodder R, Marciniuk D, McCormack D, Fox G, Cox G, Prins HB, Ford G, Bleskie D, Doucette S, Mayers I, Chapman K, Zamel N, FitzGerald M; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007 Apr 17;146(8):545-55. Epub 2007 Feb 19.
• Andréjak C, Nielsen R, Thomsen VØ, Duhaut P, Sørensen HT, Thomsen RW. Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis. Thorax. 2013 Mar;68(3):256-62. doi: 10.1136/thoraxjnl-2012-201772. Epub 2012 Jul 10.
• Anthonisen NR, Connett JE, Enright PL, Manfreda J; Lung Health Study Research Group. Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med. 2002 Aug 1;166(3):333-9.
• Arievich H, Overend T, Renard D, Gibbs M, Alagappan V, Looby M, Banerji D. A novel model-based approach for dose determination of glycopyrronium bromide in COPD. BMC Pulm Med. 2012 Dec 8;12:74. doi: 10.1186/1471-2466-12-74.
• Beeh KM, Singh D, Di Scala L, Drollmann A. Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis. 2012;7:503-13. doi: 10.2147/COPD.S32451. Epub 2012 Jul 31.
• Beier J, van Noord J, Deans A, Brooks J, Maden C, Baggen S, Mehta R, Cahn A. Safety and efficacy of dual therapy with GSK233705 and salmeterol versus monotherapy with salmeterol, tiotropium, or placebo in a crossover pilot study in partially reversible COPD patients. Int J Chron Obstruct Pulmon Dis. 2012;7:153-64. doi: 10.2147/COPD.S26100. Epub 2012 Mar 5.
• Boehringer Ingelheim Pharmaceuticals, Inc. ATROVENT® HFA US Prescribing Information. Ridgefield, Connecticut; 2012 Aug.
• Boehringer Ingelheim Pharmaceuticals, Inc. SPIRIVA® HALER® US Prescribing Information. Ridgefield, Connecticut; 2016 Jan.
• Buhl R, Banerji D. Profile of glycopyrronium for once-daily treatment of moderate-to-severe COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:729-41. doi: 10.2147/COPD.S36001. Epub 2012 Oct 26. Review. Erratum in: Int J Chron Obstruct Pulmon Dis. 2014;9:287.
• Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005 Mar;127(3):809-17.
• Chiesi Farmaceutici S.p.A. A multicentre, randomised, double-blind, active-controlled, 4-way cross-over study to evaluate the efficacy and safety of a free combination of 3 doses of glycopyrrolate with fixed combination beclomethasone dipropionate plus formoterol (FOSTER®) in a metered dose inhaler for the treatment of patients with chronic obstructive pulmonary disease (COPD). 2013 May 16; CCD-1106-PR-0066.
• Chiesi Farmaceutici S.p.A. A multinational, multicentre, randomised, double-blind, placebo-controlled, 2-way crossover study to evaluate the efficacy and safety of glycopyrrolate bromide administered via pMDI (CHF 5259), for the treatment of patients with chronic obstructive pulmonary disease. 2015 Nov 05; CCD-05993AA1-09.
• Chiesi Farmaceutici S.p.A. Randomised, double-blind, placebo-controlled, cross-over study to investigate the bronchodilator efficacy and safety after single and repeated administrations of different doses of glycopyrrolate via pMDI in moderate to severe COPD patients (GLYCO2). 2012 Jul 19; CCD-0916-CSR-0054.
• Chiesi Farmaceutici S.p.A. Randomized, double-blind, active controlled, 3-arm parallel group, multi-national, multi-centre study to evaluate the cardiac safety of two doses of glycopyrrolate bromide (25µg and 50µg BID) delivered via HFA pMDI both combined with FOSTER® 100/6µg BID delivered via HFA pMDI versus FOSTER® 100/6µg BID delivered via HFA pMDI in patients with moderate to severe COPD. 2012 Jan 10; CCD-1107-PR-0067.
• Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Willits LR, Yates JC, Vestbo J. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009 Sep;34(3):641-7. doi: 10.1183/09031936.00193908. Epub 2009 May 14.
• Crim C, Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Lettis S, Calverley PM. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD. Ann Am Thorac Soc. 2015 Jan;12(1):27-34. doi: 10.1513/AnnalsATS.201409-413OC.
• Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D, Bleasdale P, Owen R, Higgins M, Kramer B; INVOLVE (INdacaterol: Value in COPD: Longer Term Validation of Efficacy and Safety) Study Investigators. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010 Jun;65(6):473-9. doi: 10.1136/thx.2009.125435.
• Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005 Mar;2(1):111-24. Review.
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• Kerwin E, Hébert J, Gallagher N, Martin C, Overend T, Alagappan VK, Lu Y, Banerji D. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J. 2012 Nov;40(5):1106-14. doi: 10.1183/09031936.00040712. Epub 2012 Jul 26.
• Kerwin E, Siler TM, Korenblat P, White A, Eckert JH, Henley M, Patalano F, D'Andrea P. Efficacy and Safety of Twice-Daily Glycopyrrolate Versus Placebo in Patients With COPD: The GEM2 Study. Chronic Obstr Pulm Dis. 2016 Mar 28;3(2):549-559. doi: 10.15326/jcopdf.3.2.2015.0157.
• Kesten S, Casaburi R, Kukafka D, Cooper CB. Improvement in self-reported exercise participation with the combination of tiotropium and rehabilitative exercise training in COPD patients. Int J Chron Obstruct Pulmon Dis. 2008;3(1):127-36.
• Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013 Oct 15;(10):CD010177. doi: 10.1002/14651858.CD010177.pub2. Review.
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• Leidy NK, Murray LT, Monz BU, Nelsen L, Goldman M, Jones PW, Dansie EJ, Sethi S. Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials. Respir Res. 2014 Oct 7;15:124. doi: 10.1186/s12931-014-0124-z.
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• Yawn BP, Li Y, Tian H, Zhang J, Arcona S, Kahler KH. Inhaled corticosteroid use in patients with chronic obstructive pulmonary disease and the risk of pneumonia: a retrospective claims data analysis. Int J Chron Obstruct Pulmon Dis. 2013;8:295-304. doi: 10.2147/COPD.S42366. Epub 2013 Jun 27.

• Responsible Party: Chiesi Farmaceutici S.p.A.
• ClinicalTrials.gov Identifier: NCT03084796
• Other Study ID Numbers: CCD-05993AA3-02
• First Posted: Mar 21, 2017
• Last Update Posted: Jun 15, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Chiesi Farmaceutici S.p.A.: CHF 5259; Chronic Obstructive Pulmonary Disease (COPD); pMDI (pressurized metered dose inhaler); GLIMMER
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Bromides; Tiotropium Bromide

Study Results

Participant Flow

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Period Title: Overall Study
STARTED	121	123	122	123	121	123
COMPLETED	114	113	110	119	110	116
NOT COMPLETED	7	10	12	4	11	7

Baseline Characteristics

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F	Total
Arm/Group Description	CHF 5259 pMDI, 6.25 μg, 1 inhalation bid; 12.5 μg TDD CHF 5259 Dose Response: Test one of 4 different doses of CHF 5259	CHF 5259 pMDI 12.5 μg, 1 inhalation bid; 25 μg TDD CHF 5259 Dose Response: Test one of 4 different doses of CHF 5259	CHF 5259 pMDI 12.5 μg, 2 inhalations bid; 50 μg TDD CHF 5259 Dose Response: Test one of 4 different doses of CHF 5259	CHF 5259 pMDI 25 μg, 2 inhalations bid; 100 μg TDD CHF 5259 Dose Response: Test one of 4 different doses of CHF 5259	Placebo 2 inhalations of CHF 5259 pMDI-matched Placebo bid Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 μg, SPIRIVA® HandiHaler®, 2 inhalations od of the content of 1 capsule; 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule	Total of all reporting groups
Overall Participants	121	123	121	123	121	123	732
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.1 (9.13)	65.3 (9.10)	65.3 (8.16)	64.9 (9.11)	64.9 (9.25)	63.8 (9.55)	64.7 (9.05)
Age, Customized (Count of Participants)
< 65 years	59 48.8%	53 43.1%	56 46.3%	62 50.4%	60 49.6%	62 50.4%	352 48.1%
65-84 years	60 49.6%	68 55.3%	65 53.7%	60 48.8%	58 47.9%	59 48%	370 50.5%
> 85 years	2 1.7%	2 1.6%	0 0%	1 0.8%	3 2.5%	2 1.6%	10 1.4%
Sex: Female, Male (Count of Participants)
Female	58 47.9%	68 55.3%	67 55.4%	65 52.8%	52 43%	57 46.3%	367 50.1%
Male	63 52.1%	55 44.7%	54 44.6%	58 47.2%	69 57%	66 53.7%	365 49.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 5.8%	9 7.3%	12 9.9%	11 8.9%	5 4.1%	7 5.7%	51 7%
Not Hispanic or Latino	114 94.2%	114 92.7%	109 90.1%	112 91.1%	115 95%	116 94.3%	680 92.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	1 0.8%	0 0%	1 0.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	2 1.7%	0 0%	2 0.3%
Asian	1 0.8%	0 0%	0 0%	0 0%	2 1.7%	1 0.8%	4 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	13 10.7%	10 8.1%	10 8.3%	14 11.4%	12 9.9%	10 8.1%	69 9.4%
White	107 88.4%	110 89.4%	107 88.4%	108 87.8%	104 86%	110 89.4%	646 88.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	3 2.4%	4 3.3%	1 0.8%	1 0.8%	2 1.6%	11 1.5%
Region of Enrollment (Count of Participants)
United States	121 100%	123 100%	121 100%	123 100%	121 100%	123 100%	732 100%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	81.81 (20.64)	83.82 (19.33)	82.12 (22.70)	84.23 (22.41)	84.43 (21.82)	80.67 (17.40)	82.85 (20.77)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	168.95 (8.76)	169.38 (9.74)	169.21 (9.67)	168.17 (9.57)	169.34 (9.56)	169.53 (9.67)	169.10 (9.48)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.67 (7.05)	29.13 (5.98)	28.52 (6.77)	29.62 (6.73)	29.26 (6.49)	28.05 (5.54)	28.88 (6.45)
Time since first diagnosis of COPD (months) [Median (Full Range) ]
Median (Full Range) [months]	92.80	99.60	97.40	94.00	103.40	74.40	94.55
Age at first diagnosis of COPD (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.98 (9.31)	55.45 (9.29)	55.38 (8.46)	56.40 (9.41)	55.12 (8.85)	55.65 (10.19)	55.50 (9.25)
COPD medication category at study entry (Count of Participants)
Inhaled LAMA	24 19.8%	22 17.9%	31 25.6%	22 17.9%	25 20.7%	27 22%	151 20.6%
Inhaled ICS and LABA (free combination)	3 2.5%	0 0%	0 0%	1 0.8%	0 0%	2 1.6%	6 0.8%
Inhaled ICS/LABA (fixed combination)	77 63.6%	89 72.4%	74 61.2%	92 74.8%	78 64.5%	81 65.9%	491 67.1%
Inhaled ICS and LAMA	0 0%	1 0.8%	2 1.7%	1 0.8%	2 1.7%	2 1.6%	8 1.1%
Inhaled ICS+LABA+LAMA (free or fixed combination)	11 9.1%	3 2.4%	11 9.1%	6 4.9%	13 10.7%	8 6.5%	52 7.1%
Inhaled LABA/LAMA (fixed combination)	6 5%	8 6.5%	3 2.5%	1 0.8%	3 2.5%	3 2.4%	24 3.3%
Smoking habits (Count of Participants)
Current smoker	61 50.4%	59 48%	59 48.8%	68 55.3%	55 45.5%	67 54.5%	369 50.4%
Ex-smoker	60 49.6%	64 52%	62 51.2%	55 44.7%	66 54.5%	56 45.5%	363 49.6%
Duration of smoking (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.19 (9.74)	42.98 (9.86)	40.71 (10.46)	42.78 (10.44)	41.34 (10.39)	40.79 (10.83)	41.80 (10.30)
Number of pack-years (pack-years) [Median (Full Range) ]
Median (Full Range) [pack-years]	45.0	49.0	45.0	45.0	45.0	43.0	45.0
FEV1 (L) at baseline (litres) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [litres]	1.440 (0.432)	1.428 (0.439)	1.434 (0.472)	1.420 (0.419)	1.415 (0.433)	1.443 (0.487)	1.430 (0.446)
FVC at baseline (litres) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [litres]	2.717 (0.754)	2.719 (0.775)	2.669 (0.725)	2.630 (0.719)	2.683 (0.736)	2.746 (0.809)	2.694 (0.752)
IC at baseline (litres) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [litres]	2.020 (0.622)	2.065 (0.533)	2.089 (0.683)	2.066 (0.572)	2.053 (0.628)	2.175 (0.624)	2.078 (0.612)
BDI focal scores at randomization (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	5.6 (1.88)	5.9 (1.87)	5.8 (1.77)	5.8 (1.63)	6.1 (1.43)	5.7 (1.59)	5.8 (1.71)
CAT total score at randomization (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	19.6 (5.60)	19.2 (5.65)	19.2 (5.83)	20.0 (5.49)	19.3 (5.73)	20.3 (6.48)	19.6 (5.80)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6
Description	Change from baseline in FEV1 AUC(0-12h), normalized by time, at the end of treatment (Week 6). Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;
Time Frame	Baseline, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	113	111	108	118	109	114
Least Squares Mean (95% Confidence Interval) [Litres]	0.070	0.118	0.153	0.147	0.002	0.213

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Comparison groups were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates. Adjusted for multiplicity based on the parametric simulation method by Edwards and Berry.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.037
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.068
	Confidence Interval	(2-Sided) 95%; 0.003 to 0.132
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Comparison treatment groups were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis for was performed as described for the statistical analysis 1 for this outcome measure. Adjusted for multiplicity based on the parametric simulation method by Edwards and Berry.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.116
	Confidence Interval	(2-Sided) 95%; 0.051 to 0.181
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Comparison treatment groups were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis for was performed as described for the statistical analysis 1 for this outcome measure. Adjusted for multiplicity based on the parametric simulation method by Edwards and Berry.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.151
	Confidence Interval	(2-Sided) 95%; 0.086 to 0.216
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Comparison treatment groups were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis for was performed as described for the statistical analysis 1 for this outcome measure. Adjusted for multiplicity based on the parametric simulation method by Edwards and Berry.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.145
	Confidence Interval	(2-Sided) 95%; 0.081 to 0.209
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Comparison treatment groups were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West)" and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.211
	Confidence Interval	(2-Sided) 95%; 0.159 to 0.263
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Comparison treatment groups were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West)" and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.066
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.048
	Confidence Interval	(2-Sided) 95%; -0.003 to 0.100
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Comparison treatment groups were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West)" and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.083
	Confidence Interval	(2-Sided) 95%; 0.031 to 0.135
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Comparison treatment groups were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West)" and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.077
	Confidence Interval	(2-Sided) 95%; 0.026 to 0.128
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Comparison treatment groups were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD. Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West)" and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.189
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.035
	Confidence Interval	(2-Sided) 95%; -0.017 to 0.087
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Comparison treatment groups were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West)" and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.273
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95%; -0.023 to 0.080
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Comparison treatment groups were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Analyzed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West)" and smoking status at screening as fixed effects, and the baseline value and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.813
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.006
	Confidence Interval	(2-Sided) 95%; -0.058 to 0.045
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1
Description	Change from baseline in FEV1 AUC(0-12h), normalized by time, on Day 1. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;
Time Frame	Baseline, Day 1

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	120	121	121	122
Least Squares Mean (95% Confidence Interval) [Litres]	0.067	0.086	0.135	0.149	0.009	0.192

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model for repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.059
	Confidence Interval	(2-Sided) 95%; 0.022 to 0.095
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.077
	Confidence Interval	(2-Sided) 95%; 0.040 to 0.113
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.126
	Confidence Interval	(2-Sided) 95%; 0.089 to 0.163
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.140
	Confidence Interval	(2-Sided) 95%; 0.104 to 0.177
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.183
	Confidence Interval	(2-Sided) 95%; 0.147 to 0.220
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.322
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95%; -0.018 to 0.055
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.067
	Confidence Interval	(2-Sided) 95%; 0.031 to 0.104
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.082
	Confidence Interval	(2-Sided) 95%; 0.045 to 0.118
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD. Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.049
	Confidence Interval	(2-Sided) 95%; 0.013 to 0.086
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95%; 0.027 to 0.100
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 for this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.443
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.022 to 0.051
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6
Description	Change from baseline in FEV1 AUC(0-4h), normalized by time on Day 1 of treatment (Week 0). Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 and at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-4h)=Mean FEV1 after inhalation, measured at prespecified times for up to 4-h observation period (0-4h), normalized by time;
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Day 1	0.101	0.115	0.173	0.190	0.030	0.194
Week 6	0.116	0.157	0.198	0.204	0.024	0.253

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model for repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.072
	Confidence Interval	(2-Sided) 95%; 0.038 to 0.105
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.086
	Confidence Interval	(2-Sided) 95%; 0.052 to 0.119
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.143
	Confidence Interval	(2-Sided) 95%; 0.109 to 0.177
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.160
	Confidence Interval	(2-Sided) 95%; 0.127 to 0.194
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.164
	Confidence Interval	(2-Sided) 95%; 0.131 to 0.198
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.418
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.020 to 0.048
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.071
	Confidence Interval	(2-Sided) 95%; 0.038 to 0.105
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.089
	Confidence Interval	(2-Sided) 95%; 0.055 to 0.122
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.057
	Confidence Interval	(2-Sided) 95%; 0.024 to 0.091
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 95%; 0.041 to 0.108
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.308
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.017
	Confidence Interval	(2-Sided) 95%; -0.016 to 0.051
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.092
	Confidence Interval	(2-Sided) 95%; 0.038 to 0.147
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Analyzed, using linear mixed model repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.133
	Confidence Interval	(2-Sided) 95%; 0.079 to 0.188
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.174
	Confidence Interval	(2-Sided) 95%; 0.120 to 0.229
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.181
	Confidence Interval	(2-Sided) 95%; 0.127 to 0.235
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.229
	Confidence Interval	(2-Sided) 95%; 0.175 to 0.284
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.141
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.041
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.095
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.082
	Confidence Interval	(2-Sided) 95%; 0.028 to 0.137
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.088
	Confidence Interval	(2-Sided) 95%; 0.035 to 0.142
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.137
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.041
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.096
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.082
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.048
	Confidence Interval	(2-Sided) 95%; -0.006 to 0.101
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.823
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.006
	Confidence Interval	(2-Sided) 95%; -0.048 to 0.060
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6
Description	Change from baseline in FEV1 peak(0-4h) (L) on Day 1 and at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Day 1	0.197	0.211	0.260	0.288	0.136	0.299
Week 6	0.212	0.255	0.305	0.301	0.143	0.356

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.061
	Confidence Interval	(2-Sided) 95%; 0.022 to 0.100
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 95%; 0.036 to 0.113
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.124
	Confidence Interval	(2-Sided) 95%; 0.085 to 0.163
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.152
	Confidence Interval	(2-Sided) 95%; 0.113 to 0.190
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.163
	Confidence Interval	(2-Sided) 95%; 0.124 to 0.202
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.485
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.025 to 0.052
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95%; 0.025 to 0.102
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.091
	Confidence Interval	(2-Sided) 95%; 0.053 to 0.130
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.050
	Confidence Interval	(2-Sided) 95%; 0.011 to 0.088
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.077
	Confidence Interval	(2-Sided) 95%; 0.039 to 0.116
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.157
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.028
	Confidence Interval	(2-Sided) 95%; -0.011 to 0.066
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.069
	Confidence Interval	(2-Sided) 95%; 0.011 to 0.128
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.112
	Confidence Interval	(2-Sided) 95%; 0.053 to 0.170
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.162
	Confidence Interval	(2-Sided) 95%; 0.103 to 0.220
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.157
	Confidence Interval	(2-Sided) 95%; 0.099 to 0.215
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.213
	Confidence Interval	(2-Sided) 95%; 0.154 to 0.271
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.149
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.043
	Confidence Interval	(2-Sided) 95%; -0.015 to 0.101
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.092
	Confidence Interval	(2-Sided) 95%; 0.034 to 0.151
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.088
	Confidence Interval	(2-Sided) 95%; 0.031 to 0.146
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.050
	Confidence Interval	(2-Sided) 95%; -0.009 to 0.108
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.122
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.045
	Confidence Interval	(2-Sided) 95%; -0.012 to 0.103
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.886
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.004
	Confidence Interval	(2-Sided) 95%; -0.062 to 0.054
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6
Description	Change from baseline in FVC AUC(0-12h), normalized by time, on Day 1 and at the end of treatment (Week 6). Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-12h)=Mean FVC after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Day 1	0.086	0.133	0.195	0.220	0.011	0.305
Week 6	0.084	0.145	0.190	0.184	-0.029	0.298

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.029
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.074
	Confidence Interval	(2-Sided) 95%; 0.008 to 0.141
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.121
	Confidence Interval	(2-Sided) 95%; 0.055 to 0.188
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.184
	Confidence Interval	(2-Sided) 95%; 0.117 to 0.250
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.208
	Confidence Interval	(2-Sided) 95%; 0.142 to 0.275
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.293
	Confidence Interval	(2-Sided) 95%; 0.227 to 0.360
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.161
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95%; -0.019 to 0.113
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.109
	Confidence Interval	(2-Sided) 95%; 0.043 to 0.176
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.134
	Confidence Interval	(2-Sided) 95%; 0.068 to 0.201
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.066
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.062
	Confidence Interval	(2-Sided) 95%; -0.004 to 0.128
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.087
	Confidence Interval	(2-Sided) 95%; 0.021 to 0.153
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.465
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.025
	Confidence Interval	(2-Sided) 95%; -0.042 to 0.091
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.112
	Confidence Interval	(2-Sided) 95%; 0.030 to 0.195
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.173
	Confidence Interval	(2-Sided) 95%; 0.091 to 0.256
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.219
	Confidence Interval	(2-Sided) 95%; 0.136 to 0.302
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.213
	Confidence Interval	(2-Sided) 95%; 0.131 to 0.295
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.326
	Confidence Interval	(2-Sided) 95%; 0.244 to 0.409
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.144
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.061
	Confidence Interval	(2-Sided) 95%; -0.021 to 0.143
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.107
	Confidence Interval	(2-Sided) 95%; 0.024 to 0.189
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.101
	Confidence Interval	(2-Sided) 95%; 0.019 to 0.182
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.280
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.045
	Confidence Interval	(2-Sided) 95%; -0.037 to 0.128
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.342
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.039
	Confidence Interval	(2-Sided) 95%; -0.042 to 0.121
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.886
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.006
	Confidence Interval	(2-Sided) 95%; -0.088 to 0.076
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6
Description	Change from baseline in FVC AUC(0-4h), normalized by time, on Day 1 and at the end of treatment (Week 6). Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours). Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-4)=Mean FVC after inhalation, measured at prespecified times for up to 4-h observation period (0-4 h), normalized by time;
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Day 1	0.133	0.192	0.244	0.273	0.036	0.311
Week 6	0.149	0.203	0.248	0.253	0.000	0.353

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.097
	Confidence Interval	(2-Sided) 95%; 0.032 to 0.163
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.156
	Confidence Interval	(2-Sided) 95%; 0.091 to 0.221
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.208
	Confidence Interval	(2-Sided) 95%; 0.143 to 0.273
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.237
	Confidence Interval	(2-Sided) 95%; 0.172 to 0.302
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.276
	Confidence Interval	(2-Sided) 95%; 0.211 to 0.341
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.076
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.059
	Confidence Interval	(2-Sided) 95%; -0.006 to 0.124
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.111
	Confidence Interval	(2-Sided) 95%; 0.046 to 0.176
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.140
	Confidence Interval	(2-Sided) 95%; 0.075 to 0.205
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.116
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.052
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.117
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.081
	Confidence Interval	(2-Sided) 95%; 0.016 to 0.146
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.384
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95%; -0.036 to 0.094
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.150
	Confidence Interval	(2-Sided) 95%; 0.064 to 0.236
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.204
	Confidence Interval	(2-Sided) 95%; 0.118 to 0.290
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.248
	Confidence Interval	(2-Sided) 95%; 0.162 to 0.335
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.254
	Confidence Interval	(2-Sided) 95%; 0.168 to 0.339
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.354
	Confidence Interval	(2-Sided) 95%; 0.268 to 0.439
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.214
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.054
	Confidence Interval	(2-Sided) 95%; -0.031 to 0.140
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.098
	Confidence Interval	(2-Sided) 95%; 0.012 to 0.184
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.104
	Confidence Interval	(2-Sided) 95%; 0.019 to 0.189
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.313
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.044
	Confidence Interval	(2-Sided) 95%; -0.042 to 0.130
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure. Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.250
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.050
	Confidence Interval	(2-Sided) 95%; -0.035 to 0.135
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.898
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.006
	Confidence Interval	(2-Sided) 95%; -0.080 to 0.091
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6
Description	Change from baseline in FVC peak(0-4h) (L) on Day 1 and at the end of treatment at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Day 1	0.293	0.372	0.414	0.455	0.213	0.491
Week 6	0.322	0.379	0.431	0.427	0.182	0.530

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed, using linear mixed model for repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.079
	Confidence Interval	(2-Sided) 95%; 0.006 to 0.153
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.158
	Confidence Interval	(2-Sided) 95%; 0.085 to 0.232
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.201
	Confidence Interval	(2-Sided) 95%; 0.127 to 0.275
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.241
	Confidence Interval	(2-Sided) 95%; 0.168 to 0.315
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.277
	Confidence Interval	(2-Sided) 95%; 0.204 to 0.351
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.079
	Confidence Interval	(2-Sided) 95%; 0.005 to 0.152
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.121
	Confidence Interval	(2-Sided) 95%; 0.048 to 0.195
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.162
	Confidence Interval	(2-Sided) 95%; 0.088 to 0.235
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.256
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.043
	Confidence Interval	(2-Sided) 95%; -0.031 to 0.116
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.083
	Confidence Interval	(2-Sided) 95%; 0.010 to 0.156
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Day 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.281
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.040
	Confidence Interval	(2-Sided) 95%; -0.033 to 0.114
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.141
	Confidence Interval	(2-Sided) 95%; 0.050 to 0.232
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.197
	Confidence Interval	(2-Sided) 95%; 0.106 to 0.288
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.249
	Confidence Interval	(2-Sided) 95%; 0.157 to 0.340
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.245
	Confidence Interval	(2-Sided) 95%; 0.155 to 0.336
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.348
	Confidence Interval	(2-Sided) 95%; 0.258 to 0.439
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.222
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.056
	Confidence Interval	(2-Sided) 95%; -0.034 to 0.147
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.108
	Confidence Interval	(2-Sided) 95%; 0.017 to 0.199
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.105
	Confidence Interval	(2-Sided) 95%; 0.015 to 0.195
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.262
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.052
	Confidence Interval	(2-Sided) 95%; -0.039 to 0.143
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.290
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.048
	Confidence Interval	(2-Sided) 95%; -0.041 to 0.138
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.938
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.004
	Confidence Interval	(2-Sided) 95%; -0.094 to 0.087
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1
Description	Time to onset of action is defined as the time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥100 mL.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Mean (95% Confidence Interval) [minutes]	45.1	32.6	29.5	27.3	240.1	28.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using Cox proportional hazards model, including treatment, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and baseline FEV1 value as covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.64
	Confidence Interval	(2-Sided) 95%; 1.21 to 2.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.18
	Confidence Interval	(2-Sided) 95%; 1.61 to 2.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.79
	Confidence Interval	(2-Sided) 95%; 2.07 to 3.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.07
	Confidence Interval	(2-Sided) 95%; 2.27 to 4.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.10
	Confidence Interval	(2-Sided) 95%; 2.30 to 4.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.052
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 1.00 to 1.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.70
	Confidence Interval	(2-Sided) 95%; 1.28 to 2.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.87
	Confidence Interval	(2-Sided) 95%; 1.41 to 2.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; 1.08 to 1.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.494
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1
Description	Number of patients achieving onset of action was defined as a change from baseline in post-dose FEV1 ≥100 mL on Day 1. These are the patients who contributed to the results, reported as median and 95% CI for 'time to onset of action' presented in Outcome Measure 8, above.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Count of Participants [Participants]	90 74.4%	103 83.7%	103 85.1%	110 89.4%	74 61.2%	113 91.9%

10. Secondary Outcome

Title	Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6
Description	Change from baseline in FEV1 at treatment visit 3 (Week 3) and treatment visit 4 (Week 6) of treatment. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second;
Time Frame	Baseline, Week 3, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Week 3	0.059	0.080	0.122	0.111	0.000	0.122
Week 6	0.020	0.088	0.107	0.130	-0.012	0.112

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.059
	Confidence Interval	(2-Sided) 95%; 0.011 to 0.107
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.080
	Confidence Interval	(2-Sided) 95%; 0.032 to 0.128
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.122
	Confidence Interval	(2-Sided) 95%; 0.074 to 0.170
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.111
	Confidence Interval	(2-Sided) 95%; 0.063 to 0.159
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.122
	Confidence Interval	(2-Sided) 95%; 0.074 to 0.170
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.377
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.021
	Confidence Interval	(2-Sided) 95%; -0.026 to 0.069
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95%; 0.015 to 0.111
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.052
	Confidence Interval	(2-Sided) 95%; 0.005 to 0.100
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.085
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.042
	Confidence Interval	(2-Sided) 95%; -0.006 to 0.089
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.199
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.031
	Confidence Interval	(2-Sided) 95%; -0.016 to 0.079
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.657
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.011
	Confidence Interval	(2-Sided) 95%; -0.058 to 0.037
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.246
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.032
	Confidence Interval	(2-Sided) 95%; -0.022 to 0.086
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.100
	Confidence Interval	(2-Sided) 95%; 0.046 to 0.154
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.119
	Confidence Interval	(2-Sided) 95%; 0.064 to 0.173
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.142
	Confidence Interval	(2-Sided) 95%; 0.088 to 0.196
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.124
	Confidence Interval	(2-Sided) 95%; 0.070 to 0.178
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.068
	Confidence Interval	(2-Sided) 95%; 0.014 to 0.121
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.087
	Confidence Interval	(2-Sided) 95%; 0.032 to 0.141
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.110
	Confidence Interval	(2-Sided) 95%; 0.057 to 0.163
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.493
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.019
	Confidence Interval	(2-Sided) 95%; -0.035 to 0.073
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.119
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.042
	Confidence Interval	(2-Sided) 95%; -0.011 to 0.096
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.392
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.023
	Confidence Interval	(2-Sided) 95%; -0.030 to 0.077
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6
Description	Change from baseline in IC at treatment Visit 3 (Week 3) and treatment Visit 4 (Week 6). Spirometry was used to measure IC and was performed according to internationally accepted standards. Definitions: Baseline: value of the measurement recorded at 45 mins pre-dose at Visit 2 (Week 0); IC=Inspiratory capacity;
Time Frame	Baseline, Week 3, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Week 3	0.156	0.137	0.106	0.140	0.047	0.090
Week 6	0.045	0.090	0.136	0.105	0.025	0.099

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model for repeated measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.109
	Confidence Interval	(2-Sided) 95%; 0.015 to 0.203
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.090
	Confidence Interval	(2-Sided) 95%; -0.003 to 0.184
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.215
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.059
	Confidence Interval	(2-Sided) 95%; -0.035 to 0.153
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.051
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.093
	Confidence Interval	(2-Sided) 95%; -0.001 to 0.187
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.364
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.044
	Confidence Interval	(2-Sided) 95%; -0.051 to 0.138
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.694
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.019
	Confidence Interval	(2-Sided) 95%; -0.112 to 0.074
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.297
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.050
	Confidence Interval	(2-Sided) 95%; -0.143 to 0.044
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.734
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.016
	Confidence Interval	(2-Sided) 95%; -0.109 to 0.077
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.514
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.031
	Confidence Interval	(2-Sided) 95%; -0.124 to 0.062
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.957
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.003
	Confidence Interval	(2-Sided) 95%; -0.090 to 0.095
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.479
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.034
	Confidence Interval	(2-Sided) 95%; -0.060 to 0.127
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.687
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.020
	Confidence Interval	(2-Sided) 95%; -0.079 to 0.120
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.195
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.066
	Confidence Interval	(2-Sided) 95%; -0.034 to 0.165
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.111
	Confidence Interval	(2-Sided) 95%; 0.011 to 0.212
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.112
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.080
	Confidence Interval	(2-Sided) 95%; -0.019 to 0.179
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.147
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.074
	Confidence Interval	(2-Sided) 95%; -0.026 to 0.174
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.370
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.045
	Confidence Interval	(2-Sided) 95%; -0.054 to 0.144
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.091
	Confidence Interval	(2-Sided) 95%; -0.009 to 0.190
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.233
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.060
	Confidence Interval	(2-Sided) 95%; -0.039 to 0.158
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.369
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.046
	Confidence Interval	(2-Sided) 95%; -0.054 to 0.145
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.773
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.084 to 0.112
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.536
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.031
	Confidence Interval	(2-Sided) 95%; -0.130 to 0.068
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6
Description	Number of subjects achieving TDI focal score ≥1, at treatment visit 3 (Week 3) and at treatment visit 4 (Week 6). TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement); total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important. Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;
Time Frame	Baseline, Week 3, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Week 3 Focal Score ≥ 1	70 57.9%	78 63.4%	75 62%	84 68.3%	67 55.4%	74 60.2%
Week 6 Focal Score ≥ 1	74 61.2%	83 67.5%	82 67.8%	91 74%	55 45.5%	80 65%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analysis based on logistic regression model - multiple logistic regression model, with treatment, US regions, smoking status at screening, and BDI as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.848
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.264
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.35
	Confidence Interval	(2-Sided) 95%; 0.80 to 2.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.343
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.042
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95%; 1.02 to 2.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.503
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.71 to 2.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.354
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.447
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.73 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.66
	Confidence Interval	(2-Sided) 95%; 0.97 to 2.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.867
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.347
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.269
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.35
	Confidence Interval	(2-Sided) 95%; 0.79 to 2.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure. Analysis based on logistic regression model - multiple logistic regression model, with treatment, US regions, smoking status at screening, and BDI as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.92
	Confidence Interval	(2-Sided) 95%; 1.12 to 3.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.59
	Confidence Interval	(2-Sided) 95%; 1.50 to 4.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.08
	Confidence Interval	(2-Sided) 95%; 1.75 to 5.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.42
	Confidence Interval	(2-Sided) 95%; 1.94 to 6.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.45
	Confidence Interval	(2-Sided) 95%; 1.41 to 4.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.284
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.35
	Confidence Interval	(2-Sided) 95%; 0.78 to 2.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.103
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 0.91 to 2.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.045
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.78
	Confidence Interval	(2-Sided) 95%; 1.01 to 3.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.557
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.67 to 2.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.345
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 0.74 to 2.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.732
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.61 to 2.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6
Description	Transitional Dyspnea Index (TDI) focal score at treatment visit 3 (Week 3) and treatment visit 4 (Week 6). TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement), with a total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important. Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;
Time Frame	Baseline, Week 3, Week 6

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Week 3	1.29	1.55	1.54	1.94	1.14	1.66
Week 6	1.65	2.02	2.05	2.55	1.03	2.11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, visit, treatment by visit interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the BDI, BDI by visit interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.666
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; -0.52 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	week 3 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.224
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; -0.25 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.239
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; -0.27 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.13 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.124
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; -0.14 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.432
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; -0.39 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.454
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.053
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; -0.01 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.973
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.67 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.247
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; -0.27 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 3 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.235
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; -0.26 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.071
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; -0.05 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.32 to 1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.35 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95%; 0.86 to 2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.41 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; -0.29 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.235
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; -0.26 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.25 to 1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.923
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.108
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; -0.12 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Week 6 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.134
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; -0.16 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period
Description	Evaluate the number of rescue medication-free days compared with baseline. Results are shown as percentage (%) of rescue medication-free days; an increased value indicates improvement from baseline. Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3, Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0).
Time Frame	Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Inter-visit period 1	16.78	15.67	15.55	18.19	8.90	13.51
Inter-visit period 2	13.83	15.51	14.03	18.15	7.07	11.27
Entire treatment period	15.30	15.59	14.79	18.17	7.98	12.39

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model repeated for measurements (MMRM), including inter-visit period, treatment by inter-visit period interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by inter-visit period interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.88
	Confidence Interval	(2-Sided) 95%; 1.13 to 14.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.78
	Confidence Interval	(2-Sided) 95%; 0.07 to 13.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.053
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.65
	Confidence Interval	(2-Sided) 95%; -0.09 to 13.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.29
	Confidence Interval	(2-Sided) 95%; 2.55 to 16.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.191
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.61
	Confidence Interval	(2-Sided) 95%; -2.31 to 11.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.747
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.10
	Confidence Interval	(2-Sided) 95%; -7.80 to 5.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.720
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.23
	Confidence Interval	(2-Sided) 95%; -7.96 to 5.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.680
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; -5.31 to 8.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.971
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -6.82 to 6.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.460
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.52
	Confidence Interval	(2-Sided) 95%; -4.17 to 9.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Inter-Visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.441
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.64
	Confidence Interval	(2-Sided) 95%; -4.09 to 9.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.070
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.76
	Confidence Interval	(2-Sided) 95%; -0.55 to 14.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.44
	Confidence Interval	(2-Sided) 95%; 1.16 to 15.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.96
	Confidence Interval	(2-Sided) 95%; -0.40 to 14.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.08
	Confidence Interval	(2-Sided) 95%; 3.79 to 18.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.274
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.20
	Confidence Interval	(2-Sided) 95%; -3.32 to 11.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.649
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.68
	Confidence Interval	(2-Sided) 95%; -5.57 to 8.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.958
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; -7.12 to 7.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.242
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.32
	Confidence Interval	(2-Sided) 95%; -2.93 to 11.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.690
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.48
	Confidence Interval	(2-Sided) 95%; -8.77 to 5.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.473
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.64
	Confidence Interval	(2-Sided) 95%; -4.58 to 9.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Inter-Visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.267
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.13
	Confidence Interval	(2-Sided) 95%; -3.17 to 11.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.32
	Confidence Interval	(2-Sided) 95%; 0.65 to 13.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.61
	Confidence Interval	(2-Sided) 95%; 0.97 to 14.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.80
	Confidence Interval	(2-Sided) 95%; 0.12 to 13.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.19
	Confidence Interval	(2-Sided) 95%; 3.52 to 16.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.207
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.40
	Confidence Interval	(2-Sided) 95%; -2.45 to 11.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.932
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; -6.33 to 6.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.879
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -7.17 to 6.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.396
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.87
	Confidence Interval	(2-Sided) 95%; -3.77 to 9.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.812
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.80
	Confidence Interval	(2-Sided) 95%; -7.44 to 5.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.444
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.58
	Confidence Interval	(2-Sided) 95%; -4.03 to 9.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.319
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.38
	Confidence Interval	(2-Sided) 95%; -3.27 to 10.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period
Description	Evaluate the change from baseline in average use of rescue medication (number of puffs/day) during the inter-visit periods and the entire treatment period. Results are shown as number of puffs/day; a decrease (implies improvement) from baseline in average use of rescue medication. Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3 (Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0);
Time Frame	Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Inter-visit period 1	-0.72	-0.58	-0.53	-0.71	-0.30	-0.52
Inter-visit period 2	-0.59	-0.50	-0.51	-0.69	-0.17	-0.40
Entire treatment period	-0.66	-0.54	-0.52	-0.70	-0.23	-0.46

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed, using linear mixed model repeated for measurements (MMRM), including treatment, inter-visit period, treatment by inter-visit period interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by inter-visit period interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -0.67 to -0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.53 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.47 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -0.66 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.084
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.47 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.243
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.112
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.929
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.668
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.281
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.134
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -0.70 to -0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.61 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95%; -0.62 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.80 to -0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.115
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.52 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.532
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.603
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.460
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD. Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.921
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.172
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.47 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.210
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.46 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -0.67 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -0.55 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95%; -0.72 to -0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.083
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.355
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.283
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.712
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.877
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.195
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.150
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period
Description	Change from baseline in average EXACT-Respiratory Symptom (E-RS) total score during inter-visit periods and the entire treatment period E-RS in COPD uses 11 respiratory symptom items from the 14-item EXAcerbations of COPD tool (EXACT). E-RS total score quantifies respiratory symptom severity on a scale ranging from 0 to 40. Higher E-RS total scores indicate more severe symptoms and a declining total score indicates health improvement. E-RS questionnaire was completed by the patient each evening (e-diary). Definitions: For details on baseline, inter-visit periods, and the entire treatment period, please refer to outcome measure #15.
Time Frame	Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables).

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Inter-visit period 1	-1.681	-1.539	-1.941	-1.663	-0.714	-1.280
Inter-visit period 2	-2.030	-1.840	-2.147	-2.077	-0.681	-1.505
Entire treatment period	-1.855	-1.689	-2.044	-1.870	-0.698	-1.393

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Analyzed using linear mixed model repeated for measurements (MMRM), including treatment, inter-visit period, treatment by inter-visit period interaction, US regions (Midwest, Northeast, South and West), and smoking status at screening as fixed effects, and the baseline value, and baseline by inter-visit period interaction as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.967
	Confidence Interval	(2-Sided) 95%; -1.753 to -0.181
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.824
	Confidence Interval	(2-Sided) 95%; -1.606 to -0.043
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.227
	Confidence Interval	(2-Sided) 95%; -2.012 to -0.441
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.949
	Confidence Interval	(2-Sided) 95%; -1.733 to -0.164
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.169
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.566
	Confidence Interval	(2-Sided) 95%; -1.374 to 0.242
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.720
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.142
	Confidence Interval	(2-Sided) 95%; -0.638 to 0.923
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.515
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.260
	Confidence Interval	(2-Sided) 95%; -1.043 to 0.523
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.963
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95%; -0.764 to 0.800
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.311
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.402
	Confidence Interval	(2-Sided) 95%; -1.182 to 0.377
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.754
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.124
	Confidence Interval	(2-Sided) 95%; -0.903 to 0.654
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Inter-visit period 1 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.485
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.278
	Confidence Interval	(2-Sided) 95%; -0.503 to 1.060
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.349
	Confidence Interval	(2-Sided) 95%; -2.294 to -0.403
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.159
	Confidence Interval	(2-Sided) 95%; -2.100 to -0.218
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.466
	Confidence Interval	(2-Sided) 95%; -2.416 to -0.516
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.396
	Confidence Interval	(2-Sided) 95%; -2.337 to -0.454
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.097
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.824
	Confidence Interval	(2-Sided) 95%; -1.797 to 0.150
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.690
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.190
	Confidence Interval	(2-Sided) 95%; -0.746 to 1.126
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.808
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.117
	Confidence Interval	(2-Sided) 95%; -1.061 to 0.827
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.922
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.047
	Confidence Interval	(2-Sided) 95%; -0.983 to 0.889
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.522
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.307
	Confidence Interval	(2-Sided) 95%; -1.248 to 0.634
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.618
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.237
	Confidence Interval	(2-Sided) 95%; -1.170 to 0.696
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Inter-visit period 2 Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.884
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.070
	Confidence Interval	(2-Sided) 95%; -0.871 to 1.012
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment A (CHF 5259 pMDI 12.5 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.158
	Confidence Interval	(2-Sided) 95%; -1.978 to -0.337
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.992
	Confidence Interval	(2-Sided) 95%; -1.808 to -0.175
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.346
	Confidence Interval	(2-Sided) 95%; -2.168 to -0.524
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Treatment D, Treatment E
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.172
	Confidence Interval	(2-Sided) 95%; -1.991 to -0.353
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Treatment E, Treatment F
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment F (Tiotropium 18 μg TDD) versus Treatment E (Placebo). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.107
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.695
	Confidence Interval	(2-Sided) 95%; -1.539 to 0.149
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment B
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment B (CHF 5259 pMDI 25 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.689
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.166
	Confidence Interval	(2-Sided) 95%; -0.648 to 0.980
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.651
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.188
	Confidence Interval	(2-Sided) 95%; -1.007 to 0.630
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment A (CHF 5259 pMDI 12.5 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.973
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.014
	Confidence Interval	(2-Sided) 95%; -0.830 to 0.801
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment C
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment C (CHF 5259 pMDI 50 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.393
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.355
	Confidence Interval	(2-Sided) 95%; -1.170 to 0.461
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment B (CHF 5259 pMDI 25 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.663
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.181
	Confidence Interval	(2-Sided) 95%; -0.993 to 0.632
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments	Entire treatment period Comparison treatment groups for this analysis were: Treatment D (CHF 5259 pMDI 100 μg TDD) versus Treatment C (CHF 5259 pMDI 50 μg TDD). Statistical analysis was performed as described for the statistical analysis 1 of this outcome measure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.676
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.174
	Confidence Interval	(2-Sided) 95%; -0.643 to 0.991
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP)
Description	Vital signs -- Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were measured at prespecified times, using a 12-Lead single ECGs were recorded at all study visits (pre-dose at V1 (Week -2) and V3 (Week 3), as well as at pre-dose and 1.5 hours post-dose at Visit 2 (Week 0) and Visit 4 (Week 6). Results are shown by treatment group, as change from baseline (in mmHg) for representative timepoints. Definitions: Baseline=Values recorded pre-dose (Visit 2, Week 0); Day 1=Day of the first dose of randomized study drug (Visit 2, Week 0);
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
SBP, Day 1, 30 min post dose	-1.4	-0.4	-2.0	-1.9	-0.9	-1.2
DBP, Day 1, 30 min post dose	-0.7	-0.6	-2.1	-1.4	-0.8	0.1
SBP, Day 1, 1,5 h post dose	0.3	-1.1	-0.6	-1.8	0.2	-1.5
DBP, Day 1, 1,5 h post dose	-0.7	-1.8	-1.7	-1.6	-1.7	-1.5
SBP, Day 1, 11 h post dose	1.1	2.0	-0.0	1.7	1.9	0.9
DBP, Day 1, 11 h post dose	-0.9	0.3	-1.6	-1.4	-1.0	-1.2
SBP, Week 6, pre-dose	0.4	0.8	0.4	-1.0	1.6	1.3
DBP, Week 6, pre-dose	0.4	0.5	-0.3	-1.0	0.0	-0.2
SBP, Week 6, 30 min post dose	-1.6	-0.9	-0.5	-2.5	0.5	0.1
DBP, Week 6, 30 min post dose	-0.7	-0.9	-1.5	-2.0	-0.8	-1.2
SBP, Week 6, 1,5 h post dose	-1.3	-0.6	-0.5	-2.3	0.1	0.5
DBP, Week 6, 1,5 h post dose	-1.0	-2.7	-2.0	-2.3	-1.1	-0.6
SBP, Week 6, 11 h post dose	0.2	1.5	0.5	2.2	3.2	2.0
DBP, Week 6, 11 h post dose	-0.9	-2.0	-2.3	-1.4	-1.0	-0.7

18. Secondary Outcome

Title	Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR)
Description	Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Heart rate (HR) Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5m, +55m, and at +2.5 h.
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
HR, Day 1, 5 min post dose	-8.85	-6.62	-7.78	-7.64	-4.84	-5.54
HR, Day 1, 55 min post dose	-7.19	-8.29	-8.28	-9.59	-7.44	-7.19
HR, Day 1, 2.5 h post dose	-7.57	-6.75	-9.20	-7.46	-6.12	-8.96
HR, Day before Week 6, 5 min post dose	-1.72	-1.06	-1.61	-1.85	3.92	1.70
HR, Day before Week 6, 55 min post dose	-1.52	0.41	-1.10	-1.40	1.12	1.22
HR, Day before Week 6, 2.5 h post dose	-2.30	-0.01	-1.13	-0.73	2.49	-1.47

19. Secondary Outcome

Title	Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval
Description	Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - PR Interval Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
PR Interval, Day 1, 5 min post dose	7.24	6.53	6.08	6.71	3.06	4.90
PR Interval, Day 1, 55 min post dose	7.20	6.89	8.21	6.77	4.38	4.77
PR Interval, Day 1, 2.5 h post dose	8.48	9.38	7.58	6.16	5.84	4.25
PR Interval, Day before Week 6, 5 min post dose	0.44	1.36	-0.11	3.88	-1.36	0.82
PR Interval, Day before Week 6, 55 min post dose	0.88	2.37	1.91	0.82	-1.13	-1.66
PR Interval, Day before Week 6, 2.5 h post dose	2.50	3.01	0.16	0.84	-1.22	-1.94

20. Secondary Outcome

Title	Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval
Description	Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - QRS Interval Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
QRS Interval, Day 1, 5 min post dose	1.18	0.05	1.50	1.99	0.45	1.50
QRS Interval, Day 1, 55 min post dose	0.97	1.19	1.21	1.56	0.14	1.70
QRS Interval, Day 1, 2.5 h post dose	1.38	2.40	1.80	1.50	0.64	0.86
QRS Interval, Day before Week 6, 5 min post dose	0.61	-1.76	0.43	2.00	0.45	0.69
QRS Interval, Day before Week 6, 55 min post dose	1.12	-0.09	0.85	2.38	0.77	0.42
QRS Interval, Day before Week 6, 2.5 h post dose	1.49	0.74	0.30	2.18	1.14	1.35

21. Secondary Outcome

Title	Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF)
Description	Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Fridericia-corrected QT interval (QTcF). Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
QTcF, Day 1, 5 min post dose	3.62	5.37	6.81	6.25	3.59	5.56
QTcF, Day 1, 55 min post dose	8.37	5.41	6.72	9.90	6.04	5.43
QTcF, Day 1, 2.5 h post dose	7.15	8.65	7.20	5.45	4.81	6.77
QTcF, Day before Week 6, 5 min post dose	1.61	1.14	-0.60	1.67	-3.56	1.41
QTcF, Day before Week 6, 55 min post dose	2.38	0.09	1.41	4.15	1.02	3.19
QTcF, Day before Week 6, 2.5 h post dose	4.13	0.85	-0.97	1.73	0.14	2.50

22. Secondary Outcome

Title	24-hour Holter ECG - Prolonged QTcF - Male Subjects
Description	24-hour Holter ECG - Prolonged QTcF - Male subjects. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	63	55	54	58	69	66
Actual value > 450 msec	1 0.8%	0 0%	0 0%	1 0.8%	2 1.7%	1 0.8%
Actual value > 480 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	62 51.2%	55 44.7%	54 44.6%	57 46.3%	67 55.4%	65 52.8%
Actual value > 450 msec	1 0.8%	1 0.8%	1 0.8%	3 2.4%	1 0.8%	3 2.4%
Actual value > 480 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	62 51.2%	54 43.9%	53 43.8%	55 44.7%	68 56.2%	63 51.2%
Actual value > 450 msec	1 0.8%	1 0.8%	0 0%	2 1.6%	2 1.7%	0 0%
Actual value > 480 msec	0 0%	0 0%	0 0%	0 0%	1 0.8%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	62 51.2%	54 43.9%	54 44.6%	56 45.5%	66 54.5%	66 53.7%
Actual value > 450 msec	3 2.5%	4 3.3%	6 5%	4 3.3%	2 1.7%	5 4.1%
Actual value > 480 msec	1 0.8%	0 0%	1 0.8%	0 0%	0 0%	3 2.4%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	59 48.8%	51 41.5%	47 38.8%	54 43.9%	67 55.4%	58 47.2%
Actual value > 450 msec	2 1.7%	2 1.6%	3 2.5%	3 2.4%	1 0.8%	4 3.3%
Actual value > 480 msec	1 0.8%	0 0%	0 0%	0 0%	0 0%	1 0.8%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	60 49.6%	53 43.1%	51 42.1%	55 44.7%	68 56.2%	61 49.6%
Actual value > 450 msec	2 1.7%	2 1.6%	3 2.5%	3 2.4%	1 0.8%	4 3.3%
Actual value > 480 msec	1 0.8%	0 0%	1 0.8%	0 0%	0 0%	1 0.8%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	60 49.6%	53 43.1%	50 41.3%	55 44.7%	68 56.2%	61 49.6%
Actual value > 450 msec	3 2.5%	3 2.4%	3 2.5%	2 1.6%	1 0.8%	4 3.3%
Actual value > 480 msec	1 0.8%	0 0%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	59 48.8%	52 42.3%	51 42.1%	56 45.5%	68 56.2%	62 50.4%
Actual value > 450 msec	3 2.5%	1 0.8%	0 0%	3 2.4%	0 0%	2 1.6%
Actual value > 480 msec	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.8%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	60 49.6%	54 43.9%	54 44.6%	55 44.7%	69 57%	63 51.2%
Actual value > 450 msec	2 1.7%	2 1.6%	2 1.7%	2 1.6%	0 0%	3 2.4%
Actual value > 480 msec	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.8%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	61 50.4%	53 43.1%	52 43%	56 45.5%	69 57%	62 50.4%
Actual value > 450 msec	1 0.8%	1 0.8%	0 0%	1 0.8%	0 0%	3 2.4%
Actual value > 480 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 450 msec or > 480 msec or > 500 msec)	62 51.2%	54 43.9%	54 44.6%	57 46.3%	69 57%	63 51.2%

23. Secondary Outcome

Title	24-hour Holter ECG - Prolonged QTcF - Female Subjects
Description	24-hour Holter ECG - Prolonged QTcF - Female subjects. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	58	68	67	65	52	57
Actual value > 470 msec	0 0%	1 0.8%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	58 47.9%	67 54.5%	67 55.4%	65 52.8%	52 43%	57 46.3%
Actual value > 470 msec	1 0.8%	2 1.6%	0 0%	1 0.8%	0 0%	0 0%
Actual value > 500 msec	0 0%	2 1.6%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	57 47.1%	64 52%	67 55.4%	64 52%	52 43%	57 46.3%
Actual value > 470 msec	1 0.8%	2 1.6%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	57 47.1%	66 53.7%	67 55.4%	65 52.8%	52 43%	57 46.3%
Actual value > 470 msec	3 2.5%	3 2.4%	0 0%	1 0.8%	0 0%	1 0.8%
Actual value > 500 msec	0 0%	1 0.8%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	55 45.5%	64 52%	67 55.4%	64 52%	52 43%	56 45.5%
Actual value > 470 msec	1 0.8%	2 1.6%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	57 47.1%	66 53.7%	67 55.4%	65 52.8%	52 43%	57 46.3%
Actual value > 470 msec	2 1.7%	3 2.4%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	56 46.3%	65 52.8%	67 55.4%	65 52.8%	52 43%	57 46.3%
Actual value > 470 msec	1 0.8%	2 1.6%	0 0%	0 0%	0 0%	1 0.8%
Actual value > 500 msec	0 0%	1 0.8%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	57 47.1%	65 52.8%	67 55.4%	65 52.8%	52 43%	56 45.5%
Actual value > 470 msec	1 0.8%	2 1.6%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	57 47.1%	66 53.7%	67 55.4%	65 52.8%	52 43%	57 46.3%
Actual value > 470 msec	0 0%	2 1.6%	0 0%	0 0%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	58 47.9%	66 53.7%	67 55.4%	65 52.8%	52 43%	57 46.3%
Actual value > 470 msec	0 0%	1 0.8%	0 0%	1 0.8%	0 0%	0 0%
Actual value > 500 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No prolongation (> 470 msec or > 500 msec)	58 47.9%	67 54.5%	67 55.4%	64 52%	52 43%	57 46.3%

24. Secondary Outcome

Title	24-hour Holter ECG - Prolonged QTcF - Change From Baseline
Description	24-hour Holter ECG - Prolonged QTcF - Change from baseline. Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h. Results are presented as the number of subjects who had a change from baseline in QTcF of: > 30 msec, > 60 msec, and no prolongation (by > 30 msec or > 60 msec).
Time Frame	Baseline, Day 1, Week 6

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259	Placebo Control Placebo: Placebo Control	Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
Measure Participants	121	123	121	123	121	123
Change from baseline: > 30 msec	19 15.7%	20 16.3%	21 17.4%	20 16.3%	16 13.2%	18 14.6%
Change from baseline: > 60 msec	0 0%	1 0.8%	0 0%	2 1.6%	2 1.7%	1 0.8%
No change from baseline (> 30 msec or > 60 msec)	102 84.3%	102 82.9%	100 82.6%	101 82.1%	103 85.1%	104 84.6%
Change from baseline: > 30 msec	2 1.7%	4 3.3%	9 7.4%	2 1.6%	3 2.5%	4 3.3%
Change from baseline: > 60 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No change from baseline (> 30 msec or > 60 msec)	119 98.3%	119 96.7%	112 92.6%	121 98.4%	118 97.5%	119 96.7%
Change from baseline: > 30 msec	8 6.6%	4 3.3%	5 4.1%	6 4.9%	4 3.3%	5 4.1%
Change from baseline: > 60 msec	0 0%	0 0%	0 0%	1 0.8%	1 0.8%	0 0%
No change from baseline (> 30 msec or > 60 msec)	113 93.4%	119 96.7%	116 95.9%	116 94.3%	116 95.9%	118 95.9%
Change from baseline: > 30 msec	5 4.1%	12 9.8%	6 5%	5 4.1%	6 5%	8 6.5%
Change from baseline: > 60 msec	0 0%	0 0%	0 0%	1 0.8%	1 0.8%	0 0%
No change from baseline (> 30 msec or > 60 msec)	116 95.9%	111 90.2%	115 95%	117 95.1%	114 94.2%	115 93.5%
Change from baseline: > 30 msec	5 4.1%	3 2.4%	0 0%	3 2.4%	0 0%	3 2.4%
Change from baseline: > 60 msec	0 0%	1 0.8%	0 0%	0 0%	0 0%	0 0%
No change from baseline (> 30 msec or > 60 msec)	116 95.9%	119 96.7%	121 100%	120 97.6%	121 100%	120 97.6%
Change from baseline: > 30 msec	5 4.1%	0 0%	7 5.8%	7 5.7%	3 2.5%	4 3.3%
Change from baseline: > 60 msec	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.8%
No change from baseline (> 30 msec or > 60 msec)	116 95.9%	123 100%	114 94.2%	116 94.3%	118 97.5%	118 95.9%
Change from baseline: > 30 msec	6 5%	6 4.9%	3 2.5%	6 4.9%	3 2.5%	7 5.7%
Change from baseline: > 60 msec	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No change from baseline (> 30 msec or > 60 msec)	115 95%	117 95.1%	118 97.5%	117 95.1%	118 97.5%	116 94.3%

Adverse Events

Time Frame	From the first intake of study medication (visit 2, Week 0) until study completion (Visit 4, week 6) or discontinuation.
Adverse Event Reporting Description	The safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment.
Arm/Group Title	Treatment A		Treatment B		Treatment C		Treatment D		Treatment E		Treatment F
Arm/Group Description	CHF 5259 pMDI Dose 1, 12.5 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259		CHF 5259 pMDI Dose 2, 25 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259		CHF 5259 pMDI Dose 3, 50 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259		CHF 5259 pMDI Dose 4, 100 μg TDD CHF 5259 Dose Response: Test one of four different doses of CHF 5259		Placebo Control Placebo: Placebo Control		Tiotropium Bromide inhalation powder, 18 µg TDD Tiotropium Bromide Active Control, 18 µg Inhalation Capsule
All Cause Mortality
	Treatment A		Treatment B		Treatment C		Treatment D		Treatment E		Treatment F
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/121 (0%)		0/123 (0%)		0/121 (0%)		0/123 (0%)		0/121 (0%)		0/123 (0%)
Serious Adverse Events
	Treatment A		Treatment B		Treatment C		Treatment D		Treatment E		Treatment F
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/121 (1.7%)		5/123 (4.1%)		1/121 (0.8%)		1/123 (0.8%)		1/121 (0.8%)		1/123 (0.8%)
Gastrointestinal disorders
Constipation	1/121 (0.8%)	1	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0
Infections and infestations
Influenza	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	1/123 (0.8%)	1	0/121 (0%)	0	0/123 (0%)	0
Injury, poisoning and procedural complications
Femur fracture	0/121 (0%)	0	1/123 (0.8%)	1	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0
Spinal compression fracture	0/121 (0%)	0	1/123 (0.8%)	1	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	1/123 (0.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer stage I	1/121 (0.8%)	1	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/121 (0%)	0	1/123 (0.8%)	1	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/121 (0%)	0	1/123 (0.8%)	1	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/121 (0%)	0	1/123 (0.8%)	1	1/121 (0.8%)	1	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0
Vascular disorders
Hypertension	0/121 (0%)	0	0/123 (0%)	0	0/121 (0%)	0	0/123 (0%)	0	1/121 (0.8%)	1	0/123 (0%)	0
Other (Not Including Serious) Adverse Events
	Treatment A		Treatment B		Treatment C		Treatment D		Treatment E		Treatment F
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/121 (13.2%)		14/123 (11.4%)		8/121 (6.6%)		15/123 (12.2%)		11/121 (9.1%)		9/123 (7.3%)
Infections and infestations
Bronchitis	1/121 (0.8%)	1	4/123 (3.3%)	4	1/121 (0.8%)	1	1/123 (0.8%)	1	0/121 (0%)	0	0/123 (0%)	0
Upper respiratory tract infection	4/121 (3.3%)	4	2/123 (1.6%)	2	2/121 (1.7%)	2	5/123 (4.1%)	5	2/121 (1.7%)	2	3/123 (2.4%)	3
Viral upper respiratory tract infection	0/121 (0%)	0	5/123 (4.1%)	5	1/121 (0.8%)	1	1/123 (0.8%)	1	3/121 (2.5%)	3	0/123 (0%)	0
Nervous system disorders
Headache	5/121 (4.1%)	5	2/123 (1.6%)	2	1/121 (0.8%)	1	3/123 (2.4%)	3	2/121 (1.7%)	2	0/123 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/121 (1.7%)	2	0/123 (0%)	0	3/121 (2.5%)	3	4/123 (3.3%)	4	4/121 (3.3%)	4	4/123 (3.3%)	4
Dyspnoea	4/121 (3.3%)	4	1/123 (0.8%)	1	0/121 (0%)	0	1/123 (0.8%)	1	0/121 (0%)	0	2/123 (1.6%)	2

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Chiesi can publish and/or present any results of this study at scientific meetings, and to submit the clinical trial data to national and international Regulatory Authorities. Chiesi reserves the right to use such data for industrial purposes. Investigators will inform Chiesi before using the results of the study for publication or presentation, and agree to provide the Sponsor with a copy of the proposed presentation. Data from individual study sites must not be published separately.