SCO116572: A 3 Way Cross-over Study Evaluating the Effects of ADOAIR Twice Daily Plus Tiotropium Bromide Once Daily Compared With the Individual Treatments of Japanese Subjects

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01751113
• Collaborator: (none)
• Enrollment: 53
• Locations: 3
• Arms: 3
• Duration (Months): 9
• Patients Per Site: 17.7
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effects on lung function of a combination of ADOAIR 50/250mcg twice daily plus tiotropium bromide 18mcg once daily compared with the individual treatments (tiotropium bromide 18mcg once daily alone and ADOAIR 50/250mcg twice daily alone) in Japanese subjects with COPD. The study will utilize a three-way cross-over design with a 2-week wash-out period between each 4-week consecutive treatment period. The aim is to support the rationale for "triple combination" therapy by demonstrating that treatment with both ADOAIR and tiotropium can potentially produce improved, clinically relevant effects compared with either treatment alone.

This study will utilize a range of lung function measures in order to fully assess the benefits of triple therapy. The primary endpoint will be based on airways conductance measured using plethysmography (sGaw measured over 4hours post dose (AUC 0-4hr) on Day 28). Secondary endpoints will include lung function measures based on plethysmography and spirometry. The lung function measures will be supported by measurement of the use of relief salbutamol .

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: fluticasone propionate/salmeterol; Drug: tiotropium bromide; Drug: fluticasone propionate/salmeterol plus tiotropium bromide	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomised, Double-blind, Double Dummy, 3 Way Cross-over Study Evaluating the Effects of ADOAIR 50/250mcg Twice Daily Plus Tiotropium Bromide 18mcg Once Daily Compared With the Individual Treatments (Tiotropium Bromide 18mcg Alone and ADOAIR 50/250mcg Alone) in the Treatment of Japanese Subjects With COPD
• Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Nov 1, 2013
• Actual Study Completion Date: Nov 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: fluticasone propionate/salmeterol 250mcg fluticasone + 50 mcg salmeterol, twice daily 4 week treatment in each treatment sequence (crossover design)	Drug: fluticasone propionate/salmeterol; 250mcg fluticasone + 50 mcg salmeterol, twice daily 4 week treatment in each treatment sequence (crossover design); Other Names: ADOAIR is a registered trade mark of the GlaxoSmithKlline group of companies.
Active Comparator: tiotropium bromide 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)	Drug: tiotropium bromide; 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)
Active Comparator: fluticasone propionate/salmeterol plus tiotropium bromide 250mcg fluticasone + 50 mcg salmeterol, twice daily plus 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)	Drug: fluticasone propionate/salmeterol plus tiotropium bromide; 250mcg fluticasone + 50 mcg salmeterol, twice daily plus 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design); Other Names: ADOAIR is a registered trade mark of the GlaxoSmithKlline group of companies.

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve Calculated From 0 to 4 Hours (AUC[0-4hr]) Specific Conductance (sGaw) After the Morning Dose of Study Medication at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sGaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the Least Square (LS) means.

Secondary Outcome Measures

1. AUC (0-4hr) Specific Airway Resistance (sRaw) After the Morning Dose of Each Study Medication at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sRaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the LS means.

2. Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaws. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sGaw fitted as fixed effects and participant fitted as a random effect.

3. Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. A natural logarithmic transformation was applied and the data was analysed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sRaw fitted as fixed effects and participant fitted as a random effect.

4. Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the residual volume (RV). RV is defined as the volume of air remaining in the lungs. after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. Trough values were the values taken pre-dose.

5. Trough FEV1/FVC Ratio, at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. Trough values were the values taken pre-dose.

6. Trough sRaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose.

7. Trough sGaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose.

8. Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the RV. RV is defined as the volume of air remaining in the lungs after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration.

9. Post-dose FEV1/FVC Ratio (Measured at Trough) at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

   FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements.

10. Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period [Day 28 of each treatment period (up to 35 days)]

    Participants were given daily record cards for daily completion during the run-in, washout and treatment periods. Each morning, participants recorded the number of occasions in the last 24 hours when they had used their rescue medication (salbutamol) for symptomatic relief of COPD symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female aged 40 - 80 years inclusive

• Has an established clinical history of COPD (defined as per the GOLD definition)

• A signed and dated written informed consent is obtained from the subject prior to study participation

• The subject has a post-bronchodilator FEV1 of >=30% to =<75% of predicted normal at Visit 1

• The subject has a post-bronchodilator FEV1/ FVC ratio <70% at Visit 1

• The subject achieves a score of 1 on the Modified Medical Research Council (mMRC) Dyspnoea Scale at Visit 1

• The subject is a current or ex-smoker with a smoking history of > 10 pack-years (10 pack years is defined as 20 cigarettes per day for 10 years, or 10 cigarettes (or equivalent if subject smoked cigars or a pipe) per day for 20 years). Ex-smokers are required to have stopped smoking for at least 6 months prior to visit 1. Ex-smokers who stopped smoking less than 6 months ago will be defined as current smokers.

• QTc <450 msec at Visit 1; or for patients with Bundle Branch Block QTc should be <480 msec.

(QTc(F) <450msec, or <480 in subjects with right bundle branch block, should be confirmed by the mean of three readings or one reading)

• ALT < 2xULN and bilirubin/ALP < 1.5xULN (>35% direct bilirubin)

• A female is eligible to enter this study if she is: i)of non-childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal), ii)of child-bearing potential, but has a negative urinary pregnancy test at screening and agrees to take contraceptive precautions (including abstinence) which are adequate to prevent pregnancy during the study or iii)not a nursing mother

Exclusion Criteria:

• Has had a COPD exacerbation within the 4 weeks prior to Visit 1

• Had any changes in COPD medication in the 4 weeks prior to Visit 1

• Has plan to change the dosage of Xanthines or to stop receiving it during the study

• Has a current medical diagnosis of asthma

• Has a medical diagnosis of narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction that in the opinion of the investigator should prevent them from entering the study Note: As with other anticholinergic drugs, subjects with narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction should only be entered into the study at the Investigator's discretion

• Has known respiratory disorders other than COPD (e.g. lung cancer, sarcoidosis, tuberculosis or lung fibrosis)

• Has undergone lung surgery e.g., lung transplant and/or lung volume reduction

• Is currently receiving pulmonary rehabilitation

• Had a chest X-ray indicating diagnosis other than COPD that might interfere with the study (chest X-ray to be taken at entry, if subject has not had one or CT image taken within 3 months of Visit 1)

• Requires regular (daily) or long term oxygen therapy (LTOT). (LTOT is defined as . 12 hours oxygen use per day)

• Requires regular treatment with oral, parenteral, or depot corticosteroids or has received 2 or more periods of oral corticosteroids for COPD exacerbation in the last 6 months

• Received oral, parenteral, or depot corticosteroids in the 4 weeks prior to Visit 1

• Received antibiotic therapy for either a lower respiratory tract infection or for COPD exacerbation within the 4 weeks prior to Visit 1

• Has been hospitalized for a COPD exacerbation in the last year

• Receiving non-selective β-blockers (except eye drops)

• Has serious, uncontrolled disease likely to interfere with the study (e.g. Left Ventricular failure, anaemia, renal or hepatic disease or serious psychological disorders)

• Received any other investigational drugs within 4 weeks (or 5 half lives) prior to Visit 1

• Has, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse

• Has a known or suspected hypersensitivity to β2-agonists, inhaled steroids, anticholinergic treatments or any components of the formulations (e.g. lactose or milk protein)

• Has previously been enrolled and randomized to this study

• Are not considered able to tolerate three 2-weeks wash-out periods according to the study schedule with all COPD medications removed apart from rescue use of SALBUTAMOL via MDI (inhaled PRN use).

• Is not eligible to participate this study in the opinion of the investigator/subinvestigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Hokkaido		Japan	070-8644
2	GSK Investigational Site	Ibaraki		Japan	319-1113
3	GSK Investigational Site	Osaka		Japan	530-0001

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01751113
• Other Study ID Numbers: 116572
• First Posted: Dec 17, 2012
• Last Update Posted: Mar 8, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Pulmonary Disease, Chronic Obstructive; Fluticasone; Xhance; Bromides; Tiotropium Bromide; Salmeterol Xinafoate; Fluticasone-Salmeterol Drug Combination

Study Results

Participant Flow

Recruitment Details	A total of 53 Japanese participants with moderate or severe chronic obstructive pulmonary disease (COPD) entered the run-in period.
Pre-assignment Detail	Participants, who met eligibility criteria, completed a 2-week Run-in Period prior to being randomized to 1 of 6 treatment sequences. The treatment phase was comprised of three 4 week treatment periods, each separated by a 2-week washout period.

Arm/Group Title	Sequence 1: Ado 50/250 µg+Tio 18 µg, Tio 18 µg, Ado 50/250 µg	Sequence 2: Tio 18 µg, Ado 50/250 µg, Ado 50/250 µg+Tio 18 µg	Sequence 3: Ado 50/250 µg, Ado 50/250 µg+Tio 18 µg, Tio 18 µg	Sequence 4: Ado 50/250 µg, Tio 18 µg, Ado 50/250 µg+Tio 18 µg	Sequence 5: Ado 50/250 µg+Tio 18 µg, Ado 50/250 µg, Tio 18 µg	Sequence 6: Tio 18 µg, Ado 50/250 µg+Tio 18 µg, Ado 50/250 µg
Arm/Group Description	Participants received salmeterol xinafoate/fluticasone propionate (Ado) 50/250 micrograms (µg) twice daily (BID) (morning and evening) plus tiotropium bromide (Tio) 18 µg once daily (QD) (morning), Tio 18 µg QD (morning) plus Ado matching placebo BID (morning and evening), and Ado 50/250 µg BID (morning and evening) plus Tio matching placebo QD (morning) in Treatment Periods 1, 2, and 3, respectively. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Ado 50/250 µg and its matching placebo were administered via a dry powder inhaler and Tio 18 µg and its matching placebo were administered via a HandiHaler inhaler. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) plus Ado matching placebo BID (morning and evening), Ado 50/250 µg BID (morning and evening) plus Tio matching placebo QD (morning), and Ado 50/250 µg BID plus Tio 18 µg QD (morning) in Treatment Periods 1, 2, and 3, respectively. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Ado 50/250 µg and its matching placebo were administered via a dry powder inhaler and Tio 18 µg and its matching placebo were administered via a HandiHaler inhaler. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) plus Tio matching placebo QD (morning), Ado 50/250 µg BID plus Tio 18 µg QD (morning), and Tio 18 µg QD (morning) plus Ado matching placebo BID (morning and evening) in Treatment Period 1, 2, and 3, respectively. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Ado 50/250 µg and its matching placebo were administered via a dry powder inhaler and Tio 18 µg and its matching placebo were administered via HandiHaler inhaler. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) plus Tio matching placebo QD (morning), Tio 18 µg QD (morning) plus Ado matching placebo BID (morning and evening), and Ado 50/250 µg BID plus Tio 18 µg QD (morning) in Treatment Period 1, 2, and 3, respectively. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Ado 50/250 µg and its matching placebo were administered via a dry powder inhaler and Tio 18 µg and its matching placebo were administered via a HandiHaler inhaler. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID plus Tio 18 µg QD (morning), Ado 50/250 µg BID (morning and evening) plus Tio matching placebo QD (morning) and Tio 18 µg QD (morning) plus Ado matching placebo BID (morning and evening) in Treatment Period 1, 2, and 3, respectively. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Ado 50/250 µg and its matching placebo were administered via a dry powder inhaler and Tio 18 µg and its matching placebo were administered via a HandiHaler inhaler. Participants were provided with salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) plus Ado matching placebo BID (morning and evening), Ado 50/250 µg BID plus Tio 18 µg QD (morning), and Ado 50/250 µg BID (morning and evening) plus Tio matching placebo QD (morning) in Treatment Period 1, 2, and 3, respectively. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Ado 50/250 µg and its matching placebo were administered via a dry powder inhaler and Tio 18 µg and its matching placebo were administered via a HandiHaler inhaler. Participants were provided with salbutamol inhaler to be used as relief medication throughout the study.
Period Title: Treatment Period 1 (4 Weeks)
STARTED	8	8	9	9	9	10
COMPLETED	8	8	9	8	8	10
NOT COMPLETED	0	0	0	1	1	0
Period Title: Treatment Period 1 (4 Weeks)
STARTED	8	8	9	8	8	10
COMPLETED	8	8	9	8	8	10
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1 (4 Weeks)
STARTED	8	8	9	8	8	10
COMPLETED	8	8	9	8	8	10
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1 (4 Weeks)
STARTED	8	8	9	8	8	10
COMPLETED	8	8	9	8	8	10
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1 (4 Weeks)
STARTED	8	8	9	8	8	10
COMPLETED	8	8	9	8	8	9
NOT COMPLETED	0	0	0	0	0	1

Baseline Characteristics

Arm/Group Title	Ado 50/250 µg+Tio 18 µg, Ado 50/250 µg, Tio 18 µg
Arm/Group Description	All participants received one of the following 3 treatments in one of three 4-week treatment periods separated by a 2-week washout period:Ado 50/250 µg BID (morning and evening) + Tio 18 µg QD (morning), Ado 50/250 µg BID (morning and evening) + Tio matching placebo QD (morning), and Tio 18 µg QD (morning) + Ado matching placebo BID (morning and evening). Participants were randomized to one of the 6 following treatment sequences: (1) Ado 50/250 µg+Tio 18 µg, Tio 18 µg, Ado 50/250 µg (2) Tio 18 µg, Ado 50/250 µg, Ado 50/250 µg+Tio 18 µg (3) Ado 50/250 µg, Ado 50/250 µg+Tio 18 µg, Tio 18 µg (4) Ado 50/250 µg, Tio 18 µg, Ado 50/250 µg+Tio 18 µg (5) Ado 50/250 µg+Tio 18 µg, Ado 50/250 µg, Tio 18 µg (6) Tio 18 µg, Ado 50/250 µg+Tio 18 µg, Ado 50/250 µg. Ado 50/250 µg and its matching placebo were administered via DISKUS inhaler and Tio 18 µg and its matching placebo were administered via HandiHaler inhaler. Participants used salbutamol inhaler as relief medication throughout the study.
Overall Participants	53
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.2 (6.56)
Sex: Female, Male (Count of Participants)
Female	1 1.9%
Male	52 98.1%
Race/Ethnicity, Customized (Number) [Number]
Asian - Japanese Heritage	53 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve Calculated From 0 to 4 Hours (AUC[0-4hr]) Specific Conductance (sGaw) After the Morning Dose of Study Medication at Day 28 of Each Treatment Period
Description	sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sGaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the Least Square (LS) means.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: all randomized participants who received at least one dose of study medication and completed at least two treatment periods and also had a Baseline and at least one on treatment sGaw assessment measure.

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
Geometric Mean (Standard Error) [1/kilopascal*second (1/kPa*s)]	0.854 (0.0183)	0.737 (0.0183)	0.663 (0.0182)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	AUC ratio
	Estimated Value	1.158
	Confidence Interval	(2-Sided) 95%; 1.100 to 1.219
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	AUC ratio
	Estimated Value	1.288
	Confidence Interval	(2-Sided) 95%; 1.224 to 1.355
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	AUC (0-4hr) Specific Airway Resistance (sRaw) After the Morning Dose of Each Study Medication at Day 28 of Each Treatment Period
Description	sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sRaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the LS means.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
Geometric Mean (Standard Error) [kPa*s]	1.181 (0.0188)	1.380 (0.0189)	1.525 (0.0188)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	AUC ratio
	Estimated Value	0.856
	Confidence Interval	(2-Sided) 95%; 0.812 to 0.902
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	AUC ratio
	Estimated Value	0.774
	Confidence Interval	(2-Sided) 95%; 0.735 to 0.816
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period
Description	sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaws. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sGaw fitted as fixed effects and participant fitted as a random effect.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
30 min	0.833 (0.0241)	0.705 (0.0241)	0.639 (0.0240)
75 min	0.873 (0.0241)	0.743 (0.0241)	0.652 (0.0240)
120 min	0.885 (0.0241)	0.769 (0.0241)	0.680 (0.0240)
240 min	0.855 (0.0241)	0.750 (0.0241)	0.690 (0.0240)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.181
	Confidence Interval	(2-Sided) 95%; 1.104 to 1.263
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 30 minutes

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.303
	Confidence Interval	(2-Sided) 95%; 1.219 to 1.393
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 30 minutes

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.175
	Confidence Interval	(2-Sided) 95%; 1.099 to 1.257
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 75 minutes

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.340
	Confidence Interval	(2-Sided) 95%; 1.253 to 1.432
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 75 minutes

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.151
	Confidence Interval	(2-Sided) 95%; 1.076 to 1.231
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 120 minutes

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.301
	Confidence Interval	(2-Sided) 95%; 1.217 to 1.391
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 120 minutes

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.141
	Confidence Interval	(2-Sided) 95%; 1.067 to 1.220
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 240 minutes

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.239
	Confidence Interval	(2-Sided) 95%; 1.159 to 1.325
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 240 minutes

4. Secondary Outcome

Title	Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period
Description	sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. A natural logarithmic transformation was applied and the data was analysed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sRaw fitted as fixed effects and participant fitted as a random effect.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
30 min	1.201 (0.0240)	1.419 (0.0240)	1.567 (0.0240)
75 min	1.146 (0.0240)	1.348 (0.0240)	1.535 (0.0240)
120 min	1.129 (0.0240)	1.300 (0.0240)	1.468 (0.0240)
240 min	1.170 (0.0240)	1.334 (0.0240)	1.446 (0.0240)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.846
	Confidence Interval	(2-Sided) 95%; 0.792 to 0.905
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 30 minutes

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.767
	Confidence Interval	(2-Sided) 95%; 0.717 to 0.819
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 30 minutes

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.850
	Confidence Interval	(2-Sided) 95%; 0.795 to 0.909
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 75 minutes

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.746
	Confidence Interval	(2-Sided) 95%; 0.698 to 0.798
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 75 minutes

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.868
	Confidence Interval	(2-Sided) 95%; 0.812 to 0.928
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 120 minutes

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.769
	Confidence Interval	(2-Sided) 95%; 0.719 to 0.822
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 120 minutes

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.877
	Confidence Interval	(2-Sided) 95%; 0.820 to 0.938
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 240 minutes

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.809
	Confidence Interval	(2-Sided) 95%; 0.757 to 0.865
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for 240 minutes

5. Secondary Outcome

Title	Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period
Description	FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the residual volume (RV). RV is defined as the volume of air remaining in the lungs. after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. Trough values were the values taken pre-dose.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
FEV1	1.823 (0.0147)	1.666 (0.0147)	1.706 (0.0147)
FVC	3.575 (0.0182)	3.493 (0.0182)	3.439 (0.0182)
IC	2.460 (0.0177)	2.406 (0.0179)	2.395 (0.0174)
RV	3.021 (0.0282)	3.129 (0.0286)	3.123 (0.0278)
TLC	6.511 (0.0189)	6.524 (0.0191)	6.525 (0.0186)
TGV	4.053 (0.0206)	4.118 (0.0210)	4.129 (0.0204)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of FEV1
	Estimated Value	0.157
	Confidence Interval	(2-Sided) 95%; 0.116 to 0.198
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FEV1

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of FEV1
	Estimated Value	0.118
	Confidence Interval	(2-Sided) 95%; 0.077 to 0.159
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FEV1

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of FVC
	Estimated Value	0.082
	Confidence Interval	(2-Sided) 95%; 0.031 to 0.133
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FVC

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of FVC
	Estimated Value	0.135
	Confidence Interval	(2-Sided) 95%; 0.084 to 0.186
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FVC

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of IC
	Estimated Value	0.054
	Confidence Interval	(2-Sided) 95%; 0.004 to 0.104
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for IC

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of IC
	Estimated Value	0.064
	Confidence Interval	(2-Sided) 95%; 0.015 to 0.114
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for IC

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of RV
	Estimated Value	-0.107
	Confidence Interval	(2-Sided) 95%; -0.187 to -0.028
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for RV

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of RV
	Estimated Value	-0.102
	Confidence Interval	(2-Sided) 95%; -0.180 to -0.023
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for RV

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.632
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of TLC
	Estimated Value	-0.013
	Confidence Interval	(2-Sided) 95%; -0.066 to 0.040
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for TLC

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.596
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of TLC
	Estimated Value	-0.014
	Confidence Interval	(2-Sided) 95%; -0.067 to 0.038
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for TLC

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of TGV
	Estimated Value	-0.065
	Confidence Interval	(2-Sided) 95%; -0.123 to -0.007
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for TGV

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of TGV
	Estimated Value	-0.075
	Confidence Interval	(2-Sided) 95%; -0.133 to -0.018
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for TGV

6. Secondary Outcome

Title	Trough FEV1/FVC Ratio, at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period
Description	FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. Trough values were the values taken pre-dose.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
Least Squares Mean (Standard Error) [Ratio of FEV1/FVC]	0.513 (0.0032)	0.481 (0.0032)	0.496 (0.0032)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	FEV1/FVC ratio
	Estimated Value	0.032
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.041
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FEV1/FVC ratio

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	FEV1/FVC ratio
	Estimated Value	0.017
	Confidence Interval	(2-Sided) 95%; 0.008 to 0.026
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FEV1/FVC ratio

7. Secondary Outcome

Title	Trough sRaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period
Description	sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
Geometric Mean (Standard Error) [kPa*s]	1.391 (0.0288)	1.666 (0.0286)	1.732 (0.0284)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.835
	Confidence Interval	(2-Sided) 95%; 0.770 to 0.905
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	0.803
	Confidence Interval	(2-Sided) 95%; 0.741 to 0.869
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Trough sGaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period
Description	sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
Geometric Mean (Standard Error) [1/kPa*s]	0.720 (0.0287)	0.600 (0.0285)	0.577 (0.0284)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.200
	Confidence Interval	(2-Sided) 95%; 1.108 to 1.301
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	specific airway conductance ratio
	Estimated Value	1.249
	Confidence Interval	(2-Sided) 95%; 1.153 to 1.352
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period
Description	FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the RV. RV is defined as the volume of air remaining in the lungs after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
FEV1	1.766 (0.0269)	1.605 (0.0269)	1.664 (0.0269)
FVC	3.535 (0.0403)	3.430 (0.0403)	3.387 (0.0403)
IC	2.344 (0.0415)	2.351 (0.0414)	2.351 (0.0405)
RV	3.045 (0.0543)	3.275 (0.0542)	3.234 (0.0533)
TLC	6.487 (0.0395)	6.588 (0.0394)	6.592 (0.0386)
TGV	4.147 (0.0414)	4.239 (0.0414)	4.238 (0.0405)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of FEV1
	Estimated Value	0.161
	Confidence Interval	(2-Sided) 95%; 0.086 to 0.236
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FEV1

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of FEV1
	Estimated Value	0.103
	Confidence Interval	(2-Sided) 95%; 0.028 to 0.178
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FEV1

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.051
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of FVC
	Estimated Value	0.104
	Confidence Interval	(2-Sided) 95%; 0.000 to 0.209
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FVC

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of FVC
	Estimated Value	0.148
	Confidence Interval	(2-Sided) 95%; 0.043 to 0.253
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FVC

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.890
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of IC
	Estimated Value	-0.008
	Confidence Interval	(2-Sided) 95%; -0.120 to 0.104
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for IC

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.890
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of IC
	Estimated Value	-0.008
	Confidence Interval	(2-Sided) 95%; -0.118 to 0.103
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for IC

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of RV
	Estimated Value	-0.229
	Confidence Interval	(2-Sided) 95%; -0.355 to -0.103
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for RV

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of RV
	Estimated Value	-0.189
	Confidence Interval	(2-Sided) 95%; -0.314 to -0.064
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for RV

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.055
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of TLC
	Estimated Value	-0.101
	Confidence Interval	(2-Sided) 95%; -0.204 to 0.002
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for TLC

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of TLC
	Estimated Value	-0.105
	Confidence Interval	(2-Sided) 95%; -0.206 to -0.003
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for TLC

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.085
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of TGV
	Estimated Value	-0.092
	Confidence Interval	(2-Sided) 95%; -0.197 to 0.013
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for TGV

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.083
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean difference of TGV
	Estimated Value	-0.091
	Confidence Interval	(2-Sided) 95%; -0.195 to 0.012
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for TGV

10. Secondary Outcome

Title	Post-dose FEV1/FVC Ratio (Measured at Trough) at Day 28 of Each Treatment Period
Description	FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg BID	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
Least Squares Mean (Standard Error) [Ratio of FEV1/FVC]	0.500 (0.0052)	0.472 (0.0052)	0.492 (0.0052)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Tio 18 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	FEV1/FVC ratio
	Estimated Value	0.027
	Confidence Interval	(2-Sided) 95%; 0.014 to 0.041
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FEV1/FVC ratio

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ado 50/250 µg BID+Tio 18 µg QD, Ado 50/250 µg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.223
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	FEV1/FVC ratio
	Estimated Value	0.008
	Confidence Interval	(2-Sided) 95%; -0.005 to 0.021
	Parameter Dispersion	Type: Value:
	Estimation Comments	Statistical data for FEV1/FVC ratio

11. Secondary Outcome

Title	Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period
Description	Participants were given daily record cards for daily completion during the run-in, washout and treatment periods. Each morning, participants recorded the number of occasions in the last 24 hours when they had used their rescue medication (salbutamol) for symptomatic relief of COPD symptoms.
Time Frame	Day 28 of each treatment period (up to 35 days)

Outcome Measure Data

Analysis Population Description

mITT Population. Only those participants available who used rescue medication at the specified periods were analyzed (represented by n=X, X, X in the category titles).

Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD	Tio 18 µg QD	Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
Measure Participants	50	50	50
Treatment, n=20, 18, 17	0.2 (0.62)	0.3 (0.82)	0.2 (0.55)
Washout, n=15, 15, 11	0.4 (0.81)	0.5 (1.24)	0.4 (1.01)

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-serious AEs were collected from the start of administration of the study drug until follow-up contact (up to Week 18).
Adverse Event Reporting Description	SAEs and non-serious AEs are reported for members of the Safety Population, comprised of all participants randomized to treatment, who had taken at least one dose of study medication.
Arm/Group Title	Ado 50/250 µg BID+Tio 18 µg QD		Tio 18 µg QD		Ado 50/250 µg BID
Arm/Group Description	Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio 18 µg QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.		Participants received Tio 18 µg QD (morning) via a HandiHaler inhaler plus Ado matching placebo BID (morning and evening) via dry powder inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.		Participants received Ado 50/250 µg BID (morning and evening) via a dry powder inhaler plus Tio matching placebo QD (morning) via a HandiHaler inhaler, in one of the three treatment periods. Each treatment period consisted of 4 weeks and separated by a 2-week washout period. Participants were provided with a salbutamol inhaler to be used as relief medication throughout the study.
All Cause Mortality
	Ado 50/250 µg BID+Tio 18 µg QD		Tio 18 µg QD		Ado 50/250 µg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ado 50/250 µg BID+Tio 18 µg QD		Tio 18 µg QD		Ado 50/250 µg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/52 (3.8%)		0/51 (0%)		0/51 (0%)
Cardiac disorders
Prinzmetal angina	1/52 (1.9%)		0/51 (0%)		0/51 (0%)
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis	1/52 (1.9%)		0/51 (0%)		0/51 (0%)
Other (Not Including Serious) Adverse Events
	Ado 50/250 µg BID+Tio 18 µg QD		Tio 18 µg QD		Ado 50/250 µg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/52 (28.8%)		8/51 (15.7%)		11/51 (21.6%)
Gastrointestinal disorders
Constipation	0/52 (0%)		0/51 (0%)		1/51 (2%)
Dry mouth	1/52 (1.9%)		1/51 (2%)		1/51 (2%)
General disorders
Oedema peripheral	0/52 (0%)		0/51 (0%)		1/51 (2%)
Infections and infestations
Lower respiratory tract infection	1/52 (1.9%)		0/51 (0%)		0/51 (0%)
Nasopharyngitis	3/52 (5.8%)		1/51 (2%)		1/51 (2%)
Pericoronitis	1/52 (1.9%)		0/51 (0%)		0/51 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/52 (3.8%)		0/51 (0%)		0/51 (0%)
Muscle spasms	0/52 (0%)		1/51 (2%)		1/51 (2%)
Pain in extremity	0/52 (0%)		0/51 (0%)		1/51 (2%)
Nervous system disorders
Headache	0/52 (0%)		1/51 (2%)		0/51 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/52 (1.9%)		0/51 (0%)		0/51 (0%)
Dysphonia	5/52 (9.6%)		1/51 (2%)		3/51 (5.9%)
Productive cough	0/52 (0%)		1/51 (2%)		0/51 (0%)
Rhinitis allergic	0/52 (0%)		0/51 (0%)		1/51 (2%)
Upper respiratory tract inflammation	0/52 (0%)		0/51 (0%)		1/51 (2%)
Skin and subcutaneous tissue disorders
Eczema	0/52 (0%)		1/51 (2%)		0/51 (0%)
Rash	1/52 (1.9%)		0/51 (0%)		0/51 (0%)
Vascular disorders
Hypertension	0/52 (0%)		1/51 (2%)		0/51 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.