Characterization of Lung Function Profile of Inhaled Tiotropium + Olodaterol Fixed Dose Combination Compared to Fluticasone Propionate + Salmeterol Fixed Dose Combination in COPD Patients

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01969721
• Collaborator: (none)
• Enrollment: 229
• Locations: 29
• Arms: 4
• Duration (Months): 16
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The objective of the trial is to compare the lung function profile of once daily treatment with tiotropium+olodaterol FDC [2.5/ 5µg and 5/ 5µg] delivered by the RESPIMAT with the lung function profile of twice daily treatment with fluticasone propionate+salmeterol FDC [250/50µg and 500/50µg] delivered by the Accuhaler® after 6 weeks of treatment.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: fluticasone propionate; Drug: salmeterol; Drug: placebo; Drug: placebo; Drug: tiotropium; Drug: olodaterol; Drug: olodaterol; Drug: placebo; Drug: placebo; Drug: tiotropium; Drug: fluticasone propionate; Drug: salmeterol	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 229 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: Randomized, Double-blind, Double-dummy, Active-controlled, 4 Period Complete Cross-over Study to Compare the Effect on Lung Function of 6 Weeks Once Daily Treatment With Orally Inhaled Tiotropium+Olodaterol Fixed Dose Combination Delivered by the Respimat® Inhaler vs. 6 Weeks Twice Daily Treatment With Fluticasone Propionate+Salmeterol Fixed Dose Combination Delivered by the Accuhaler® in Patients With Chronic Obstructive Pulmonary Disease (COPD)
• Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: T+O FDC dosage 1 Low dose	Drug: olodaterol; Drug: placebo; placebo/dummy for blinding purposes; Drug: tiotropium; tiotropium low dose
Experimental: T+O FDC dosage 2 High dose	Drug: placebo; placebo/dummy for blinding purposes; Drug: tiotropium; tiotropium high dose; Drug: olodaterol
Active Comparator: ICS/LABA FDC Dosage 1 Low dose	Drug: fluticasone propionate; low dose; Drug: salmeterol; Drug: placebo; placebo/dummy for blinding purposes
Active Comparator: ICS/LABA FDC Dosage 2 High dose	Drug: placebo; placebo/dummy for blinding purposes; Drug: fluticasone propionate; low dose; Drug: salmeterol

Outcome Measures

Primary Outcome Measures

1. FEV1 AUC (0-12h) Change From Patient Baseline After 6 Weeks of Treatment [Baseline and 6 weeks.]

   Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 12hours post-dose (AUC 0-12h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.

Secondary Outcome Measures

1. FEV1 AUC (0-24h) Change From Patient Baseline After 6 Weeks of Treatment [Baseline and 6 weeks.]

   Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 24 hours post-dose (AUC 0-24h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.

2. Trough FEV1 Change From Patient Baseline After 6 Weeks of Treatment [Baseline and 6 weeks.]

   Change from patient baseline in Trough Forced Expiratory Volume in one second (FEV1) after 6 weeks of treatment. Trough FEV1 was defined as the mean of the 23h and 23h 50min (minutes) post-dose FEV1 measurements. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.

3. FEV1 AUC (12-24h) Change From Patient Baseline After 6 Weeks of Treatment [Baseline and 6 weeks.]

   Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 12 to 24 hours post-dose (AUC 12-24h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.

4. FEV1 Peak (0-3h) Change From Patient Baseline After 6 Weeks of Treatment [Baseline and 6 weeks.]

   Change from patient baseline in Forced Expiratory Volume in one second (FEV1) peak (0-3 hours) after 6 weeks of treatment. FEV1 peak (0-3 hours) was defined as the maximum FEV1 value measured within the first three hours post dosing. Measured values presented are actually adjusted means.

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. Diagnosis of chronic obstructive pulmonary disease

2. Relatively stable airway obstruction with a post-bronchodilator 30% </= Forced Expiratory Volume in 1 second (FEV1)<80% of predicted normal and a post-bronchodilator FEV1/(Forced Vital Capacity)FVC <70%

3. Male or female patients, 40 years of age or older

4. Smoking history of more than 10 pack years

5. Ability to perform technically acceptable pulmonary function tests and maintain records

6. Ability to inhale medication in a competent manner from the RESPIMAT Inhaler, Accuhaler and from a metered dose inhaler (MDI)

Exclusion criteria:

1. Significant disease other than COPD

2. COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or

1. or hospitalization in the last 3 months.

1. Clinically relevant abnormal lab values

2. History of asthma

3. Diagnosis of thyrotoxicosis

4. Diagnosis of paroxysmal tachycardia

5. History of myocardial infarction

6. Unstable or life-threatening cardiac arrhythmia

7. Hospitalization for heart failure within the past year

8. Known active tuberculosis

9. malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years

10. History of life-threatening pulmonary obstruction

11. History of cystic fibrosis

12. Clinically evident bronchiectasis

13. History of significant alcohol or drug abuse

14. History of thoracotomy with pulmonary resection

15. oral or patch ß-adrenergics

16. Oral corticosteroid medication within 6 weeks prior to Visit 1

17. Regular use daytime oxygen therapy for more than one hour per day

18. Pulmonary rehabilitation program in the six weeks prior to the screening visit

19. Investigational drug within one month or six half lives (whichever is greater) prior to screening visit

20. Known hypersensitivity to ß-adrenergic drugs, BAC, EDTA

21. Pregnant or nursing women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1237.11.32002 Boehringer Ingelheim Investigational Site	Genk		Belgium
2	1237.11.32001 Boehringer Ingelheim Investigational Site	Gent		Belgium
3	1237.11.42003 Boehringer Ingelheim Investigational Site	Kyjov		Czech Republic
4	1237.11.42004 Boehringer Ingelheim Investigational Site	Rokycany		Czech Republic
5	1237.11.42002 Boehringer Ingelheim Investigational Site	Tabor		Czech Republic
6	1237.11.42001 Boehringer Ingelheim Investigational Site	Trebic		Czech Republic
7	1237.11.45002 Boehringer Ingelheim Investigational Site	Hvidovre		Denmark
8	1237.11.45004 Boehringer Ingelheim Investigational Site	Kolding		Denmark
9	1237.11.45001 Boehringer Ingelheim Investigational Site	Odense C		Denmark
10	1237.11.45003 Boehringer Ingelheim Investigational Site	Silkeborg		Denmark
11	1237.11.49003 Boehringer Ingelheim Investigational Site	Großhansdorf		Germany
12	1237.11.49005 Boehringer Ingelheim Investigational Site	Hamburg		Germany
13	1237.11.49001 Boehringer Ingelheim Investigational Site	Mannheim		Germany
14	1237.11.49004 Boehringer Ingelheim Investigational Site	Mönchengladbach		Germany
15	1237.11.49002 Boehringer Ingelheim Investigational Site	Wiesbaden		Germany
16	1237.11.36001 Boehringer Ingelheim Investigational Site	Debrecen		Hungary
17	1237.11.36004 Boehringer Ingelheim Investigational Site	Pecs		Hungary
18	1237.11.36003 Boehringer Ingelheim Investigational Site	Szeged		Hungary
19	1237.11.36002 Boehringer Ingelheim Investigational Site	Szombathely		Hungary
20	1237.11.31005 Boehringer Ingelheim Investigational Site	Almelo		Netherlands
21	1237.11.31002 Boehringer Ingelheim Investigational Site	Breda		Netherlands
22	1237.11.31006 Boehringer Ingelheim Investigational Site	Eindhoven		Netherlands
23	1237.11.31001 Boehringer Ingelheim Investigational Site	Heerlen		Netherlands
24	1237.11.31007 Boehringer Ingelheim Investigational Site	Hoorn		Netherlands
25	1237.11.31003 Boehringer Ingelheim Investigational Site	Zutphen		Netherlands
26	1237.11.34003 Boehringer Ingelheim Investigational Site	Alicante		Spain
27	1237.11.34001 Boehringer Ingelheim Investigational Site	Barcelona		Spain
28	1237.11.34002 Boehringer Ingelheim Investigational Site	Pozuelo de Alarcón		Spain
29	1237.11.46001 Boehringer Ingelheim Investigational Site	Lund		Sweden

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01969721
• Other Study ID Numbers: 1237.11; 2013-000808-41
• First Posted: Oct 25, 2013
• Last Update Posted: Feb 12, 2016
• Last Verified: Jan 1, 2016

• Additional relevant MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive; Fluticasone; Xhance; Tiotropium Bromide; Salmeterol Xinafoate; Olodaterol

Study Results

Participant Flow

Recruitment Details	This was a randomized, double-blind, double-dummy, active-controlled, 4-treatment, 4-period, complete cross-over design.
Pre-assignment Detail	After signing informed consent, patients entered a 4-week screening period to ensure clinical stability (i.e. no exacerbations).

Arm/Group Title	T+O 2.5/5 / T+O 5/5 / F+S 250/50 / F+S 500/50	T+O 5/5 / F+S 500/50 / T+O 2.5/5 / F+S 250/50	F+S 250/50 / T+O 2.5/5 / F+S 500/50 / T+O 5/5	F+S 500/50 / F+S 250/50 / T+O 5/5 / T+O 2.5/5
Arm/Group Description	Patients received a total of four treatments. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. The treatments were orally inhaled . Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo (T+O 2.5/5). Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo (T+O 5/5). Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo (F+S 250/50). Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo (F+S 500/50). Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily, Fluticasone propionate+Salmeterol FDC inhalation powders were administered orally twice daily via Accuhaler®.	Patients received a total of four treatments. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. The treatments were orally inhaled. Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo. Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo. Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo. Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily, Fluticasone propionate+Salmeterol FDC inhalation powders were administered orally twice daily via Accuhaler®.	Patients received a total of four treatments. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. The treatments were orally inhaled. Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo. Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo. Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo. Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily, Fluticasone propionate+Salmeterol FDC inhalation powders were administered orally twice daily via Accuhaler®.	Patients received a total of four treatments. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. The treatments were orally inhaled. Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo. Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo. Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo. Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily, Fluticasone propionate+Salmeterol FDC inhalation powders were administered orally twice daily via Accuhaler®.
Period Title: Overall Study
STARTED	58	69	50	52
COMPLETED	54	57	45	46
NOT COMPLETED	4	12	5	6

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	Patients received a total of four treatments. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. The treatments were orally inhaled. Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo. Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo. Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo. Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily, Fluticasone propionate+Salmeterol FDC inhalation powders were administered orally twice daily via Accuhaler®.
Overall Participants	229
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.6 (7.6)
Sex: Female, Male (Count of Participants)
Female	81 35.4%
Male	148 64.6%

Outcome Measures

1. Primary Outcome

Title	FEV1 AUC (0-12h) Change From Patient Baseline After 6 Weeks of Treatment
Description	Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 12hours post-dose (AUC 0-12h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
Time Frame	Baseline and 6 weeks.

Outcome Measure Data

Analysis Population Description

FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.

Arm/Group Title	T+O 2.5/5 / F+S Placebo	T+O 5/5 / F+S Placebo	F+S 250/50 / T+O Placebo	F+S 500/50 / T+O Placebo
Arm/Group Description	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (T+O 2.5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg (T+O 5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg (F+S 250/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg (F+S 500/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.
Measure Participants	214	216	211	217
Mean (Standard Error) [Litres]	0.295 (0.014)	0.317 (0.014)	0.192 (0.015)	0.188 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 0-12h change from patient baseline (Tiotropium + Olodaterol 5/5 µg) = Mean FEV1 AUC 0-12h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 µg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.125
	Confidence Interval	(2-Sided) 95%; 0.103 to 0.147
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 5/5 - F+S 250/50 adjusted mean FEV1 AUC 0-12h change from patient baseline (L)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 0-12h change from patient baseline (Tiotropium + Olodaterol 5/5 µg) = Mean FEV1 AUC 0-12h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 µg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.129
	Confidence Interval	(2-Sided) 95%; 0.107 to 0.150
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 5/5 - F+S 500/50 adjusted mean FEV1 AUC 0-12h change from patient baseline (L)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 0-12h change from patient baseline (Tiotropium + Olodaterol 2.5/5 µg) = Mean FEV1 AUC 0-12h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 µg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.103
	Confidence Interval	() 95%; 0.081 to 0.124
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 250/50 adjusted mean FEV1 AUC 0-12h change from patient baseline (L)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 0-12h change from patient baseline (Tiotropium + Olodaterol 2.5/5 µg) = Mean FEV1 AUC 0-12h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 µg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.106
	Confidence Interval	(2-Sided) 95%; 0.085 to 0.128
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 500/50 adjusted mean FEV1 AUC 0-12h change from patient baseline (L)

2. Secondary Outcome

Title	FEV1 AUC (0-24h) Change From Patient Baseline After 6 Weeks of Treatment
Description	Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 24 hours post-dose (AUC 0-24h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
Time Frame	Baseline and 6 weeks.

Outcome Measure Data

Analysis Population Description

FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.

Arm/Group Title	T+O 2.5/5 / F+S Placebo	T+O 5/5 / F+S Placebo	F+S 250/50 / T+O Placebo	F+S 500/50 / T+O Placebo
Arm/Group Description	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (T+O 2.5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg (T+O 5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg (F+S 250/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg (F+S 500/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.
Measure Participants	214	216	211	217
Mean (Standard Error) [Litres]	0.228 (0.014)	0.244 (0.014)	0.162 (0.014)	0.159 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 0-24h change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 AUC 0-24h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.082
	Confidence Interval	(2-Sided) 95%; 0.061 to 0.103
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 5/5 - F+S 250/50 adjusted mean FEV1 AUC 0-24h change from patient baseline (L)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 0-24h change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 AUC 0-24h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.086
	Confidence Interval	(2-Sided) 95%; 0.065 to 0.107
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 5/5 - F+S 500/50 adjusted mean FEV1 AUC 0-24h change from patient baseline (L)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 0-24h change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 AUC 0-24h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.065
	Confidence Interval	(2-Sided) 95%; 0.045 to 0.086
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 250/50 adjusted mean FEV1 AUC 0-24h change from patient baseline (L)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 0-24h change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 AUC 0-24h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.069
	Confidence Interval	(2-Sided) 95%; 0.048 to 0.090
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 500/50 adjusted mean FEV1 AUC 0-24h change from patient baseline (L)

3. Secondary Outcome

Title	Trough FEV1 Change From Patient Baseline After 6 Weeks of Treatment
Description	Change from patient baseline in Trough Forced Expiratory Volume in one second (FEV1) after 6 weeks of treatment. Trough FEV1 was defined as the mean of the 23h and 23h 50min (minutes) post-dose FEV1 measurements. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
Time Frame	Baseline and 6 weeks.

Outcome Measure Data

Analysis Population Description

FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.

Arm/Group Title	T+O 2.5/5 / F+S Placebo	T+O 5/5 / F+S Placebo	F+S 250/50 / T+O Placebo	F+S 500/50 / T+O Placebo
Arm/Group Description	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (T+O 2.5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg (T+O 5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg (F+S 250/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg (F+S 500/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.
Measure Participants	214	216	211	217
Mean (Standard Error) [Litres]	0.192 (0.014)	0.197 (0.014)	0.150 (0.014)	0.139 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean trough FEV1 change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean trough FEV1 change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95%; 0.022 to 0.071
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Difference calculated as T+O 5/5 - F+S 250/50 adjusted mean trough FEV1 change from patient baseline (L)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean trough FEV1 change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean trough FEV1 change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.058
	Confidence Interval	(2-Sided) 95%; 0.034 to 0.082
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Difference calculated as T+O 5/5 - F+S 500/50 adjusted mean trough FEV1 change from patient baseline (L)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean trough FEV1 change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean trough FEV1 change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.042
	Confidence Interval	(2-Sided) 95%; 0.018 to 0.067
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 250/50 adjusted mean trough FEV1 change from patient baseline (L)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean trough FEV1 change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean trough FEV1 change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.054
	Confidence Interval	(2-Sided) 95%; 0.029 to 0.078
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 500/50 adjusted mean trough FEV1 change from patient baseline (L)

4. Secondary Outcome

Title	FEV1 AUC (12-24h) Change From Patient Baseline After 6 Weeks of Treatment
Description	Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 12 to 24 hours post-dose (AUC 12-24h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
Time Frame	Baseline and 6 weeks.

Outcome Measure Data

Analysis Population Description

FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.

Arm/Group Title	T+O 2.5/5 / F+S Placebo	T+O 5/5 / F+S Placebo	F+S 250/50 / T+O Placebo	F+S 500/50 / T+O Placebo
Arm/Group Description	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (T+O 2.5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg (T+O 5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg (F+S 250/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg (F+S 500/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.
Measure Participants	214	216	211	217
Mean (Standard Error) [Litres]	0.160 (0.014)	0.172 (0.014)	0.132 (0.014)	0.129 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 12-24h change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 AUC 12-24h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.039
	Confidence Interval	(2-Sided) 95%; 0.017 to 0.062
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Difference calculated T+O 5/5 - F+S 250/50 adjusted mean FEV1 AUC 12-24h change from patient baseline (L)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 12-24h change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 AUC 12-24h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.043
	Confidence Interval	(2-Sided) 95%; 0.021 to 0.065
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 5/5 - F+S 500/50 adjusted mean FEV1 AUC 12-24h change from patient baseline (L)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 12-24h change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 AUC 12-24h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0146
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.028
	Confidence Interval	(2-Sided) 95%; 0.006 to 0.051
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 250/50 adjusted mean FEV1 AUC 12-24h change from patient baseline (L)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 AUC 12-24h change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 AUC 12-24h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0055
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.032
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.054
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 500/50 adjusted mean FEV1 AUC 12-24h change from patient baseline (L)

5. Secondary Outcome

Title	FEV1 Peak (0-3h) Change From Patient Baseline After 6 Weeks of Treatment
Description	Change from patient baseline in Forced Expiratory Volume in one second (FEV1) peak (0-3 hours) after 6 weeks of treatment. FEV1 peak (0-3 hours) was defined as the maximum FEV1 value measured within the first three hours post dosing. Measured values presented are actually adjusted means.
Time Frame	Baseline and 6 weeks.

Outcome Measure Data

Analysis Population Description

FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.

Arm/Group Title	T+O 2.5/5 / F+S Placebo	T+O 5/5 / F+S Placebo	F+S 250/50 / T+O Placebo	F+S 500/50 / T+O Placebo
Arm/Group Description	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (T+O 2.5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg (T+O 5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg (F+S 250/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg (F+S 500/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.
Measure Participants	214	216	211	217
Mean (Standard Error) [Litres]	0.401 (0.016)	0.432 (0.016)	0.291 (0.016)	0.285 (0.015)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 peak (0-3h) change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 peak (0-3h) change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.142
	Confidence Interval	(2-Sided) 95%; 0.118 to 0.166
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Difference calculated as T+O 5/5 - F+S 250/50 adjusted mean FEV1 peak (0-3h) change from patient baseline (L)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	T+O 5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 peak (0-3h) change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 peak (0-3h) change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.147
	Confidence Interval	(2-Sided) 95%; 0.123 to 0.171
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Difference calculated as T+O 5/5 - F+S 500/50 adjusted mean FEV1 peak (0-3h) change from patient baseline (L)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 250/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 peak (0-3h) change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 peak (0-3h) change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.111
	Confidence Interval	(2-Sided) 95%; 0.087 to 0.135
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 250/50 adjusted mean FEV1 peak (0-3h) change from patient baseline (L)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	T+O 2.5/5 / F+S Placebo, F+S 500/50 / T+O Placebo
	Comments	Null hypothesis: Mean FEV1 peak (0-3h) change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 peak (0-3h) change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
	Method	Mixed Models Analysis
	Comments	Compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.116
	Confidence Interval	(2-Sided) 95%; 0.092 to 0.140
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Difference calculated as T+O 2.5/5 - F+S 500/50 adjusted mean FEV1 peak (0-3h) change from patient baseline (L)

Adverse Events

Time Frame	From first drug intake until 21 days after last drug intake, up to 88 days.
Adverse Event Reporting Description	AEs are displayed by treatment, however in total patients were in the study for up to 223 days
Arm/Group Title	T+O 2.5/5 / F+S Placebo		T+O 5/5 / F+S Placebo		F+S 250/50 / T+O Placebo		F+S 500/50 / T+O Placebo
Arm/Group Description	Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (T+O 2.5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.		Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg (T+O 5/5) administered orally via the Respimat® inhaler once daily plus Fluticasone propionate+Salmeterol (F+S) placebo treatment administered orally twice daily via Accuhaler®.		Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg (F+S 250/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.		Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. • Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg (F+S 500/50) administered orally twice daily via Accuhaler® plus Tiotropium+Olodaterol (T+O) placebo treatment administered orally once daily via the Respimat® inhaler.
All Cause Mortality
	T+O 2.5/5 / F+S Placebo		T+O 5/5 / F+S Placebo		F+S 250/50 / T+O Placebo		F+S 500/50 / T+O Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	T+O 2.5/5 / F+S Placebo		T+O 5/5 / F+S Placebo		F+S 250/50 / T+O Placebo		F+S 500/50 / T+O Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/215 (2.8%)		7/221 (3.2%)		4/212 (1.9%)		9/219 (4.1%)
Cardiac disorders
Angina pectoris	0/215 (0%)		0/221 (0%)		0/212 (0%)		1/219 (0.5%)
Atrial flutter	1/215 (0.5%)		0/221 (0%)		0/212 (0%)		0/219 (0%)
Cardiac failure	1/215 (0.5%)		0/221 (0%)		0/212 (0%)		0/219 (0%)
Myocardial infarction	0/215 (0%)		0/221 (0%)		0/212 (0%)		1/219 (0.5%)
Myocardial ischaemia	0/215 (0%)		1/221 (0.5%)		0/212 (0%)		0/219 (0%)
Gastrointestinal disorders
Diarrhoea	0/215 (0%)		1/221 (0.5%)		0/212 (0%)		0/219 (0%)
General disorders
Death	0/215 (0%)		1/221 (0.5%)		0/212 (0%)		0/219 (0%)
Hepatobiliary disorders
Cholecystitis	0/215 (0%)		0/221 (0%)		1/212 (0.5%)		0/219 (0%)
Immune system disorders
Drug hypersensitivity	0/215 (0%)		0/221 (0%)		0/212 (0%)		1/219 (0.5%)
Infections and infestations
Gastroenteritis	0/215 (0%)		1/221 (0.5%)		0/212 (0%)		0/219 (0%)
Lobar pneumonia	0/215 (0%)		0/221 (0%)		1/212 (0.5%)		0/219 (0%)
Osteomyelitis	1/215 (0.5%)		0/221 (0%)		0/212 (0%)		0/219 (0%)
Pneumonia	0/215 (0%)		0/221 (0%)		1/212 (0.5%)		1/219 (0.5%)
Sialoadenitis	1/215 (0.5%)		0/221 (0%)		0/212 (0%)		0/219 (0%)
Injury, poisoning and procedural complications
Fibula fracture	1/215 (0.5%)		0/221 (0%)		0/212 (0%)		0/219 (0%)
Tibia fracture	1/215 (0.5%)		0/221 (0%)		0/212 (0%)		0/219 (0%)
Toxicity to various agents	0/215 (0%)		0/221 (0%)		1/212 (0.5%)		0/219 (0%)
Vascular graft occlusion	1/215 (0.5%)		0/221 (0%)		0/212 (0%)		1/219 (0.5%)
Metabolism and nutrition disorders
Dehydration	0/215 (0%)		1/221 (0.5%)		0/212 (0%)		0/219 (0%)
Musculoskeletal and connective tissue disorders
Osteonecrosis	0/215 (0%)		0/221 (0%)		0/212 (0%)		1/219 (0.5%)
Nervous system disorders
Cerebral haemorrhage	0/215 (0%)		1/221 (0.5%)		0/212 (0%)		0/219 (0%)
Transient ischaemic attack	0/215 (0%)		0/221 (0%)		1/212 (0.5%)		0/219 (0%)
Renal and urinary disorders
Nephrolithiasis	0/215 (0%)		1/221 (0.5%)		0/212 (0%)		0/219 (0%)
Renal failure	0/215 (0%)		1/221 (0.5%)		0/212 (0%)		0/219 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/215 (0.9%)		2/221 (0.9%)		2/212 (0.9%)		4/219 (1.8%)
Other (Not Including Serious) Adverse Events
	T+O 2.5/5 / F+S Placebo		T+O 5/5 / F+S Placebo		F+S 250/50 / T+O Placebo		F+S 500/50 / T+O Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/215 (9.8%)		28/221 (12.7%)		19/212 (9%)		24/219 (11%)
Infections and infestations
Nasopharyngitis	12/215 (5.6%)		12/221 (5.4%)		13/212 (6.1%)		11/219 (5%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	10/215 (4.7%)		18/221 (8.1%)		7/212 (3.3%)		15/219 (6.8%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.