Clinical Trial Results:
A multicentre, randomised, doubleblind, activecontrolled, 3way crossover study to evaluate the efficacy and safety of a free combination of 3 doses of CHF 5259 (glycopyrrolate) plus Foster® 100/6µg (fixed combination of beclomethasone dipropionate plus formoterol) in a metered dose inhaler for the treatment of patients with uncontrolled asthma under medium doses of inhaled corticosteroids plus longacting β2agonists
Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
Summary


EudraCT number 
201300304336 
Trial protocol 
DE GB HU IT PL BG 
Global end of trial date 
08 Mar 2015

Results information


Results version number 
v1(current) 
This version publication date 
28 Jul 2016

First version publication date 
28 Jul 2016

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


Trial identification


Sponsor protocol code 
CCD1206PR0088


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT02127866  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
Chiesi Farmaceutici S.p.A.


Sponsor organisation address 
Via Palermo 26/A, Parma, Italy, 43122


Public contact 
Clinical Trial Transparency, CHIESI FARMACEUTICI S.p.A, clinicalTrials_info@chiesi.com


Scientific contact 
Clinical Trial Transparency, CHIESI FARMACEUTICI S.p.A, ClinicalTrial_info@chiesi.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 
08 Mar 2015


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
08 Mar 2015


Global end of trial reached? 
Yes


Global end of trial date 
08 Mar 2015


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
To evaluate the efficacy of a free combination of CHF 5259 (glycopyrrolate bromide [GB]) at 3 dose levels plus Foster 100/6 µg (fixed combination of beclomethasone dipropionate [BDP] plus formoterol [FF]) in a pressurised metered dose inhaler by comparison with Foster 100/6 µg in terms of FEV1 AUC012h normalised by time on Day 42.


Protection of trial subjects 
The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.


Background therapy 
  
Evidence for comparator 
Foster® 100/6µg (fixed combination of beclometasone dipropionate plus formoterol) administered via pMDI.  
Actual start date of recruitment 
11 Apr 2014


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
No


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
United Kingdom: 2


Country: Number of subjects enrolled 
Bulgaria: 48


Country: Number of subjects enrolled 
Germany: 35


Country: Number of subjects enrolled 
Hungary: 59


Country: Number of subjects enrolled 
Italy: 5


Country: Number of subjects enrolled 
Poland: 62


Worldwide total number of subjects 
211


EEA total number of subjects 
211


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) 
186


From 65 to 84 years 
25


85 years and over 
0



Recruitment


Recruitment details 
This multinational study was conducted at 44 clinical sites (43 active) in 6 countries. The recruitment took place in: Bulgaria (10 sites) Germany (8 sites) Hungary (7 sites) Italy (5 sites: 4 active and 1 nonactive) Poland (12 sites) UK (2 sites)  
Preassignment


Screening details 
A total of 322 patients were screened, of whom 211 were randomised to one of the following treatment sequence groups: •Sequence ACB: n = 53; •Sequence BDC: n = 53; •Sequence CAD: n = 53; •Sequence DBA: n = 52. 201 (95.3%) patients completed the study.  
Period 1


Period 1 title 
Overall trial by sequence (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Subject, Investigator, Monitor, Data analyst, Carer  
Blinding implementation details 
To maintain the blind during the treatment period, patients inhaled study medication from four identical white canisters daily, regardless of treatment regimen. The randomisation list was provided to the labelling facility but was not available to patients, investigators, monitors or employees of CROMSOURCE involved in the management of the trial before unblinding of the data, unless in case of emergency. The Sponsor’s clinical team was also blinded during the study.


Arms


Are arms mutually exclusive 
Yes


Arm title

Sequence ACB  
Arm description 
Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg.  
Arm type 
Experimental  
Investigational medicinal product name 
CHF 5259 pMDI


Investigational medicinal product code 

Other name 
glycopyrronium bromide [GB]


Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
• Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg;
• Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg;
• Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.


Investigational medicinal product name 
Foster® 100/6 μg pMDI


Investigational medicinal product code 

Other name 
fixed dose combination [FDC] of beclometasone dipropionate [BDP] plus formoterol [FF]


Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
• Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg;
• Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg;
• Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.


Arm title

Sequence BDC  
Arm description 
Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg. Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.  
Arm type 
Experimental  
Investigational medicinal product name 
CHF 5259 pMDI


Investigational medicinal product code 

Other name 
glycopyrronium bromide [GB]


Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
• Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg;
• Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg; or
• Treatment D: two puffs of CHF 5259 placebo BID (plus Foster alone).


Investigational medicinal product name 
Foster® 100/6 μg pMDI


Investigational medicinal product code 

Other name 
fixed dose combination [FDC] of beclometasone dipropionate [BDP] plus formoterol [FF]


Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
• Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg;
• Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.
• Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.


Arm title

Sequence CAD  
Arm description 
Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.  
Arm type 
Experimental  
Investigational medicinal product name 
CHF 5259 pMDI


Investigational medicinal product code 

Other name 
glycopyrronium bromide [GB]


Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
• Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg;
• Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg; or
• Treatment D: two puffs of CHF 5259 placebo BID (plus Foster alone).


Investigational medicinal product name 
Foster® 100/6 μg pMDI


Investigational medicinal product code 

Other name 
fixed dose combination [FDC] of beclometasone dipropionate [BDP] plus formoterol [FF]


Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
• Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg;
• Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.
• Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.


Arm title

Sequence DBA  
Arm description 
Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg; Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg.  
Arm type 
Experimental  
Investigational medicinal product name 
CHF 5259 pMDI


Investigational medicinal product code 

Other name 
glycopyrronium bromide [GB]


Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
• Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg;
• Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg;
• Treatment D: two puffs of CHF 5259 placebo BID (plus Foster alone).


Investigational medicinal product name 
Foster® 100/6 μg pMDI


Investigational medicinal product code 

Other name 
fixed dose combination [FDC] of beclometasone dipropionate [BDP] plus formoterol [FF]


Pharmaceutical forms 
Inhalation solution


Routes of administration 
Inhalation use


Dosage and administration details 
• Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg;
• Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg;
• Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.





Baseline characteristics reporting groups


Reporting group title 
Sequence ACB


Reporting group description 
Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg.  
Reporting group title 
Sequence BDC


Reporting group description 
Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg. Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.  
Reporting group title 
Sequence CAD


Reporting group description 
Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.  
Reporting group title 
Sequence DBA


Reporting group description 
Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg; Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg.  



End points reporting groups


Reporting group title 
Sequence ACB


Reporting group description 
Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg.  
Reporting group title 
Sequence BDC


Reporting group description 
Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg. Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.  
Reporting group title 
Sequence CAD


Reporting group description 
Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.  
Reporting group title 
Sequence DBA


Reporting group description 
Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg; Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg.  
Subject analysis set title 
Treatment A  ITT population


Subject analysis set type 
Intentiontotreat  
Subject analysis set description 
IntentiontoTreat (ITT) population: all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after the Baseline were included in the ITT population.


Subject analysis set title 
Treatment A  safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Safety population: all randomised patients who received at least one dose of study treatment were included in the safety population.


Subject analysis set title 
Treatment B  ITT population


Subject analysis set type 
Intentiontotreat  
Subject analysis set description 
IntentiontoTreat (ITT) population: all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after the Baseline were included in the ITT population.


Subject analysis set title 
Treatment B  safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Safety population: all randomised patients who received at least one dose of study treatment were included in the safety population.


Subject analysis set title 
Treatment C  ITT population


Subject analysis set type 
Intentiontotreat  
Subject analysis set description 
IntentiontoTreat (ITT) population: all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after the Baseline were included in the ITT population.


Subject analysis set title 
Treatment C  safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Safety population: all randomised patients who received at least one dose of study treatment were included in the safety population.


Subject analysis set title 
Treatment D  ITT population


Subject analysis set type 
Intentiontotreat  
Subject analysis set description 
IntentiontoTreat (ITT) population: all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after the Baseline were included in the ITT population.


Subject analysis set title 
Treatment D  safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Safety population: all randomised patients who received at least one dose of study treatment were included in the safety population.



End point title 
FEV1 AUC012h normalised by time on Day 42  
End point description 
AUC012= area under the curve between the time 0 and 12 hours.
Postdose FEV1 on Day 42 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h poststudy drug intake. The baseline FEV1 was the average FEV1 recorded on Day 1 at 45 and 10 minutes prior to study intake.


End point type 
Primary


End point timeframe 
On Day 42




Notes [1]  This is the actual number of patients on which the analysis was performed. [2]  This is the actual number of patients on which the analysis was performed. [3]  This is the actual number of patients on which the analysis was performed. [4]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[5]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.059


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.021  
upper limit 
0.096  
Notes [5]  FEV1 AUC012h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 predose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each dose level of the free combination and Foster alone will be calculated with their simultaneous 95% confidence intervals (CIs) and pvalues. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[6]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.084


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.047  
upper limit 
0.121  
Notes [6]  FEV1 AUC012h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 predose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each dose level of the free combination and Foster alone will be calculated with their simultaneous 95% confidence intervals (CIs) and pvalues. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[7]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.084


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.047  
upper limit 
0.121  
Notes [7]  FEV1 AUC012h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 predose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each dose level of the free combination and Foster alone will be calculated with their simultaneous 95% confidence intervals (CIs) and pvalues. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=299 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
299


Analysis specification 
Prespecified


Analysis type 
superiority ^{[8]}  
Pvalue 
= 0.113  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.025


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.006  
upper limit 
0.057  
Notes [8]  FEV1 AUC012h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 predose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each higher dose of the free combination (Treatment B and Treatment C) and the lowest dose of the free combination (Treatment A) will be calculated with their simultaneous 95% CIs and pvalues. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[9]}  
Pvalue 
= 0.106  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.026


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.006  
upper limit 
0.057  
Notes [9]  FEV1 AUC012h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 predose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each higher dose of the free combination (Treatment B and Treatment C) and the lowest dose of the free combination (Treatment A) will be calculated with their simultaneous 95% CIs and pvalues. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[10]}  
Pvalue 
= 0.983  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.031  
upper limit 
0.031  
Notes [10]  FEV1 AUC012h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 predose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each higher dose of the free combination (Treatment B and Treatment C) and the lowest dose of the free combination (Treatment A) will be calculated with their simultaneous 95% CIs and pvalues. 


End point title 
Change from baseline in peak FEV1 on Day 42  
End point description 
The maximum FEV1 value obtained between 15 minutes and 12 hours postdose is the peak FEV1.
Postdose FEV1 on Day 42 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h poststudy drug intake.
Baseline is the average of the FEV1 predose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).


End point type 
Secondary


End point timeframe 
On Day 42.




Notes [11]  This is the actual number of patients on which the analysis was performed. [12]  This is the actual number of patients on which the analysis was performed. [13]  This is the actual number of patients on which the analysis was performed. [14]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[15]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
least square mean difference  
Point estimate 
0.06


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.022  
upper limit 
0.098  
Notes [15]  The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[16]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.091


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.054  
upper limit 
0.128  
Notes [16]  The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[17]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.076


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.038  
upper limit 
0.113  
Notes [17]  The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable. 

Statistical analysis title 
treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[18]}  
Pvalue 
= 0.051  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.031


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0.062  
Notes [18]  The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[19]}  
Pvalue 
= 0.32  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.016


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.015  
upper limit 
0.047  
Notes [19]  The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[20]}  
Pvalue 
= 0.332  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.015


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.046  
upper limit 
0.016  
Notes [20]  The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable 


End point title 
FEV1 AUC03h normalised by time on Day 1  
End point description 
AUC03h = area under the curve between time 0 and 3 hours.
The predose and postdose lung function assessments were recorded under supervision at the following timings:
•Predose FEV1 on Day 1 at 45 and 10 minutes prior to study drug intake (baseline FEV1);
•Postdose FEV1 on Day 1 of each treatment period: at 15’; 30’; 45’; 1h; 2h; 3h poststudy drug intake.


End point type 
Secondary


End point timeframe 
On Day 1




Notes [21]  This is the actual number of patients on which the analysis was performed. [22]  This is the actual number of patients on which the analysis was performed. [23]  This is the actual number of patients on which the analysis was performed. [24]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[25]}  
Pvalue 
= 0.002  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.049


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.019  
upper limit 
0.079  
Notes [25]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment D  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[26]}  
Pvalue 
= 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.049


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.019  
upper limit 
0.079  
Notes [26]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[27]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.053


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.023  
upper limit 
0.083  
Notes [27]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[28]}  
Pvalue 
= 0.995  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.03  
upper limit 
0.03  
Notes [28]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[29]}  
Pvalue 
= 0.778  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.004


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.026  
upper limit 
0.034  
Notes [29]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
308


Analysis specification 
Prespecified


Analysis type 
superiority ^{[30]}  
Pvalue 
= 0.771  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.004


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.025  
upper limit 
0.034  
Notes [30]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates 


End point title 
FEV1 AUC03h normalised by time on Day 42  
End point description 
AUC03h = area under the curve between time 0 and 3 hours.
The predose and postdose lung function assessments were recorded under supervision at the following timings:
•Predose FEV1 on Day 1 at 45 and 10 minutes prior to study drug intake (baseline FEV1);
•Postdose FEV1 on Day 42 of each treatment period: at 15’; 30’; 45’; 1h; 2h; 3h poststudy drug intake.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [31]  This is the actual number of patients on which the analysis was performed. [32]  This is the actual number of patients on which the analysis was performed. [33]  This is the actual number of patients on which the analysis was performed. [34]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[35]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.056


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.024  
upper limit 
0.089  
Notes [35]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[36]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.092


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.06  
upper limit 
0.124  
Notes [36]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[37]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.089


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.057  
upper limit 
0.122  
Notes [37]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[38]}  
Pvalue 
= 0.029  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.036


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.004  
upper limit 
0.069  
Notes [38]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[39]}  
Pvalue 
= 0.044  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.033


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.001  
upper limit 
0.066  
Notes [39]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[40]}  
Pvalue 
= 0.859  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.003


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.035  
upper limit 
0.029  
Notes [40]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 


End point title 
Change from baseline in FEV1 predose on Day 14  
End point description 
The predose morning FEV1 is defined as the mean of the two measurements at 45 and 10 minutes predose.


End point type 
Secondary


End point timeframe 
On Day 14




Notes [41]  This is the actual number of patients on which the analysis was performed. [42]  This is the actual number of patients on which the analysis was performed. [43]  This is the actual number of patients on which the analysis was performed. [44]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[45]}  
Pvalue 
= 0.168  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.031


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.013  
upper limit 
0.075  
Notes [45]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[46]}  
Pvalue 
= 0.016  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.053


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
0.096  
Notes [46]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[47]}  
Pvalue 
= 0.058  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.042


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.001  
upper limit 
0.086  
Notes [47]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[48]}  
Pvalue 
= 0.315  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.022


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.021  
upper limit 
0.066  
Notes [48]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[49]}  
Pvalue 
= 0.607  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.011


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.032  
upper limit 
0.055  
Notes [49]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=310 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
310


Analysis specification 
Prespecified


Analysis type 
superiority ^{[50]}  
Pvalue 
= 0.621  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.011


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.054  
upper limit 
0.032  
Notes [50]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 


End point title 
Change from baseline in FEV1 predose on Day 42  
End point description 
The predose morning FEV1 is defined as the mean of the two measurements at 45 and 10 minutes predose.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [51]  This is the actual number of patients on which the analysis was performed. [52]  This is the actual number of patients on which the analysis was performed. [53]  This is the actual number of patients on which the analysis was performed. [54]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[55]}  
Pvalue 
= 0.484  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.015


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.027  
upper limit 
0.058  
Notes [55]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[56]}  
Pvalue 
= 0.005  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.06


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.018  
upper limit 
0.102  
Notes [56]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[57]}  
Pvalue 
= 0.016  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.052


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
0.094  
Notes [57]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[58]}  
Pvalue 
= 0.038  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.045


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.002  
upper limit 
0.087  
Notes [58]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[59]}  
Pvalue 
= 0.087  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.037


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.005  
upper limit 
0.079  
Notes [59]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
308


Analysis specification 
Prespecified


Analysis type 
superiority ^{[60]}  
Pvalue 
= 0.709  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.008


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.05  
upper limit 
0.034  
Notes [60]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 


End point title 
Change from baseline in through FEV1 at 12 h postdose on Day 1  
End point description 
Trough FEV1 at 12 hours is determined as the average of the 11.5 and 12 hours postdose FEV1 assessments. Baseline value is the mean of the predose measurement of FEV1 at Day 1 of each treatment period recorded at 45 and 10 minutes prior to study drug intake.


End point type 
Secondary


End point timeframe 
On Day 1




Notes [61]  This is the actual number of patients on which the analysis was performed. [62]  This is the actual number of patients on which the analysis was performed. [63]  This is the actual number of patients on which the analysis was performed. [64]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=299 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
299


Analysis specification 
Prespecified


Analysis type 
superiority ^{[65]}  
Pvalue 
= 0.159  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.028


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.011  
upper limit 
0.067  
Notes [65]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[66]}  
Pvalue 
= 0.089  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.033


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.005  
upper limit 
0.072  
Notes [66]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[67]}  
Pvalue 
= 0.008  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.053


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.014  
upper limit 
0.091  
Notes [67]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[68]}  
Pvalue 
= 0.781  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.005


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.033  
upper limit 
0.044  
Notes [68]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[69]}  
Pvalue 
= 0.205  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.025


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.014  
upper limit 
0.063  
Notes [69]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
309


Analysis specification 
Prespecified


Analysis type 
superiority ^{[70]}  
Pvalue 
= 0.32  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.019


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.019  
upper limit 
0.057  
Notes [70]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 


End point title 
Change from baseline in through FEV1 at 12 h postdose on Day 42  
End point description 
Trough FEV1 at 12 hours is determined as the average of the 11.5 and 12 hours postdose FEV1 assessments. Baseline value is the mean of the predose measurement of FEV1 at Day 1 of each treatment period recorded at 45 and 10 minutes prior to study drug intake.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [71]  This is the actual number of patients on which the analysis was performed. [72]  This is the actual number of patients on which the analysis was performed. [73]  This is the actual number of patients on which the analysis was performed. [74]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment D  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[75]}  
Pvalue 
= 0.015  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.046


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.009  
upper limit 
0.083  
Notes [75]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[76]}  
Pvalue 
= 0.008  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.05


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.013  
upper limit 
0.087  
Notes [76]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[77]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.068


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.031  
upper limit 
0.105  
Notes [77]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=299 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
299


Analysis specification 
Prespecified


Analysis type 
superiority ^{[78]}  
Pvalue 
= 0.832  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.004


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.033  
upper limit 
0.041  
Notes [78]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[79]}  
Pvalue 
= 0.234  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.022


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.015  
upper limit 
0.059  
Notes [79]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[80]}  
Pvalue 
= 0.328  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.018


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.018  
upper limit 
0.055  
Notes [80]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 


End point title 
Change from baseline in peak FEV1 on Day 1  
End point description 
The peak FEV1 is the maximum FEV1 value obtained between 15 minutes and 12 hours postdose.
Postdose FEV1 on Day 1 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h poststudy drug intake.
Baseline is the average of the FEV1 predose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).


End point type 
Secondary


End point timeframe 
On Day 1




Notes [81]  This is the actual number of patients on which the analysis was performed. [82]  This is the actual number of patients on which the analysis was performed. [83]  This is the actual number of patients on which the analysis was performed. [84]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[85]}  
Pvalue 
= 0.002  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.058


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.022  
upper limit 
0.094  
Notes [85]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[86]}  
Pvalue 
= 0.012  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.045


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
0.081  
Notes [86]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
309


Analysis specification 
Prespecified


Analysis type 
superiority ^{[87]}  
Pvalue 
= 0.004  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.053


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.017  
upper limit 
0.088  
Notes [87]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[88]}  
Pvalue 
= 0.492  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.012


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.048  
upper limit 
0.023  
Notes [88]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a Crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[89]}  
Pvalue 
= 0.772  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.005


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.041  
upper limit 
0.03  
Notes [89]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and Baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
309


Analysis specification 
Prespecified


Analysis type 
superiority ^{[90]}  
Pvalue 
= 0.689  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.007


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.028  
upper limit 
0.042  
Notes [90]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 


End point title 
FEV1 AUC012h normalised by time on Day 1  
End point description 
AUC012h = area under the curve between time 0 and 12 hours.
Postdose FEV1 on Day 1 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h poststudy drug intake. The baseline FEV1 was the average FEV1 recorded on Day 1 at 45 and 10 minutes prior to study intake.


End point type 
Secondary


End point timeframe 
On Day 1




Notes [91]  This is the actual number of patients on which the analysis was performed. [92]  This is the actual number of patients on which the analysis was performed. [93]  This is the actual number of patients on which the analysis was performed. [94]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=297 (subject analysis set) is an innate error of the EudraCT database system


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
297


Analysis specification 
Prespecified


Analysis type 
superiority ^{[95]}  
Pvalue 
= 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.051


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.02  
upper limit 
0.082  
Notes [95]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=300 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
300


Analysis specification 
Prespecified


Analysis type 
superiority ^{[96]}  
Pvalue 
= 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.052


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.021  
upper limit 
0.083  
Notes [96]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[97]}  
Pvalue 
< 0.001  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.065


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.034  
upper limit 
0.096  
Notes [97]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[98]}  
Pvalue 
= 0.972  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.001


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.03  
upper limit 
0.031  
Notes [98]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[99]}  
Pvalue 
= 0.375  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.017  
upper limit 
0.045  
Notes [99]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[100]}  
Pvalue 
= 0.389  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.013


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.017  
upper limit 
0.044  
Notes [100]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 


End point title 
FEV1 percentage of predicted normal value at each time point postdose on Day 1 and mean changes from Baseline  
End point description 
Baseline is the average of the predose measurements of FEV1 Percentage of Predicted Normal Value.
Measurements were done: 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11h and 30 min, 12h postdose on Day 1.
Only data about the change from baseline at the last timepoint (12h postdose) of the Day 1 are reported in the database.
For the data about the other timepoints on Day 1 see pdf attached.


End point type 
Secondary


End point timeframe 
On Day 1




Attachments 
Untitled (Filename: FEV1 Change D1.pdf) Untitled (Filename: FEV1 Value D1.pdf) 

Notes [101]  This is the actual number of patients on which the analysis was performed. [102]  This is the actual number of patients on which the analysis was performed. [103]  This is the actual number of patients on which the analysis was performed. [104]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
FEV1 percentage of predicted normal value at 2h postdose on Day 14 and mean changes from Baseline  
End point description 
Baseline is the average of the predose measurements of FEV1 Percentage of Predicted Normal Value.
Measurements were done 2h postdose on Day 14.
Only the change from baseline (not the actual value) is reported in the database. For the actual values on the same endpoint , please see the pdf attached.


End point type 
Secondary


End point timeframe 
On Day 14




Attachments 
Untitled (Filename: FEV1 Value D14.pdf) 

Notes [105]  This is the actual number of patients on which the analysis was performed. [106]  This is the actual number of patients on which the analysis was performed. [107]  This is the actual number of patients on which the analysis was performed. [108]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
FEV1 percentage of predicted normal value at each time point postdose on Day 42 and mean changes from Baseline  
End point description 
Baseline is the average of the predose measurements of FEV1 Percentage of Predicted Normal Value.
Measurements were done: 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11h and 30 min, 12h postdose on Day 42.
Only data about the change from baseline at the last timepoint (12h postdose) of the Day 42 are reported in the database.
For the data about the other timepoints on Day 42, please see the pdf attached.


End point type 
Secondary


End point timeframe 
On Day 42




Attachments 
Untitled (Filename: FEV1 changes D42.pdf) Untitled (Filename: FEV1 Value D42.pdf) 

Notes [109]  This is the actual number of patients on which the analysis was performed. [110]  This is the actual number of patients on which the analysis was performed. [111]  This is the actual number of patients on which the analysis was performed. [112]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
FEV1 at 2 hours postdose on Day 14  
End point description 
Post dose FEV1 on Day 14 of each treatment period was recorded at 2h poststudy drug intake.


End point type 
Secondary


End point timeframe 
On Day 14




Notes [113]  This is the actual number of patients on which the analysis was performed. [114]  This is the actual number of patients on which the analysis was performed. [115]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
Change from baseline in FEV1 2 Hours PostDose on Day 14  
End point description 
Baseline is the average of the predose measurements FEV1 measurements that were recorded at 45 and 10 minutes prior to study intake.
Post dose FEV1 on Day 14 of each treatment period was recorded at 2h poststudy drug intake.


End point type 
Secondary


End point timeframe 
On Day 14




Notes [116]  This is the actual number of patients on which the analysis was performed. [117]  This is the actual number of patients on which the analysis was performed. [118]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
Average daily morning PEF  
End point description 
Epeakflow meter/ediary was completed at home on a daily basis morning and evening (daily download of the epeakflow meter/ediary). During the two washout periods, only the compliance to the washout medication was collected.
During the runin period and the three treatment periods, PEF (L/min) was monitored twice daily before the intake of the runin medication or study medication. Morning measurements were done approximately between 7:00 am and 9:00 am and evening measurements approximately between 7:00 pm and 9:00 pm. An alarm reminded the patients to perform measurements. During each measurement session, the patient performed three blows and data were recorded in the device.


End point type 
Secondary


End point timeframe 
Daily during runin and treatment periods.




Notes [119]  This is the actual number of patients on which the analysis was performed. [120]  This is the actual number of patients on which the analysis was performed. [121]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[122]}  
Pvalue 
< 0.001  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
10.07


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.52  
upper limit 
14.63  
Notes [122]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[123]}  
Pvalue 
< 0.001  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
11.12


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.6  
upper limit 
15.64  
Notes [123]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[124]}  
Pvalue 
< 0.001  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
9.49


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.98  
upper limit 
14  
Notes [124]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[125]}  
Pvalue 
= 0.649  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
1.05


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.47  
upper limit 
5.57  
Notes [125]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system


Comparison groups 
Treatment A  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[126]}  
Pvalue 
= 0.798  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.59


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.09  
upper limit 
3.92  
Notes [126]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
308


Analysis specification 
Prespecified


Analysis type 
superiority ^{[127]}  
Pvalue 
= 0.474  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
1.64


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.12  
upper limit 
2.85  
Notes [127]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 


End point title 
Average daily evening PEF  
End point description 
Epeakflow meter/ediary was completed at home on a daily basis morning and evening (daily download of the epeakflow meter/ediary). During the two washout periods, only the compliance to the washout medication was collected.
During the runin period and the three treatment periods, PEF (L/min) was monitored twice daily before the intake of the runin medication or study medication. Morning measurements were done approximately between 7:00 am and 9:00 am and evening measurements approximately between 7:00 pm and 9:00 pm. An alarm reminded the patients to perform measurements. During each measurement session, the patient performed three blows and data were recorded in the device.


End point type 
Secondary


End point timeframe 
Daily during runin and treatment periods.




Notes [128]  This is the actual number of patients on which the analysis was performed. [129]  This is the actual number of patients on which the analysis was performed. [130]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[131]}  
Pvalue 
< 0.001  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
11.94


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.41  
upper limit 
16.47  
Notes [131]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[132]}  
Pvalue 
< 0.001  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
14.22


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
9.72  
upper limit 
18.72  
Notes [132]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[133]}  
Pvalue 
< 0.001  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
11.94


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.44  
upper limit 
16.44  
Notes [133]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[134]}  
Pvalue 
= 0.32  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
2.29


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.23  
upper limit 
6.8  
Notes [134]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[135]}  
Pvalue 
= 0.999  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.49  
upper limit 
4.5  
Notes [135]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
308


Analysis specification 
Prespecified


Analysis type 
superiority ^{[136]}  
Pvalue 
= 0.317  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
2.28


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.76  
upper limit 
2.2  
Notes [136]  This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects. 


End point title 
Change from baseline in predose FVC on Day 14  
End point description 
Predose FVC was recorded on Day 14 at 45 minutes and 10 minutes prior to study drug intake.


End point type 
Secondary


End point timeframe 
On Day 14




Notes [137]  This is the actual number of patients on which the analysis was performed. [138]  This is the actual number of patients on which the analysis was performed. [139]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[140]}  
Pvalue 
= 0.645  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.044  
upper limit 
0.072  
Notes [140]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[141]}  
Pvalue 
= 0.01  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.076


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.018  
upper limit 
0.133  
Notes [141]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[142]}  
Pvalue 
= 0.508  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.019


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.038  
upper limit 
0.077  
Notes [142]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[143]}  
Pvalue 
= 0.035  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.062


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.004  
upper limit 
0.12  
Notes [143]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[144]}  
Pvalue 
= 0.842  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.006


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.052  
upper limit 
0.063  
Notes [144]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=310 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
310


Analysis specification 
Prespecified


Analysis type 
superiority ^{[145]}  
Pvalue 
= 0.054  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.056


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.113  
upper limit 
0.001  
Notes [145]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 


End point title 
Change from baseline in predose FVC on Day 42  
End point description 
Predose FVC was recorded on Day 42 at 45 minutes and 10 minutes prior to study drug intake.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [146]  This is the actual number of patients on which the analysis was performed. [147]  This is the actual number of patients on which the analysis was performed. [148]  This is the actual number of patients on which the analysis was performed. [149]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
TReatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[150]}  
Pvalue 
= 0.503  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.017


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.034  
upper limit 
0.068  
Notes [150]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and Baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[151]}  
Pvalue 
= 0.046  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.052


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.001  
upper limit 
0.102  
Notes [151]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[152]}  
Pvalue 
= 0.118  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.04


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
0.091  
Notes [152]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[153]}  
Pvalue 
= 0.188  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.034


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.017  
upper limit 
0.085  
Notes [153]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305(subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[154]}  
Pvalue 
= 0.374  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.023


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.028  
upper limit 
0.074  
Notes [154]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
308


Analysis specification 
Prespecified


Analysis type 
superiority ^{[155]}  
Pvalue 
= 0.663  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.011


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.062  
upper limit 
0.039  
Notes [155]  This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates. 


End point title 
Change from baseline in peak FVC on Day 1  
End point description 
The peak FVC is the maximum FVC value obtained between 15 minutes and 12 hours postdose.
Postdose FVC on Day 1 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h poststudy drug intake.
Baseline is the average of the FVC predose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).


End point type 
Secondary


End point timeframe 
On Day 1.




Notes [156]  This is the actual number of patients on which the analysis was performed. [157]  This is the actual number of patients on which the analysis was performed. [158]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[159]}  
Pvalue 
= 0.085  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.037


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.005  
upper limit 
0.079  
Notes [159]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[160]}  
Pvalue 
= 0.502  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.028  
upper limit 
0.056  
Notes [160]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=309 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
309


Analysis specification 
Prespecified


Analysis type 
superiority ^{[161]}  
Pvalue 
= 0.16  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.03


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.012  
upper limit 
0.072  
Notes [161]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment B vs treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[162]}  
Pvalue 
= 0.285  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.023


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.065  
upper limit 
0.019  
Notes [162]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[163]}  
Pvalue 
= 0.735  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.007


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.049  
upper limit 
0.035  
Notes [163]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=309 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
309


Analysis specification 
Prespecified


Analysis type 
superiority ^{[164]}  
Pvalue 
= 0.46  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.016


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.026  
upper limit 
0.057  
Notes [164]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 


End point title 
Change from baseline in peak FVC on Day 42  
End point description 
The peak FVC is the maximum FVC value obtained between 15 minutes and 12 hours postdose.
Postdose FVC on Day 1 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h poststudy drug intake.
Baseline is the average of the FVC predose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).


End point type 
Secondary


End point timeframe 
On Day 42.




Notes [165]  This is the actual number of patients on which the analysis was performed. [166]  This is the actual number of patients on which the analysis was performed. [167]  This is the actual number of patients on which the analysis was performed. [168]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[169]}  
Pvalue 
= 0.4  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.02


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.026  
upper limit 
0.066  
Notes [169]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[170]}  
Pvalue 
= 0.043  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.047


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.001  
upper limit 
0.092  
Notes [170]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[171]}  
Pvalue 
= 0.029  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.051


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.005  
upper limit 
0.097  
Notes [171]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=301 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
301


Analysis specification 
Prespecified


Analysis type 
superiority ^{[172]}  
Pvalue 
= 0.245  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.027


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.019  
upper limit 
0.073  
Notes [172]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[173]}  
Pvalue 
= 0.179  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.031


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.014  
upper limit 
0.077  
Notes [173]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an
innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[174]}  
Pvalue 
= 0.859  
Method 
ANCOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.004


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.041  
upper limit 
0.05  
Notes [174]  The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes predose FVC at Day 1) as covariate. 


End point title 
Change from baseline in FVC at each time point postdose on Day 1  
End point description 
The baseline FVC is the mean of the predose measurements recorded on Day 1 of each treatment period.
Postdose FVC was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h poststudy drug intake on Day 1.
Only change from baseline at the last timepoint (12h postdose) on Day 1 is reported in the system. For the data on the other timepoints on the same day see pdf attached.


End point type 
Secondary


End point timeframe 
On Day 1




Attachments 
Untitled (Filename: FVC Change D1.pdf) 

Notes [175]  This is the actual number of patients on which the analysis was performed. [176]  This is the actual number of patients on which the analysis was performed. [177]  This is the actual number of patients on which the analysis was performed. [178]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
Change from baseline in FVC at 2h postdose on Day 14  
End point description 
The baseline FVC is the mean of the predose measurements recorded on Day 1 of each treatment period.
Postdose FVC was recorded at 2h on Day 14.


End point type 
Secondary


End point timeframe 
On Day 14




Attachments 
Untitled (Filename: FVC Change D14.pdf) 

Notes [179]  This is the actual number of patients on which the analysis was performed. [180]  This is the actual number of patients on which the analysis was performed. [181]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
Change from baseline in FVC at each time point postdose on Day 42  
End point description 
The baseline FVC is the mean of the predose measurements recorded on Day 1 of each treatment period.
Postdose FVC was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h poststudy drug intake on Day 42.
Only change from baseline at the last timepoint (12h postdose) on Day 42 is reported in the system. For the data on the other timepoints on the same day, please see the pdf attached.


End point type 
Secondary


End point timeframe 
On Day 42.




Attachments 
Untitled (Filename: FVC Change D42.pdf) 

Notes [182]  This is the actual number of patients on which the analysis was performed. [183]  This is the actual number of patients on which the analysis was performed. [184]  This is the actual number of patients on which the analysis was performed. [185]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
Average total daily asthma symptoms, nighttime  
End point description 
The average of daily asthma symptoms (morning/ evening) of a subgroup (Cough, Wheeze, Chest Tightness, Breathlessness) is the mean value of all morning/ evening measurements of that subgroup.
Results on the average total daily asthma symptoms score (nighttime) during the treatment period are presented for the ITT population.


End point type 
Secondary


End point timeframe 
At visit 1 (Screening Visit) and at the first and third visit of each tratment period.




Notes [186]  This is the actual number of patients on which the analysis was performed. [187]  This is the actual number of patients on which the analysis was performed. [188]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[189]}  
Pvalue 
= 0.77  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.022


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.173  
upper limit 
0.128  
Notes [189]  This secondary efficacy variables were analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[190]}  
Pvalue 
= 0.682  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.031


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.181  
upper limit 
0.118  
Notes [190]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[191]}  
Pvalue 
= 0.85  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.164  
upper limit 
0.135  
Notes [191]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[192]}  
Pvalue 
= 0.909  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.009


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.158  
upper limit 
0.141  
Notes [192]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[193]}  
Pvalue 
= 0.915  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.008


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.141  
upper limit 
0.157  
Notes [193]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
309


Analysis specification 
Prespecified


Analysis type 
superiority ^{[194]}  
Pvalue 
= 0.825  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.017


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.132  
upper limit 
0.165  
Notes [194]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 


End point title 
Average total daily asthma symptoms, daytime  
End point description 
The average of daily asthma symptoms (morning/ evening) of a subgroup (Cough, Wheeze, Chest Tightness, Breathlessness) is the mean value of all morning/ evening measurements of that subgroup.
Results on the average total daily asthma symptoms score (daytime) during the treatment period are presented for the ITT population.


End point type 
Secondary


End point timeframe 
At visit 1 (Screening Visit) and at the first and third visit of each tratment period.




Notes [195]  This is the actual number of patients on which the analysis was performed. [196]  This is the actual number of patients on which the analysis was performed. [197]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[198]}  
Pvalue 
= 0.917  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.008


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.165  
upper limit 
0.148  
Notes [198]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[199]}  
Pvalue 
= 0.792  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.021


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.134  
upper limit 
0.176  
Notes [199]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[200]}  
Pvalue 
= 0.656  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.035


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.12  
upper limit 
0.19  
Notes [200]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[201]}  
Pvalue 
= 0.713  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.029


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.127  
upper limit 
0.185  
Notes [201]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[202]}  
Pvalue 
= 0.582  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.043


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.112  
upper limit 
0.199  
Notes [202]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
308


Analysis specification 
Prespecified


Analysis type 
superiority ^{[203]}  
Pvalue 
= 0.855  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.14  
upper limit 
0.169  
Notes [203]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 


End point title 
Percentage of asthma control days  
End point description 
The percentage is calculated as the number of asthma control days / number of days with available data.


End point type 
Secondary


End point timeframe 
Measured between the first and the third visit of each treatment period.




Notes [204]  This is the actual number of patients on which the analysis was performed. [205]  This is the actual number of patients on which the analysis was performed. [206]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[207]}  
Pvalue 
= 0.481  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
1.3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.3  
upper limit 
4.8  
Notes [207]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[208]}  
Pvalue 
= 0.484  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
1.3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.3  
upper limit 
4.8  
Notes [208]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[209]}  
Pvalue 
= 0.562  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
1


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.5  
upper limit 
4.6  
Notes [209]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[210]}  
Pvalue 
= 0.99  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.6  
upper limit 
3.5  
Notes [210]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[211]}  
Pvalue 
= 0.896  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.8  
upper limit 
3.3  
Notes [211]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
309


Analysis specification 
Prespecified


Analysis type 
superiority ^{[212]}  
Pvalue 
= 0.906  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.7  
upper limit 
3.3  
Notes [212]  This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects. 


End point title 
Average use of rescue medication (number of puffs/day)  
End point description 
The average use of rescue medication (number of puffs per day) is determined as the total number of puffs of rescue mediation taken / number of days with available data.


End point type 
Secondary


End point timeframe 
Daily during runin/washout & treatment periods.




Notes [213]  This is the actual number of patients on which the analysis was performed. [214]  This is the actual number of patients on which the analysis was performed. [215]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[216]}  
Pvalue 
= 0.55  
Method 
ANOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.2  
upper limit 
0.1  
Notes [216]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment D  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[217]}  
Pvalue 
= 0.883  
Method 
ANOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.1  
Notes [217]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment D  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[218]}  
Pvalue 
= 0.325  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0.1


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.2  
upper limit 
0.1  
Notes [218]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[219]}  
Pvalue 
= 0.649  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.1  
Notes [219]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[220]}  
Pvalue 
= 0.701  
Method 
ANOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.1  
Notes [220]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
309


Analysis specification 
Prespecified


Analysis type 
superiority ^{[221]}  
Pvalue 
= 0.4  
Method 
ANOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.2  
upper limit 
0.1  
Notes [221]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 


End point title 
Average use of rescue medication (number of times/day)  
End point description 
The average use of rescue medication (number of times per day) is determined as the total number of times of rescue medication taken/ number of days with available data.


End point type 
Secondary


End point timeframe 
Daily during runin/washout & treatment periods.




Notes [222]  This is the actual number of patients on which the analysis was performed. [223]  This is the actual number of patients on which the analysis was performed. [224]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
304


Analysis specification 
Prespecified


Analysis type 
superiority ^{[225]}  
Pvalue 
= 0.95  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.1  
Notes [225]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment D  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[226]}  
Pvalue 
= 0.744  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.1  
Notes [226]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment D  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[227]}  
Pvalue 
= 0.629  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.1  
Notes [227]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
306


Analysis specification 
Prespecified


Analysis type 
superiority ^{[228]}  
Pvalue 
= 0.793  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.1  
Notes [228]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[229]}  
Pvalue 
= 0.674  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.1  
Notes [229]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
309


Analysis specification 
Prespecified


Analysis type 
superiority ^{[230]}  
Pvalue 
= 0.875  
Method 
ANOVA  
Parameter type 
adjusted mean difference  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.1  
Notes [230]  The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments. 


End point title 
Change from baseline in ACQ total score on Day 42  
End point description 
Baseline is the calculated Asthma Control Questionnaire (ACQ) score of Day 1 of the respective treatment period.


End point type 
Secondary


End point timeframe 
On Day 42.




Notes [231]  This is the actual number of patients on which the analysis was performed. [232]  This is the actual number of patients on which the analysis was performed. [233]  This is the actual number of patients on which the analysis was performed. [234]  This is the actual number of patients on which the analysis was performed. 

Statistical analysis title 
Treatment A vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment D  ITT population


Number of subjects included in analysis 
302


Analysis specification 
Prespecified


Analysis type 
superiority ^{[235]}  
Pvalue 
= 0.835  
Method 
ANCOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0.011


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.116  
upper limit 
0.093  
Notes [235]  The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done. 

Statistical analysis title 
Treatment B vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment D  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[236]}  
Pvalue 
= 0.583  
Method 
ANCOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0.029


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.132  
upper limit 
0.074  
Notes [236]  The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done. 

Statistical analysis title 
Treatment C vs Treatment D  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment D  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
307


Analysis specification 
Prespecified


Analysis type 
superiority ^{[237]}  
Pvalue 
= 0.727  
Method 
ANCOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0.018


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.122  
upper limit 
0.085  
Notes [237]  The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done. 

Statistical analysis title 
Treatment B vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment B  ITT population v Treatment A  ITT population


Number of subjects included in analysis 
303


Analysis specification 
Prespecified


Analysis type 
superiority ^{[238]}  
Pvalue 
= 0.737  
Method 
ANCOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0.018


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.122  
upper limit 
0.086  
Notes [238]  The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done. 

Statistical analysis title 
Treatment C vs Treatment A  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment A  ITT population v Treatment C  ITT population


Number of subjects included in analysis 
305


Analysis specification 
Prespecified


Analysis type 
superiority ^{[239]}  
Pvalue 
= 0.89  
Method 
ANCOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0.007


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.111  
upper limit 
0.086  
Notes [239]  The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done. 

Statistical analysis title 
Treatment C vs Treatment B  
Statistical analysis description 
In a crossover study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.


Comparison groups 
Treatment C  ITT population v Treatment B  ITT population


Number of subjects included in analysis 
308


Analysis specification 
Prespecified


Analysis type 
superiority ^{[240]}  
Pvalue 
= 0.841  
Method 
ANCOVA  
Parameter type 
Adjusted mean difference  
Point estimate 
0.011


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.093  
upper limit 
0.114  
Notes [240]  The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done. 


End point title 
SBP change from baseline on Day 14  
End point description 
Baseline is the predose measurement on Day 1 in each treatment period.


End point type 
Secondary


End point timeframe 
On Day 14




Notes [241]  This is the actual number of patients on which the analysis was performed. [242]  This is the actual number of patients on which the analysis was performed. [243]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
HR change from baseline postdose on Day 1  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 1




Notes [244]  This is the actual number of patients on which the analysis was performed. [245]  This is the actual number of patients on which the analysis was performed. [246]  This is the actual number of patients on which the analysis was performed. [247]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
PR change from baseline postdose on Day 1  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 1




Notes [248]  This is the actual number of patients on which the analysis was performed. [249]  This is the actual number of patients on which the analysis was performed. [250]  This is the actual number of patients on which the analysis was performed. [251]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
QRS change from baseline postdose on Day 1  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 1




Notes [252]  This is the actual number of patients on which the analysis was performed. [253]  This is the actual number of patients on which the analysis was performed. [254]  This is the actual number of patients on which the analysis was performed. [255]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
QTcF change from baseline postdose on Day 1  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 1




Notes [256]  This is the actual number of patients on which the analysis was performed. [257]  This is the actual number of patients on which the analysis was performed. [258]  This is the actual number of patients on which the analysis was performed. [259]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
SBP change from baseline on Day 42  
End point description 
Baseline is the predose measurement on Day 1 in each treatment period.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [260]  This is the actual number of patients on which the analysis was performed. [261]  This is the actual number of patients on which the analysis was performed. [262]  This is the actual number of patients on which the analysis was performed. [263]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
DBP change from baseline on Day 14  
End point description 
Baseline is the predose measurement on Day 1 in each treatment period.


End point type 
Secondary


End point timeframe 
On Day 14




Notes [264]  This is the actual number of patients on which the analysis was performed. [265]  This is the actual number of patients on which the analysis was performed. [266]  This is the actual number of patients on which the analysis was performed. [267]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
DBP change from baseline on Day 42  
End point description 
Baseline is the predose measurement on Day 1 in each treatment period.


End point type 
Secondary


End point timeframe 
On day 42




Notes [268]  This is the actual number of patients on which the analysis was performed. [269]  This is the actual number of patients on which the analysis was performed. [270]  This is the actual number of patients on which the analysis was performed. [271]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
QTcF change from baseline predose on Day 42  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [272]  This is the actual number of patients on which the analysis was performed. [273]  This is the actual number of patients on which the analysis was performed. [274]  This is the actual number of patients on which the analysis was performed. [275]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
QTcF change from baseline postdose on Day 42  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [276]  This is the actual number of patients on which the analysis was performed. [277]  This is the actual number of patients on which the analysis was performed. [278]  This is the actual number of patients on which the analysis was performed. [279]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
HR change from baseline predose on Day 42  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [280]  This is the actual number of patients on which the analysis was performed. [281]  This is the actual number of patients on which the analysis was performed. [282]  This is the actual number of patients on which the analysis was performed. [283]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
HR change from baseline postdose on Day 42  
End point description 
Baseline is the average of the 3 individual predose values on Day1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On day 42




Notes [284]  This is the actual number of patients on which the analysis was performed. [285]  This is the actual number of patients on which the analysis was performed. [286]  This is the actual number of patients on which the analysis was performed. [287]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
PR change from baseline predose on Day 42  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [288]  This is the actual number of patients on which the analysis was performed. [289]  This is the actual number of patients on which the analysis was performed. [290]  This is the actual number of patients on which the analysis was performed. [291]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
PR change from baseline postdose on Day 42  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [292]  This is the actual number of patients on which the analysis was performed. [293]  This is the actual number of patients on which the analysis was performed. [294]  This is the actual number of patients on which the analysis was performed. [295]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
QRS change from baseline predose on Day 42  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [296]  This is the actual number of patients on which the analysis was performed. [297]  This is the actual number of patients on which the analysis was performed. [298]  This is the actual number of patients on which the analysis was performed. [299]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


End point title 
QRS change from baseline postdose on Day 42  
End point description 
Baseline is the average of the 3 individual predose values on Day 1 in each treatment period.
Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.


End point type 
Secondary


End point timeframe 
On Day 42




Notes [300]  This is the actual number of patients on which the analysis was performed. [301]  This is the actual number of patients on which the analysis was performed. [302]  This is the actual number of patients on which the analysis was performed. [303]  This is the actual number of patients on which the analysis was performed. 

No statistical analyses for this end point 


Adverse events information


Timeframe for reporting adverse events 
At each visit from Visit 1 (Screening) to Visit 10 and, afterwards, to followup.


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
17.0


Reporting groups


Reporting group title 
Treatment A  safety population


Reporting group description 
  
Reporting group title 
Treatment B  safety population


Reporting group description 
  
Reporting group title 
Treatment C  safety population


Reporting group description 
  
Reporting group title 
Treatment D  safety population


Reporting group description 
  


Frequency threshold for reporting nonserious adverse events: 1%  
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