Clinical Trial Results:
A randomised, doubleblind, parallel group study to assess the efficacy and safety of 52 weeks of once daily treatment of orally inhaled tiotropium + olodaterol fixed dose combination (2.5 μg / 5 μg; 5 μg / 5 μg) (delivered by the Respimat® Inhaler) compared with the individual components (2.5 μg and 5 μg tiotropium, 5 μg olodaterol) (delivered by the Respimat® Inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD).
Due to a system error, the data reported in v1 is not correct and has been removed from public view.
Summary


EudraCT number 
200901066840 
Trial protocol 
NL FI PT SI CZ DE HU DK EE IT 
Global end of trial date 
19 Sep 2013

Results information


Results version number 
v2(current) 
This version publication date 
01 Jul 2016

First version publication date 
01 Aug 2015

Other versions 
v1 (removed from public view) 
Version creation reason 

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 
1237.5


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT01431274  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
Boehringer Ingelheim


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


Public contact 
QRPE Processes and Systems Coordination Clinical Trial
Information Disclosure, Boehringer Ingelheim, +1 800 2430127, clintriage.rdg@boehringeringelheim.com


Scientific contact 
QRPE Processes and Systems Coordination Clinical Trial
Information Disclosure, Boehringer Ingelheim, +1 800 2430127, 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 
05 Nov 2013


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
06 Mar 2013


Global end of trial reached? 
Yes


Global end of trial date 
19 Sep 2013


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
The overall objective of this study is to assess the efficacy and safety of 52 weeks once daily treatment with orally inhaled tiotropium + olodaterol fixed dose combination ((2.5 µg / 5 µg; 5 µg / 5 µg) (delivered by the Respimat® Inhaler) compared with the individual components (2.5 and 5 μg tiotropium, 5 µg olodaterol) (delivered by the Respimat® Inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD).


Protection of trial subjects 
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time without the need to provide a reason. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
15 Sep 2011


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 
Slovenia: 105


Country: Number of subjects enrolled 
Denmark: 150


Country: Number of subjects enrolled 
Finland: 81


Country: Number of subjects enrolled 
Italy: 49


Country: Number of subjects enrolled 
Netherlands: 119


Country: Number of subjects enrolled 
Portugal: 74


Country: Number of subjects enrolled 
Bulgaria: 94


Country: Number of subjects enrolled 
Czech Republic: 59


Country: Number of subjects enrolled 
Estonia: 49


Country: Number of subjects enrolled 
France: 80


Country: Number of subjects enrolled 
Germany: 301


Country: Number of subjects enrolled 
Hungary: 89


Country: Number of subjects enrolled 
United States: 553


Country: Number of subjects enrolled 
Australia: 22


Country: Number of subjects enrolled 
Canada: 131


Country: Number of subjects enrolled 
Guatemala: 110


Country: Number of subjects enrolled 
India: 99


Country: Number of subjects enrolled 
Japan: 279


Country: Number of subjects enrolled 
Mexico: 45


Country: Number of subjects enrolled 
New Zealand: 30


Country: Number of subjects enrolled 
China: 316


Country: Number of subjects enrolled 
Argentina: 206


Country: Number of subjects enrolled 
Russian Federation: 56


Country: Number of subjects enrolled 
Korea, Republic of: 175


Country: Number of subjects enrolled 
Turkey: 97


Worldwide total number of subjects 
3369


EEA total number of subjects 
1250


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) 
1703


From 65 to 84 years 
1651


85 years and over 
15



Recruitment


Recruitment details 
A "Missing" category is unavailable for the age group breakdown of enrolled patients. Hence, 8 subjects with a missing data for age group have been added to agecategory "1864 years".  
Preassignment


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


Period 1 title 
Treatment period (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


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


Are arms mutually exclusive 
Yes


Arm title

Olodaterol (Olo) 5 μg  
Arm description 
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
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 
5 μg Once daily with orally inhalation


Arm title

Tiotropium (Tio) 2.5 μg  
Arm description 
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
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 
2.5 μg once daily with orally inhalation


Arm title

Tiotropium (Tio) 5 μg  
Arm description 
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
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 
5 μg once daily with orally inhalation


Arm title

Tio + Olo (T+O) 2.5 /5 μg  
Arm description 
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Arm type 
Experimental  
Investigational medicinal product name 
Tiotropium


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
2.5 μg once daily with orally inhalation


Investigational medicinal product name 
Olodaterol


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
5 μg once daily with orally inhalation


Arm title

Tio + Olo (T + O) 5/5 μg  
Arm description 
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Arm type 
Experimental  
Investigational medicinal product name 
Olodaterol


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
5 μg once daily with orally inhalation


Investigational medicinal product name 
Tiotropium


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
5 μg once daily with orally inhalation




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 the patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication. 


Baseline characteristics reporting groups


Reporting group title 
Olodaterol (Olo) 5 μg


Reporting group description 
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tiotropium (Tio) 2.5 μg


Reporting group description 
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tiotropium (Tio) 5 μg


Reporting group description 
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tio + Olo (T+O) 2.5 /5 μg


Reporting group description 
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tio + Olo (T + O) 5/5 μg


Reporting group description 
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  



End points reporting groups


Reporting group title 
Olodaterol (Olo) 5 μg


Reporting group description 
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tiotropium (Tio) 2.5 μg


Reporting group description 
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tiotropium (Tio) 5 μg


Reporting group description 
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tio + Olo (T+O) 2.5 /5 μg


Reporting group description 
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tio + Olo (T + O) 5/5 μg


Reporting group description 
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning. 


End point title 
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (03h) Response on Day 169.  
End point description 
Area under the FEVtime curve from 0 to 3h postdose(FEV1 AUC(03h)) was calculated using trapezoidal rule, divided by duration(3h) to report in litres. FEV1 AUC(03h) response was defined as FEV1 AUC(03h) minus baseline FEV1. Baseline was defined as the mean of 2 predose measurements performed 1h & at 10 min prior to first dose at visit 2(day1). The adjusted means(SE) were obtained by fitting MMRM model with fixed effects of treatment,planned test day,treatmentbytest day interaction, baseline & baselinebytest day interaction,patient as random effect,& spatial power covariance structure for withinpatient errors & KenwardRoger approximation for denominator degrees of freedom.The Full analysis set(FAS) included all randomized patients, dispensed study medication,documented to have taken any dose of study medication & who had nonmissing baseline & at least one nonmissing postbaseline measurement for at least one primary or key secondary efficacy endpoints.


End point type 
Primary


End point timeframe 
1 hour (h) and at 10 minutes (min) prior to dose on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h postdose on Day 169




Notes [1]  Number of FAS (full analysis set) patients actually contributing to the model. [2]  Number of FAS (full analysis set) patients actually contributing to the model. [3]  Number of FAS (full analysis set) patients actually contributing to the model. [4]  Number of FAS (full analysis set) patients actually contributing to the model. [5]  Number of FAS (full analysis set) patients actually contributing to the model. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.123


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.146  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1048


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.117


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.094  
upper limit 
0.14  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.109


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.086  
upper limit 
0.132  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg.The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1045


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.093


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.07  
upper limit 
0.116  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.102


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.08  
upper limit 
0.125  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1043


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2169  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.008  
upper limit 
0.037  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 2.5  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.108


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.085  
upper limit 
0.13  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Olo 5  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1051


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.5849  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.006


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.017  
upper limit 
0.029  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 2.5 vs Olo 5  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1049


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1863  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.016


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.007  
upper limit 
0.039  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Tio 2.5  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1050


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4352  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.009


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.032  
upper limit 
0.014  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012



End point title 
Trough FEV1 response on Day 170  
End point description 
Trough FEV1 defined as the FEV1 value at the end of the dosing interval (24h)&calculated as mean of 2 FEV1 measurements performed at 23h &at 23h 50 min after inhalation of study medication at clinic visit on the previous day.Trough FEV1 response was defined as trough FEV1 minus baseline FEV1.Baseline was defined as mean of 2 predose measurements performed 1h&at 10 min prior to administration of first dose at visit2(day 1).The adjusted means (SE) obtained by fitting mixed effect model repeated measures(MMRM) including fixed effects of treatment,planned test day,treatmentbytest day interaction,baseline&baselinebytest day interaction,patient as random effect,&spatial power covariance structure for withinpatient errors&Kenward Roger approximation for denominator degrees of freedom.Since it is possible for patient to meet the data criterion for only a subset of the primary endpoints,it is possible that the number of patients used in the FAS analysis for different endpoint will vary.


End point type 
Primary


End point timeframe 
1 h and at 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170




Notes [6]  Number of FAS (full analysis set) patients actually contributing to the model. [7]  Number of FAS (full analysis set) patients actually contributing to the model. [8]  Number of FAS (full analysis set) patients actually contributing to the model. [9]  Number of FAS (full analysis set) patients actually contributing to the model. [10]  Number of FAS (full analysis set) patients actually contributing to the model. 

Statistical analysis title 
T+O 5/5 vs Olo 5  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.082


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.059  
upper limit 
0.106  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 5  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.071


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.047  
upper limit 
0.094  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Olo 5  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.058


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.034  
upper limit 
0.081  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0174  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.029


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.005  
upper limit 
0.052  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 5  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.046


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.023  
upper limit 
0.07  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0407  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.024


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.001  
upper limit 
0.048  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 2.5  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.053


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.03  
upper limit 
0.077  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Olo 5  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3326  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.012


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.012  
upper limit 
0.035  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 2.5 vs Olo 5  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0151  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.029


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.006  
upper limit 
0.053  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Tio 2.5  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1421  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.018


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.041  
upper limit 
0.006  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012



End point title 
FEV1 AUC(03h) response on Day 1, Day 85, and Day 365  
End point description 
FEV1 AUC(03h) was calculated as the area under the FEV1 time curve from 0 to 3 h postdose using the trapezoidal rule,divided by the duration (3 h) to report in litres.FEV1 AUC(03h) response was defined as FEV1 AUC(03h) minus baseline FEV1.Baseline was defined as the mean of the 2 predose measurements performed 1 h & at 10 min prior to administration of the first dose of randomised treatment at Day1.The adjusted means (SE) were obtained by fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment,planned test day, treatmentbytest day interaction,baseline & baselinebytest day interaction, patient as random effect, & spatial power covariance structure for within−patient errors and KenwardRoger approximation for denominator degrees of freedom.Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints,it is possible that the number of patients used in the FAS analysis for different endpoint vary.


End point type 
Secondary


End point timeframe 
1 hour (h) and at 10 minutes (min) prior to dose on the first day of randomized treatment and on Days 85 and 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h postdose on the first day of randomized treatment and on Days 85 and 365.




Notes [11]  Number of FAS (full analysis set) patients actually contributing to the model. [12]  Number of FAS (full analysis set) patients actually contributing to the model. [13]  Number of FAS (full analysis set) patients actually contributing to the model. [14]  Number of FAS (full analysis set) patients actually contributing to the model. [15]  Number of FAS (full analysis set) patients actually contributing to the model. 

Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0067  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.033


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.009  
upper limit 
0.056  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1048


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.081


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.057  
upper limit 
0.104  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0746  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.022


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.002  
upper limit 
0.045  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1045


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.078


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.054  
upper limit 
0.101  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.07


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.046  
upper limit 
0.093  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1043


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3549  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.011


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.013  
upper limit 
0.035  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.089


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.065  
upper limit 
0.113  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Olo 5 on Day 1  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1051


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.048


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.072  
upper limit 
0.025  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 1  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1049


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.056


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.08  
upper limit 
0.033  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 1  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1050


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.5018  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.008


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.016  
upper limit 
0.032  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.128


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.104  
upper limit 
0.152  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1048


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.126


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.102  
upper limit 
0.15  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.111


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.087  
upper limit 
0.135  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.109


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.085  
upper limit 
0.133  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1045


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.096


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.072  
upper limit 
0.12  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1043


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1569  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.017


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.007  
upper limit 
0.041  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.113


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.089  
upper limit 
0.137  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Olo 5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1051


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.8834  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.002


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.022  
upper limit 
0.026  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1049


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2129  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.015


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.009  
upper limit 
0.039  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1050


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2702  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.013


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.037  
upper limit 
0.01  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.141


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.117  
upper limit 
0.166  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1048


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.115


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.09  
upper limit 
0.139  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.119


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.094  
upper limit 
0.143  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1045


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.099


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.074  
upper limit 
0.123  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.092


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.067  
upper limit 
0.117  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1043


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0717  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.023


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.002  
upper limit 
0.047  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.121


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.097  
upper limit 
0.146  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
Tio 5 vs Olo 5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1051


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0344  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.027


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.002  
upper limit 
0.051  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1049


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1126  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.02


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.005  
upper limit 
0.045  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1050


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.6009  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.007


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.018  
upper limit 
0.031  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013



End point title 
Trough FEV1 response on Day 15, Day 43, Day 85, Day 169, and Day 365  
End point description 
Trough FEV1 defined as the FEV1 value at the end of the dosing interval (24 hours),calculated as mean of the predose measurements.Trough FEV1 response was defined as trough FEV1 minus baseline FEV1.Baseline was defined as mean of 2 predose measurements performed 1h&at 10 min prior to administration of the first dose of randomised treatment at Day1.The adjusted means (SE) were obtained by MMRM model including fixed effects of treatment,planned test day, treatmentbytest day interaction, baseline&baselinebytest day interaction,patient as random effect,&spatial power covariance structure for withinpatient errors &KenwardRoger approximation for denominator degrees of freedom.Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoint vary.


End point type 
Secondary


End point timeframe 
1 hour (h) and at 10 minutes (min) prior to dose on the first day of randomized treatment and on Days 85, 169 and 365 and 10 minutes (min) prior to randomized treatment on days 15 and 43.




Notes [16]  Number of FAS (full analysis set) patients actually contributing to the model. [17]  Number of FAS (full analysis set) patients actually contributing to the model. [18]  Number of FAS (full analysis set) patients actually contributing to the model. [19]  Number of FAS (full analysis set) patients actually contributing to the model. [20]  Number of FAS (full analysis set) patients actually contributing to the model. 

Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.072


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.049  
upper limit 
0.096  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.063


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.039  
upper limit 
0.087  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.047


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.023  
upper limit 
0.07  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0122  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.03


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.007  
upper limit 
0.054  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0021  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.037


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.014  
upper limit 
0.061  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0347  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.026


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.002  
upper limit 
0.049  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.056


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.032  
upper limit 
0.08  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Olo 5 on Day 15  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5μg.The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,
treatmentbytest day interaction, baseline and baselinebytest day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and KenwardRoger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4407  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.009


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.014  
upper limit 
0.033  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 15  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1777  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.016


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.007  
upper limit 
0.04  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 15  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.5641  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.007


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.031  
upper limit 
0.017  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.08


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.057  
upper limit 
0.104  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.075


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.051  
upper limit 
0.099  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0018  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.038


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.014  
upper limit 
0.062  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0517  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.024


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0.047  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0072  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.033


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.009  
upper limit 
0.056  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0005  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.042


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.019  
upper limit 
0.066  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.066


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.042  
upper limit 
0.09  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Olo 5 on Day 43  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.6619  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.005


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.018  
upper limit 
0.029  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 43  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2401  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
0.038  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 43  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4601  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.009


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.033  
upper limit 
0.015  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.088


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.064  
upper limit 
0.112  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.076


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.052  
upper limit 
0.1  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.07


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.046  
upper limit 
0.094  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.051


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.027  
upper limit 
0.075  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.058


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.034  
upper limit 
0.082  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1405  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.018


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.006  
upper limit 
0.042  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.069


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.045  
upper limit 
0.093  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Olo 5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3118  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.012


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.012  
upper limit 
0.036  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1171  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.019


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.005  
upper limit 
0.043  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.5759  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.007


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.031  
upper limit 
0.017  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.079


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.055  
upper limit 
0.103  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.062


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.038  
upper limit 
0.086  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.061


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.037  
upper limit 
0.085  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0002  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.047


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.022  
upper limit 
0.071  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0004  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.044


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.019  
upper limit 
0.068  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.136  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.018


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.006  
upper limit 
0.042  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.065


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.041  
upper limit 
0.089  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Olo 5 on Day 169  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1617  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.017


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.007  
upper limit 
0.041  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 169  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2476  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
0.039  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 169  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.8083  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.003


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.021  
upper limit 
0.027  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.1


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.075  
upper limit 
0.124  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.064


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.039  
upper limit 
0.088  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.076


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.051  
upper limit 
0.1  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.048


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.023  
upper limit 
0.072  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0014  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.04


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.015  
upper limit 
0.064  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0554  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.024


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.001  
upper limit 
0.048  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg.. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.071


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.047  
upper limit 
0.096  
Variability estimate 
Standard error of the mean


Dispersion value 
0.012


Statistical analysis title 
Tio 5 vs Olo 5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0041  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.036


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.011  
upper limit 
0.06  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0248  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.028


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.004  
upper limit 
0.053  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.5338  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.008


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.017  
upper limit 
0.032  
Variability estimate 
Standard error of the mean


Dispersion value 
0.013



End point title 
Forced vital capacity (FVC) AUC (03h) response on Day 1, Day 85, Day 169, and Day 365  
End point description 
FVC AUC(03h) calculated as area under FVCtime curve from 0to3h postdose using trapezoidal rule,divided by duration(3h) to report in litres.FVC AUC(03h) response defined as FVC AUC(03h) minus baseline FVC.Baseline was defined as mean of 2 predose measurements performed 1h&at10 min prior to administration of first dose at visit2(day 1).The adjusted means (SE) were obtained by fitting MMRM model including fixed effects of treatment,planned test day,treatmentbytest day interaction,baseline&baselinebytest day interaction,patient as random effect,&spatial power covariance structure for withinpatient errors&KenwardRoger approximation for denominator degrees of freedom.Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints,it is possible that the number of patients used in the FAS analysis for different endpoints will vary.


End point type 
Secondary


End point timeframe 
1 hour (h) and at 10 minutes (min) prior to dose and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h postdose on the first day of randomized treatment and on each of the days specified in the title.




Notes [21]  Number of FAS (full analysis set) patients actually contributing to the model. [22]  Number of FAS (full analysis set) patients actually contributing to the model. [23]  Number of FAS (full analysis set) patients actually contributing to the model. [24]  Number of FAS (full analysis set) patients actually contributing to the model. [25]  Number of FAS (full analysis set) patients actually contributing to the model. 

Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0017  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.077


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.029  
upper limit 
0.125  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1048


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.138


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.09  
upper limit 
0.186  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0426  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.05


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.002  
upper limit 
0.098  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1045


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.122


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.074  
upper limit 
0.17  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.111


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.063  
upper limit 
0.159  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1043


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2661  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.027


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.021  
upper limit 
0.075  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 1  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.15


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.102  
upper limit 
0.198  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
Tio 5 vs Olo 5 on Day 1  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1051


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0119  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.061


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.109  
upper limit 
0.014  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 1  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1049


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0029  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.073


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.121  
upper limit 
0.025  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 1  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1050


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.6408  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.011


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.036  
upper limit 
0.059  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.221


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.173  
upper limit 
0.27  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1048


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.193


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.145  
upper limit 
0.242  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.185


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.136  
upper limit 
0.233  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1045


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.114


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.065  
upper limit 
0.162  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.157


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.108  
upper limit 
0.205  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1043


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1355  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.037


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.012  
upper limit 
0.085  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.151


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.102  
upper limit 
0.199  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Olo 5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1051


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2562  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.028


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.02  
upper limit 
0.076  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1049


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0041  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.071


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.022  
upper limit 
0.119  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1050


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0815  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.043


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.091  
upper limit 
0.005  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.195


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.149  
upper limit 
0.242  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1048


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.153


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.107  
upper limit 
0.199  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.174


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.128  
upper limit 
0.221  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1045


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.107


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.061  
upper limit 
0.154  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.132


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.086  
upper limit 
0.178  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1043


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3727  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.021


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.025  
upper limit 
0.067  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 169  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.128


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.082  
upper limit 
0.175  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
Tio 5 vs Olo 5 on Day 169  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1051


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0744  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.042


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.004  
upper limit 
0.089  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 169  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1049


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0047  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.067


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.021  
upper limit 
0.114  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 169  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1050


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2945  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.025


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.071  
upper limit 
0.022  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.205


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.155  
upper limit 
0.255  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1048


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.156


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.107  
upper limit 
0.206  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.192


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.142  
upper limit 
0.242  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1045


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.124


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.074  
upper limit 
0.174  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1047


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.144


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.094  
upper limit 
0.193  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1043


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.6103  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.013


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.037  
upper limit 
0.062  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1046


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.137


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.087  
upper limit 
0.186  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Olo 5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1051


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0559  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.049


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.001  
upper limit 
0.098  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1049


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0073  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.068


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.018  
upper limit 
0.118  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1050


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4368  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.02


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.07  
upper limit 
0.03  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025



End point title 
Trough FVC response on Day 15, Day 43, Day 85, Day 170, and Day 365  
End point description 
Trough FVC defined as the FVC value at the end of the dosing interval (24 hours),calculated as mean of the predose measurements.Trough FVC response defined as trough FVC minus baseline FVC. Baseline was defined as mean of 2 predose measurements performed 1h&at 10min prior to administration of first dose at visit 2(day 1).The adjusted means (SE) were obtained by fitting MMRM including fixed effects of treatment,planned test day,treatmentbytest day interaction,baseline and baselinebytest day interaction,patient as random effect, &spatial power covariance structure for withinpatient errors &KenwardRoger approximation for denominator degrees of freedom. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.


End point type 
Secondary


End point timeframe 
1 h and at 10 min prior to dose on the first day of randomized treatment (baseline), day 85, day 365, at 10 min predose on day 15 and 43 and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170.




Notes [26]  Number of FAS (full analysis set) patients actually contributing to the model. [27]  Number of FAS (full analysis set) patients actually contributing to the model. [28]  Number of FAS (full analysis set) patients actually contributing to the model. [29]  Number of FAS (full analysis set) patients actually contributing to the model. [30]  Number of FAS (full analysis set) patients actually contributing to the model. 

Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.147


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.098  
upper limit 
0.196  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0023  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.076


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.027  
upper limit 
0.125  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
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


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0545  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.048


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.001  
upper limit 
0.097  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0456  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.05


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.001  
upper limit 
0.099  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2949  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.026


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.023  
upper limit 
0.075  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 15  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0029  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.074


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.025  
upper limit 
0.123  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Olo 5 on Day 15  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0045  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.071


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.022  
upper limit 
0.12  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 15  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0035  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.073


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.024  
upper limit 
0.122  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 15  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.9369  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.002


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.051  
upper limit 
0.047  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.168


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.119  
upper limit 
0.217  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.105


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.056  
upper limit 
0.154  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.103


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.054  
upper limit 
0.152  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0585  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.047


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.002  
upper limit 
0.096  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1042  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.041


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.008  
upper limit 
0.09  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0097  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.065


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.016  
upper limit 
0.114  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 43  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.112


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.063  
upper limit 
0.161  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Olo 5 on Day 43  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.012  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.063


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.014  
upper limit 
0.112  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 43  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.025  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.056


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.007  
upper limit 
0.105  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 43  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.7889  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.007


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.042  
upper limit 
0.056  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.187


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.138  
upper limit 
0.237  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
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


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.153


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.103  
upper limit 
0.202  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0134  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.062


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.013  
upper limit 
0.111  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0006  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.086


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.037  
upper limit 
0.136  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.167  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.035


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.015  
upper limit 
0.084  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.097


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.048  
upper limit 
0.146  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Olo 5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0085  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.066


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.017  
upper limit 
0.115  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0003  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.09


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.041  
upper limit 
0.14  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 85  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3332  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.024


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.074  
upper limit 
0.025  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 170  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.153


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.105  
upper limit 
0.201  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 170  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0016  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.077


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.029  
upper limit 
0.125  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 170  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.132


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.084  
upper limit 
0.18  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 170  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0926  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.041


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.007  
upper limit 
0.089  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 170  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0231  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.055


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.008  
upper limit 
0.103  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 170  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3802  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.021


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.026  
upper limit 
0.069  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 170  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0105  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.062


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.015  
upper limit 
0.11  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
Tio 5 vs Olo 5 on Day 170  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0018  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.076


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.028  
upper limit 
0.125  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 170  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0002  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.091


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.043  
upper limit 
0.139  
Variability estimate 
Standard error of the mean


Dispersion value 
0.025


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 170  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.5554  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.062  
upper limit 
0.034  
Variability estimate 
Standard error of the mean


Dispersion value 
0.024


Statistical analysis title 
T+O 5/5 vs Olo 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.178


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.127  
upper limit 
0.228  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026


Statistical analysis title 
T+O 5/5 vs Tio 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1041


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0011  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.084


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.033  
upper limit 
0.134  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026


Statistical analysis title 
T+O 2.5/5 vs Olo 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.142


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.091  
upper limit 
0.192  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026


Statistical analysis title 
T+O 2.5/5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1037


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1112  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.041


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.009  
upper limit 
0.091  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026


Statistical analysis title 
T+O 2.5/5 vs Tio 5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T+O) 2.5 /5 μg v Tiotropium (Tio) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0632  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.048


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.003  
upper limit 
0.098  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026


Statistical analysis title 
T+O 5/5 vs T+O 2.5/5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tio + Olo (T+O) 2.5 /5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1615  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.036


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.014  
upper limit 
0.086  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026


Statistical analysis title 
T+O 5/5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tio + Olo (T + O) 5/5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1040


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0027  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.077


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.027  
upper limit 
0.127  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026


Statistical analysis title 
Tio 5 vs Olo 5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0003  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.094


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.044  
upper limit 
0.144  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026


Statistical analysis title 
Tio 2.5 vs Olo 5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 2.5 μg v Olodaterol (Olo) 5 μg


Number of subjects included in analysis 
1038


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.0001  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.101


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.05  
upper limit 
0.151  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026


Statistical analysis title 
Tio 5 vs Tio 2.5 on Day 365  
Statistical analysis description 
Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.


Comparison groups 
Tiotropium (Tio) 5 μg v Tiotropium (Tio) 2.5 μg


Number of subjects included in analysis 
1039


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.7925  
Method 
Mixed models analysis  
Parameter type 
Adjusted mean difference  
Point estimate 
0.007


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.057  
upper limit 
0.044  
Variability estimate 
Standard error of the mean


Dispersion value 
0.026



Adverse events information


Timeframe for reporting adverse events 
All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 447 days)


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
16.1


Reporting groups


Reporting group title 
Olodaterol (5 μg)


Reporting group description 
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tiotropium (2.5 μg)


Reporting group description 
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tiotropium (5 μg)


Reporting group description 
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tio+Olo FDC (2.5/5 μg)


Reporting group description 
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.  
Reporting group title 
Tio+Olo FDC (5/5 μg)


Reporting group description 
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning  
