Clinical Trial Results:
Randomised, doubleblind, placebocontrolled, 6 treatment, 4 period, incomplete crossover trial to characterise the 24hour lung function profiles of tiotropium + olodaterol fixed dose combination (2.5/5 µg, 5/5 µg), tiotropium (2.5 µg, 5 µg) and olodaterol (5 µg) (oral inhalation, delivered by the Respimat® Inhaler) after 6 weeks once daily treatment in patients with Chronic Obstructive Pulmonary Disease (COPD)
Summary


EudraCT number 
201100471042 
Trial protocol 
DE NL DK BE HU 
Global end of trial date 
12 Aug 2013

Results information


Results version number 
v1(current) 
This version publication date 
20 Jun 2016

First version publication date 
16 Jul 2015

Other versions 
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information


Trial identification


Sponsor protocol code 
1237.20


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT01559116  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
Boehringer Ingelheim


Sponsor organisation address 
Binger Strasse 173 , 55216 Ingelheim am Rhein , Germany,


Public contact 
Clinical Trial Information Disclosure , QRPE Processes and Systems Coordination , +1 800 243 0127 , clintriage.rdg@boehringeringelheim.com


Scientific contact 
Clinical Trial Information Disclosure , QRPE Processes and Systems Coordination , +1 800 243 0127 , clintriage.rdg@boehringeringelheim.com


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
No


Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
27 Sep 2013


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
18 Jul 2013


Global end of trial reached? 
Yes


Global end of trial date 
12 Aug 2013


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
The primary objective of the trial is to determine the 24hour FEV1time profile of tiotropium + olodaterol FDC (2.5/5 μg, 5/5 μg), administered once daily by the RESPIMAT Inhaler, after 6 weeks of treatment.


Protection of trial subjects 
An independent DMC was formed to ensure patient safety and was to make recommendations to the sponsor with regard to the continuation and potential modification or termination of the trial.
All patients were informed that they were free to withdraw their consent at any time during the study without penalty or prejudice. The patients were informed that their personal trial related data would be considered confidential and used by BI in accordance with the local data protection laws.


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
27 Mar 2012


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
Yes


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
Netherlands: 40


Country: Number of subjects enrolled 
Belgium: 27


Country: Number of subjects enrolled 
Denmark: 23


Country: Number of subjects enrolled 
Germany: 94


Country: Number of subjects enrolled 
Hungary: 21


Country: Number of subjects enrolled 
Canada: 7


Country: Number of subjects enrolled 
United States: 47


Worldwide total number of subjects 
259


EEA total number of subjects 
205


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
0


Children (211 years) 
0


Adolescents (1217 years) 
0


Adults (1864 years) 
172


From 65 to 84 years 
87


85 years and over 
0



Recruitment


Recruitment details 
  
Preassignment


Screening details 
All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the entry criteria were violated.  
Period 1


Period 1 title 
Overall trial


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Subject, Investigator, Monitor, Data analyst  
Arms


Arm title

All subjects  
Arm description 
All enrolled subject were included.  
Arm type 
all treatments combined subjects  
Investigational medicinal product name 
Tiotropium (Tio), Olodaterol (Olo), Tio+Olo, placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
Randomised, doubleblind, placebocontrolled, 6 treatment, 4 period, incomplete crossover trial to characterise the 24hour lung function profiles of tiotropium + olodaterol fixed dose combination (2.5/5 μg, 5/5 μg), tiotropium (2.5 μg, 5 μg) and olodaterol (5 μg) (oral inhalation, delivered by the Respimat® Inhaler) after 6 weeks once daily treatment in patients with Chronic Obstructive Pulmonary Disease (COPD)




Notes [1]  The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication. Thus, even though 259 subjects were enrolled in the trail, 40 subjects were not treated. Therefore only 219 subjects were reported in the baseline period. 

Period 2


Period 2 title 
Overall trial (treatment period)


Is this the baseline period? 
No  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Subject, Investigator, Monitor, Data analyst, Carer, Assessor  
Arms


Are arms mutually exclusive 
No


Arm title

Placebo  
Arm description 
2 inhalations once daily (a.m. dosing) for 6 weeks  
Arm type 
Placebo  
Investigational medicinal product name 
Placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
2 placebo inhalations once daily (a.m. dosing) for 6 weeks


Arm title

Olo 5 μg  
Arm description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Olodaterol (Olo): one dose (5 μg) only  
Arm type 
Active comparator  
Investigational medicinal product name 
Olodaterol


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
2 inhalations once daily (a.m. dosing) for 6 weeks. Olodaterol: one dose only


Arm title

Tio 2.5 μg  
Arm description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium (Tio): low dose  
Arm type 
Active comparator  
Investigational medicinal product name 
Tiotropium


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
2 inhalations once daily (a.m. dosing) for 6 weeks.
Tiotropium: low dose


Arm title

Tio 5 μg  
Arm description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium (Tio): high dose  
Arm type 
Active comparator  
Investigational medicinal product name 
Tiotropium


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
2 inhalations once daily (a.m. dosing) for 6 weeks.
Tiotropium: high dose


Arm title

T+O 2.5/5 μg  
Arm description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium + Olodaterol (T+O) fixed dose combination (FDC) low dose: low dose + one dose only  
Arm type 
Experimental  
Investigational medicinal product name 
Tiotropium, Olodaterol FDC


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
2 inhalations once daily (a.m. dosing) for 6 weeks.
Tiotropium + Olodaterol (T+O) fixed dose combination (FDC) low dose: low dose + one dose only.


Arm title

T+O 5/5 μg  
Arm description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium+Olodaterol (T+O) fixed dose combination (FDC) high dose: high dose + one dose only  
Arm type 
Experimental  
Investigational medicinal product name 
Tio, Olo FDC


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium+Olodaterol fixed dose combination (FDC) high dose: high dose + one dose only





Baseline characteristics reporting groups


Reporting group title 
Overall trial


Reporting group description 
Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication. Therefore 219 subjects were in baseline characteristic reporting group.  



End points reporting groups


Reporting group title 
All subjects


Reporting group description 
All enrolled subject were included.  
Reporting group title 
Placebo


Reporting group description 
2 inhalations once daily (a.m. dosing) for 6 weeks  
Reporting group title 
Olo 5 μg


Reporting group description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Olodaterol (Olo): one dose (5 μg) only  
Reporting group title 
Tio 2.5 μg


Reporting group description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium (Tio): low dose  
Reporting group title 
Tio 5 μg


Reporting group description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium (Tio): high dose  
Reporting group title 
T+O 2.5/5 μg


Reporting group description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium + Olodaterol (T+O) fixed dose combination (FDC) low dose: low dose + one dose only  
Reporting group title 
T+O 5/5 μg


Reporting group description 
2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium+Olodaterol (T+O) fixed dose combination (FDC) high dose: high dose + one dose only 


End point title 
Forced Expiratory Volume in 1 Second (FEV1) AUC024h Response [L] After 6 Weeks Treatment.  
End point description 
Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatementtime curve from 0 to 24 h postdose, using the trapezoidal rule, divided by the duration (24 h) to report in litres. Response was defined as the change from patient baseline.
Full Analysis Set (FAS): included all randomised patients who received at least 1 dose of study medication, had a period baseline measurement, and at least 1 evaluable postbaseline measurement for the primary endpoint at any Week 6 visit.
Pulmonary function test (PFT) time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose.
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Primary


End point timeframe 
Day 1 and week 6 (details in description)




Notes [1]  Full analysis set (FAS): definition in description [2]  FAS [3]  FAS [4]  FAS [5]  FAS [6]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[7]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.28


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.252  
upper limit 
0.309  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [7]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
274


Analysis specification 
Prespecified


Analysis type 
superiority ^{[8]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.115


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.087  
upper limit 
0.143  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [8]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[9]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.11


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.082  
upper limit 
0.139  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [9]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
267


Analysis specification 
Prespecified


Analysis type 
superiority ^{[10]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.277


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.249  
upper limit 
0.306  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [10]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[11]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.111


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.083  
upper limit 
0.14  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [11]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[12]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.124


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.096  
upper limit 
0.152  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [12]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[13]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.107


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.079  
upper limit 
0.136  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [13]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs T+O 2.5/5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus T+O 2.5/5.


Comparison groups 
T+O 2.5/5 μg v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[14]}  
Pvalue 
= 0.8238  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.003


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.025  
upper limit 
0.031  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [14]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 5/5 μg


Number of subjects included in analysis 
274


Analysis specification 
Prespecified


Analysis type 
superiority ^{[15]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.127


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.099  
upper limit 
0.155  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [15]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number. 

Statistical analysis title 
Tio 5 vs Olo 5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as Tio 5 minus Olo 5.


Comparison groups 
Olo 5 μg v Tio 5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[16]}  
Pvalue 
= 0.7722  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.004


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.024  
upper limit 
0.032  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [16]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
Tio 2.5 vs Olo 5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as Tio 2.5 minus Olo 5.


Comparison groups 
Olo 5 μg v Tio 2.5 μg


Number of subjects included in analysis 
272


Analysis specification 
Prespecified


Analysis type 
superiority ^{[17]}  
Pvalue 
= 0.3842  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.012


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.041  
upper limit 
0.016  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [17]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (272) does not reflect the actual number. 

Statistical analysis title 
Tio 5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as Tio 5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v Tio 5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[18]}  
Pvalue 
= 0.2487  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.017


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.012  
upper limit 
0.045  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [18]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
Olo 5 vs placebo  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as Olo 5 minus Placebo.


Comparison groups 
Placebo v Olo 5 μg


Number of subjects included in analysis 
268


Analysis specification 
Prespecified


Analysis type 
superiority ^{[19]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.166


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.137  
upper limit 
0.194  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [19]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (268) does not reflect the actual number. 

Statistical analysis title 
Tio 2.5 vs placebo  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as Tio 2.5 minus Placebo.


Comparison groups 
Tio 2.5 μg v Placebo


Number of subjects included in analysis 
268


Analysis specification 
Prespecified


Analysis type 
superiority ^{[20]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.153


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.125  
upper limit 
0.182  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [20]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (268) does not reflect the actual number. 

Statistical analysis title 
Tio 5 vs placebo  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures
(MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient
as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger
approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as Tio 5 minus Placebo.


Comparison groups 
Placebo v Tio 5 μg


Number of subjects included in analysis 
267


Analysis specification 
Prespecified


Analysis type 
superiority ^{[21]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.17


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.141  
upper limit 
0.198  
Variability estimate 
Standard error of the mean


Dispersion value 
0.014


Notes [21]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number. 


End point title 
FEV1 AUC012h Response [L] After 6 Weeks Treatment  
End point description 
This is a key secondary endpoint.
Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatementtime curve from 0 to 12 h postdose, using the trapezoidal rule, divided by the duration (12h) to report in litres. Response was defined as the change from patient baseline.
PFT time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Secondary


End point timeframe 
baseline and after 6 weeks (details in description)




Notes [22]  FAS [23]  FAS [24]  FAS [25]  FAS [26]  FAS [27]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[28]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.319


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.289  
upper limit 
0.349  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [28]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
274


Analysis specification 
Prespecified


Analysis type 
superiority ^{[29]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.126


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.096  
upper limit 
0.156  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [29]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[30]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.119


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.089  
upper limit 
0.149  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [30]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
267


Analysis specification 
Prespecified


Analysis type 
superiority ^{[31]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.323


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.293  
upper limit 
0.354  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [31]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[32]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.131


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.101  
upper limit 
0.161  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [32]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[33]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.139


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.109  
upper limit 
0.169  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [33]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[34]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.124


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.093  
upper limit 
0.154  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [34]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 


End point title 
FEV1 AUC1224h Response [L] After 6 Weeks Treatment  
End point description 
This is a key secondary endpoint.
Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatementtime curve from 12 to 24 h postdose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Response was defined as the change from patient baseline.
PFT time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose.
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Secondary


End point timeframe 
baseline and after 6 weeks (details in description)




Notes [35]  FAS [36]  FAS [37]  FAS [38]  FAS [39]  FAS [40]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[41]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.243


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.212  
upper limit 
0.273  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [41]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
274


Analysis specification 
Prespecified


Analysis type 
superiority ^{[42]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.103


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.074  
upper limit 
0.133  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [42]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[43]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.102


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.072  
upper limit 
0.132  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [43]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
267


Analysis specification 
Prespecified


Analysis type 
superiority ^{[44]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.232


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.201  
upper limit 
0.262  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [44]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[45]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.093


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.063  
upper limit 
0.123  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [45]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[46]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.11


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.08  
upper limit 
0.14  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [46]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[47]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.091


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.061  
upper limit 
0.121  
Variability estimate 
Standard error of the mean


Dispersion value 
0.015


Notes [47]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 


End point title 
Trough FEV1 Response [L] After 6 Weeks Treatment  
End point description 
The trough was defined as the mean of the 23 h and 23 h50 min measurements at Visits 3, 5, 7, 9 and Response was defined as the change from patient baseline.
PFT time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose.
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Secondary


End point timeframe 
baseline and after 6 weeks (details in description)




Notes [48]  FAS [49]  FAS [50]  FAS [51]  FAS [52]  FAS [53]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[54]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.207


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.173  
upper limit 
0.241  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [54]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
274


Analysis specification 
Prespecified


Analysis type 
superiority ^{[55]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.092


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.059  
upper limit 
0.126  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [55]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[56]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.079


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.045  
upper limit 
0.113  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [56]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
267


Analysis specification 
Prespecified


Analysis type 
superiority ^{[57]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.201


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.167  
upper limit 
0.235  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [57]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[58]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.086


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.052  
upper limit 
0.12  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [58]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[59]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.101


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.067  
upper limit 
0.135  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [59]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[60]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.073


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.039  
upper limit 
0.107  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [60]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 


End point title 
Peak(03h) FEV1 Response [L] After 6 Weeks Treatment  
End point description 
The peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline.
PFT time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose.
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Secondary


End point timeframe 
baseline and after 6 weeks (details in description)




Notes [61]  FAS [62]  FAS [63]  FAS [64]  FAS [65]  FAS [66]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[67]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.338


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.305  
upper limit 
0.371  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [67]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
276


Analysis specification 
Prespecified


Analysis type 
superiority ^{[68]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.12


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.087  
upper limit 
0.153  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [68]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (276) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
275


Analysis specification 
Prespecified


Analysis type 
superiority ^{[69]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.111


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.078  
upper limit 
0.143  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [69]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (275) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[70]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.35


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.317  
upper limit 
0.383  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [70]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[71]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.131


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.098  
upper limit 
0.164  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [71]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[72]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.132


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.099  
upper limit 
0.165  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [72]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
272


Analysis specification 
Prespecified


Analysis type 
superiority ^{[73]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.122


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.089  
upper limit 
0.155  
Variability estimate 
Standard error of the mean


Dispersion value 
0.017


Notes [73]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (272) does not reflect the actual number. 


End point title 
FVC AUC024h Response [L] After 6 Weeks Treatment  
End point description 
Area under the Forced Vital Capacity (FVC) after 6 weeks treatment periodtime curve from 0 to 24 h postdose using the trapezoidal rule, divided by the duration (24 h) to report in litres. Response was defined as the change from patient baseline.
PFT time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose.
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Secondary


End point timeframe 
baseline and after 6 weeks (details in description)




Notes [74]  FAS [75]  FAS [76]  FAS [77]  FAS [78]  FAS [79]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[80]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.433


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.389  
upper limit 
0.477  
Variability estimate 
Standard error of the mean


Dispersion value 
0.022


Notes [80]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
274


Analysis specification 
Prespecified


Analysis type 
superiority ^{[81]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.21


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.166  
upper limit 
0.253  
Variability estimate 
Standard error of the mean


Dispersion value 
0.022


Notes [81]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[82]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.177


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.133  
upper limit 
0.221  
Variability estimate 
Standard error of the mean


Dispersion value 
0.022


Notes [82]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
267


Analysis specification 
Prespecified


Analysis type 
superiority ^{[83]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.396


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.352  
upper limit 
0.441  
Variability estimate 
Standard error of the mean


Dispersion value 
0.023


Notes [83]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[84]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.173


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.129  
upper limit 
0.217  
Variability estimate 
Standard error of the mean


Dispersion value 
0.022


Notes [84]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[85]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.159


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.115  
upper limit 
0.203  
Variability estimate 
Standard error of the mean


Dispersion value 
0.022


Notes [85]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[86]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.14


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.096  
upper limit 
0.184  
Variability estimate 
Standard error of the mean


Dispersion value 
0.022


Notes [86]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 


End point title 
FVC AUC012h Response [L] After 6 Weeks Treatment  
End point description 
Area under the Forced Vital Capacity (FVC) after 6 weeks treatment periodtime curve from 0 to 12 h postdose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Response was defined as the change from patient baseline.
PFT time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose.
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Secondary


End point timeframe 
baseline and after 6 weeks (details in description)




Notes [87]  FAS [88]  FAS [89]  FAS [90]  FAS [91]  FAS [92]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[93]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.463


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.417  
upper limit 
0.509  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Notes [93]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
274


Analysis specification 
Prespecified


Analysis type 
superiority ^{[94]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.154  
upper limit 
0.246  
Variability estimate 
Standard error of the mean


Dispersion value 
0.023


Notes [94]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[95]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.179


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.133  
upper limit 
0.225  
Variability estimate 
Standard error of the mean


Dispersion value 
0.023


Notes [95]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
267


Analysis specification 
Prespecified


Analysis type 
superiority ^{[96]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.443


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.396  
upper limit 
0.49  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Notes [96]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[97]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.181


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.134  
upper limit 
0.227  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Notes [97]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[98]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.171


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.125  
upper limit 
0.218  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Notes [98]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[99]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.159


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.113  
upper limit 
0.206  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Notes [99]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 


End point title 
FVC AUC1224h Response [L] After 6 Weeks Treatment  
End point description 
Area under the Forced Vital Capacity (FVC) after 6 weeks treatment periodtime curve from 12 to 24 h postdose
using the trapezoidal rule, divided by the duration (12 h) to report in litres. Response was defined as the change from patient baseline.
PFT time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose.
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Secondary


End point timeframe 
baseline and after 6 weeks (details in description)




Notes [100]  FAS [101]  FAS [102]  FAS [103]  FAS [104]  FAS [105]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[106]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.404


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.355  
upper limit 
0.453  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Notes [106]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
274


Analysis specification 
Prespecified


Analysis type 
superiority ^{[107]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.219


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.17  
upper limit 
0.267  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Notes [107]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[108]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.174


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.126  
upper limit 
0.223  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Notes [108]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
267


Analysis specification 
Prespecified


Analysis type 
superiority ^{[109]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.351


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.301  
upper limit 
0.4  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Notes [109]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[110]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.166


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.117  
upper limit 
0.214  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Notes [110]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[111]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.148


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.099  
upper limit 
0.197  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Notes [111]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[112]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.121


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.072  
upper limit 
0.17  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Notes [112]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 


End point title 
Trough FVC Response [L] After 6 Weeks Treatment  
End point description 
The trough was defined as the mean of the 23 h and 23 h50 min measurements at visits 3, 5, 7, 9 and response was defined as the
change from patient baseline.
PFT time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose.
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Secondary


End point timeframe 
baseline and after 6 weeks (details in description)




Notes [113]  FAS [114]  FAS [115]  FAS [116]  FAS [117]  FAS [118]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[119]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.329


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.274  
upper limit 
0.385  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [119]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
274


Analysis specification 
Prespecified


Analysis type 
superiority ^{[120]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.17


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.115  
upper limit 
0.225  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [120]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[121]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.121


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.066  
upper limit 
0.176  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [121]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
267


Analysis specification 
Prespecified


Analysis type 
superiority ^{[122]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.307


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.251  
upper limit 
0.363  
Variability estimate 
Standard error of the mean


Dispersion value 
0.029


Notes [122]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[123]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.147


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.092  
upper limit 
0.203  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [123]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[124]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.166


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.111  
upper limit 
0.222  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [124]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[125]}  
Pvalue 
= 0.0005  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.099


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.043  
upper limit 
0.154  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [125]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 


End point title 
Peak (03h) FVC Response [L] After 6 Weeks Treatment  
End point description 
Peak (03h) Forced Vital Capacity (FVC) responses.
Peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline.
PFT time schedule:
At Visits 2, 4, 6, 8: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2 and 3 h postdose.
At Visits 3, 5, 7, 9: predose PFT: 30 mins prior to inhalation of dose of study medication; postdose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min postdose.


End point type 
Secondary


End point timeframe 
baseline and after 6 weeks (details in description)




Notes [126]  FAS [127]  FAS [128]  FAS [129]  FAS [130]  FAS [131]  FAS 

Statistical analysis title 
T+O 5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Placebo.


Comparison groups 
Placebo v T+O 5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[132]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.462


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.408  
upper limit 
0.516  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [132]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
276


Analysis specification 
Prespecified


Analysis type 
superiority ^{[133]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.159


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.105  
upper limit 
0.212  
Variability estimate 
Standard error of the mean


Dispersion value 
0.027


Notes [133]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (276) does not reflect the actual number. 

Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 5/5 μg


Number of subjects included in analysis 
275


Analysis specification 
Prespecified


Analysis type 
superiority ^{[134]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.151


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.098  
upper limit 
0.205  
Variability estimate 
Standard error of the mean


Dispersion value 
0.027


Notes [134]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (275) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs placebo  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.


Comparison groups 
Placebo v T+O 2.5/5 μg


Number of subjects included in analysis 
270


Analysis specification 
Prespecified


Analysis type 
superiority ^{[135]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.452


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.398  
upper limit 
0.507  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [135]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.


Comparison groups 
Olo 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
273


Analysis specification 
Prespecified


Analysis type 
superiority ^{[136]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.149


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.095  
upper limit 
0.203  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [136]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.


Comparison groups 
Tio 2.5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
271


Analysis specification 
Prespecified


Analysis type 
superiority ^{[137]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.161


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.107  
upper limit 
0.216  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [137]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number. 

Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed
effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect;
compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of
denominator degrees of freedom.
The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.


Comparison groups 
Tio 5 μg v T+O 2.5/5 μg


Number of subjects included in analysis 
272


Analysis specification 
Prespecified


Analysis type 
superiority ^{[138]}  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.142


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.087  
upper limit 
0.196  
Variability estimate 
Standard error of the mean


Dispersion value 
0.028


Notes [138]  The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the prespecified, automatically calculated number that is provided in the statistical analysis (272) does not reflect the actual number. 


Adverse events information


Timeframe for reporting adverse events 
From drug administration until 21 days after the last administration, up to 92 days.


Adverse event reporting additional description 
AE additional description


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
16.0


Reporting groups


Reporting group title 
Placebo


Reporting group description 
Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation  RESPIMAT: 2 Oral inhalations once daily in the morning for 6 weeks.  
Reporting group title 
Olodaterol (5 µg)


Reporting group description 
Olodaterol solution for inhalation  RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.  
Reporting group title 
Tiotropium (2.5 µg)


Reporting group description 
Tiotropium solution for inhalation  RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.  
Reporting group title 
Tiotropium (5 µg)


Reporting group description 
Tiotropium solution for inhalation  RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.  
Reporting group title 
Tiotropium+Olodaterol FDC (2.5/5 µg)


Reporting group description 
Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation  RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.  
Reporting group title 
Tiotropium+Olodaterol FDC (5/5 µg)


Reporting group description 
Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation  RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.  


Frequency threshold for reporting nonserious adverse events: 5%  



Substantial protocol amendments (globally) 

Were there any global substantial amendments to the protocol? Yes  
Date 
Amendment 

21 Mar 2012 
Additional guidance was provided regarding individual withdrawal criteria, and regarding medication restrictions. It was specified that adjudication was to be carried out for all SAEs (rather than only fatal events), and that clinically significant laboratory values were to be entered as AEs. Modifications were introduced regarding the time points of vital sign acquisition and regarding the predose time window for PFT measurements. Administrative changes, corrections, and further clarifications were introduced. 

Interruptions (globally) 

Were there any global interruptions to the trial? No  
Limitations and caveats 

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.  
None reported 