Clinical Trial Results:
A randomised, doubleblind, doubledummy, placebo and activecontrolled, threeway crossover study to evaluate the safety, tolerability and efficacy of 28day inhaled CHF 6001 DPI (1200 microgrammes daily) in subjects with COPD.
Summary


EudraCT number 
201200100525 
Trial protocol 
GB 
Global end of trial date 
25 Oct 2013

Results information


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

First version publication date 
09 Aug 2015

Other versions 
v1 
Version creation reason 

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


Trial identification


Sponsor protocol code 
CCD1201PR0079


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT01730404  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
Chiesi Farmaceutici SpA


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., ClinicalTrials_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 
25 Oct 2013


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
25 Oct 2013


Global end of trial reached? 
Yes


Global end of trial date 
25 Oct 2013


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
The primary objectives of the study are:
 to evaluate the effect of CHF 6001 DPI on biological markers of inflammation in induced sputum and in the blood, and on pulmonary function.
 to evaluate the safety and tolerability of CHF 6001 DPI after 28 days of inhaled dosing.
 to assess the blood PK profile of CHF6001 and its metabolite at steadystate in GOLD stage 23 COPD patients.


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 
  
Actual start date of recruitment 
04 Oct 2012


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: 55


Worldwide total number of subjects 
55


EEA total number of subjects 
55


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) 
43


From 65 to 84 years 
12


85 years and over 
0



Recruitment


Recruitment details 
  
Preassignment


Screening details 
Fiftyfive patients were actually randomised into the study; following the randomization 13 patients were withdrawn due to adverse events (AE), and 5 patients withdrew their consent for participation. All 55 patients were analysed as part of the Safety population. Fiftythree patients were analysed as part of the modified ITT population.  
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 
Carer, Assessor, Subject, Investigator, Monitor, Data analyst  
Arms


Are arms mutually exclusive 
Yes


Arm title

Sequence CRP  
Arm description 
• Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
CHF 6001


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 400 μg administered using Aerolizer® DPI; giving a total dose of 1200 μg of CHF 6001


Investigational medicinal product name 
Roflumilast


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast


Investigational medicinal product name 
CHF 6001 placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 Placebo DPI


Investigational medicinal product name 
Roflumilast placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast Placebo


Arm title

Sequence PCR  
Arm description 
• Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
CHF 6001


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 400 μg administered using Aerolizer® DPI; giving a total dose of 1200 μg of CHF 6001


Investigational medicinal product name 
Roflumilast


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast


Investigational medicinal product name 
CHF 6001 placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 Placebo DPI


Investigational medicinal product name 
Roflumilast placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast Placebo


Arm title

Sequence RPC  
Arm description 
• Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
Roflumilast


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast


Investigational medicinal product name 
Roflumilast placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast Placebo


Investigational medicinal product name 
CHF 6001 placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 Placebo DPI


Investigational medicinal product name 
CHF 6001


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 400 μg ; giving a total dose of 1200 μg of CHF 6001


Arm title

Sequence CPR  
Arm description 
• Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
CHF 6001


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 400 μg; giving a total dose of 1200 μg of CHF 6001


Investigational medicinal product name 
CHF 6001 placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 Placebo DPI


Investigational medicinal product name 
Roflumilast placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast Placebo


Investigational medicinal product name 
Roflumilast


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast


Arm title

Sequence PRC  
Arm description 
• Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
CHF 6001 placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 Placebo DPI


Investigational medicinal product name 
Roflumilast placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast Placebo


Investigational medicinal product name 
Roflumilast


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast


Investigational medicinal product name 
CHF 6001


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 400 μg ; giving a total dose of 1200 μg of CHF 6001


Arm title

Sequence RCP  
Arm description 
• Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
Roflumilast


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast


Investigational medicinal product name 
CHF 6001


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 400 μg ; giving a total dose of 1200 μg of CHF 6001


Investigational medicinal product name 
CHF 6001 placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
3 inhalations of CHF 6001 Placebo DPI


Investigational medicinal product name 
Roflumilast placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
1 tablet Roflumilast Placebo





Baseline characteristics reporting groups


Reporting group title 
Sequence CRP


Reporting group description 
• Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence PCR


Reporting group description 
• Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence RPC


Reporting group description 
• Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence CPR


Reporting group description 
• Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence PRC


Reporting group description 
• Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence RCP


Reporting group description 
• Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  


Subject analysis sets


Subject analysis set title 
Test treatment  Safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
All randomised subjects who will take at least one administration of study medication


Subject analysis set title 
Reference treatment  Safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
All randomised subjects who will take at least one administration of study medication


Subject analysis set title 
Placebo  Safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
All randomised subjects who will take at least one administration of study medication


Subject analysis set title 
Test treatment  mITT population


Subject analysis set type 
Modified intentiontotreat  
Subject analysis set description 
All randomised subjects who take at least one administration of study medication and with at least one postbaseline efficacy assessment


Subject analysis set title 
Reference treatment  mITT population


Subject analysis set type 
Modified intentiontotreat  
Subject analysis set description 
All randomised subjects who take at least one administration of study medication and with at least one postbaseline efficacy assessment.


Subject analysis set title 
Placebo  mITT population


Subject analysis set type 
Modified intentiontotreat  
Subject analysis set description 
All randomised subjects who take at least one administration of study medication and with at least one postbaseline efficacy assessment.


Subject analysis set title 
Test treatment  PK population


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
All subjects from the safety population excluding subjects without any valid PK measurement and with major Protocol deviations affecting the PK evaluations





End points reporting groups


Reporting group title 
Sequence CRP


Reporting group description 
• Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence PCR


Reporting group description 
• Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence RPC


Reporting group description 
• Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence CPR


Reporting group description 
• Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence PRC


Reporting group description 
• Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Reporting group title 
Sequence RCP


Reporting group description 
• Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days runin Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a washout Period of 45 weeks.  
Subject analysis set title 
Test treatment  Safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
All randomised subjects who will take at least one administration of study medication


Subject analysis set title 
Reference treatment  Safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
All randomised subjects who will take at least one administration of study medication


Subject analysis set title 
Placebo  Safety population


Subject analysis set type 
Safety analysis  
Subject analysis set description 
All randomised subjects who will take at least one administration of study medication


Subject analysis set title 
Test treatment  mITT population


Subject analysis set type 
Modified intentiontotreat  
Subject analysis set description 
All randomised subjects who take at least one administration of study medication and with at least one postbaseline efficacy assessment


Subject analysis set title 
Reference treatment  mITT population


Subject analysis set type 
Modified intentiontotreat  
Subject analysis set description 
All randomised subjects who take at least one administration of study medication and with at least one postbaseline efficacy assessment.


Subject analysis set title 
Placebo  mITT population


Subject analysis set type 
Modified intentiontotreat  
Subject analysis set description 
All randomised subjects who take at least one administration of study medication and with at least one postbaseline efficacy assessment.


Subject analysis set title 
Test treatment  PK population


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
All subjects from the safety population excluding subjects without any valid PK measurement and with major Protocol deviations affecting the PK evaluations



End point title 
Total cell count  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline was used in the analyses and reported here (see Table 14.2.1.4).
This is an exploratory study therefore the objectives and the endpoints have not been identified as either primary or secondary.


End point type 
Primary


End point timeframe 
Total cell count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF 6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[1]}  
Pvalue 
= 0.6544  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.912


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.605  
upper limit 
1.376  
Notes [1]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Placebo  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[2]}  
Pvalue 
= 0.0835  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.673


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.4292  
upper limit 
1.0564  
Notes [2]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF 6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[3]}  
Pvalue 
= 0.1875  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.355


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.8571  
upper limit 
2.1422  
Notes [3]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Basophils  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Basophils/Leukocytes  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Eosinophils  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Eosinophis/Leukocytes  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Erythrocytes  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Hematocrit  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Hemoglobin  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Leukocytes  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Lymphocytes  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Lymphocytes/Leukocytes  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Monocytes  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Monocytes/Leukocytes  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Neutrophils  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Neutrophils/Leukocytes  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Platelets  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Alanine aminotransferase  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Albumin  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Akaline phosphatase  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Aspartate amintransferase  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Bilirubin  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Calcium  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Chloride  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Creatinine  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Gamma glutamyl transferase  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Glucose  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Phosphate  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Potassium  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Protein  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Sodium  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Urate  
End point description 

End point type 
Secondary


End point timeframe 
Routine hematology and chemistry were performed at screening and Day 28.




No statistical analyses for this end point 


End point title 
Neutrophils  absolute count  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline was used in the analyses and reported here (see Table 14.2.1.5)


End point type 
Other prespecified


End point timeframe 
Neutrophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF 6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[4]}  
Pvalue 
= 0.565  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.879


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.5611  
upper limit 
1.3774  
Notes [4]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF 6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[5]}  
Pvalue 
= 0.2238  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.358


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.823  
upper limit 
2.241  
Notes [5]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[6]}  
Pvalue 
= 0.0815  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.647


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.3958  
upper limit 
1.0587  
Notes [6]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Neutrophils  differential count  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and reported here (see Table 14.2.1.9 of CSR))


End point type 
Other prespecified


End point timeframe 
Neutrophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF 6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[7]}  
Pvalue 
= 0.1779  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.953


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.888  
upper limit 
1.023  
Notes [7]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[8]}  
Pvalue 
= 0.2549  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.957


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.885  
upper limit 
1.0339  
Notes [8]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF 6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[9]}  
Pvalue 
= 0.9277  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.996


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9208  
upper limit 
1.0783  
Notes [9]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Eosinophils  absolute count  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and reported here (see Table 14.2.1.6 of CSR)


End point type 
Other prespecified


End point timeframe 
Eosinophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF 6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.1521  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.241


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0335  
upper limit 
1.7296  
Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[10]}  
Pvalue 
= 0.5608  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.536


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0626  
upper limit 
4.5957  
Notes [10]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF 6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[11]}  
Pvalue 
= 0.4489  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.449


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0541  
upper limit 
3.7301  
Notes [11]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Eosinophils  differential count  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.10 of CSR)


End point type 
Other prespecified


End point timeframe 
Eosinophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF 6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[12]}  
Pvalue 
= 0.2485  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.238


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.02  
upper limit 
2.8363  
Notes [12]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[13]}  
Pvalue 
= 0.9687  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.949


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0639  
upper limit 
14.094  
Notes [13]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF 6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[14]}  
Pvalue 
= 0.2957  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.251


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.018  
upper limit 
3.5089  
Notes [14]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Macrophages  absolute count  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.7 of CSR)


End point type 
Other prespecified


End point timeframe 
Macrophage count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF 6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[15]}  
Pvalue 
= 0.9379  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.983


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.6379  
upper limit 
1.5159  
Notes [15]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[16]}  
Pvalue 
= 0.3588  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.808


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.5069  
upper limit 
1.2864  
Notes [16]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF 6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[17]}  
Pvalue 
= 0.4097  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.218


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7549  
upper limit 
1.9643  
Notes [17]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Macrophages  differential count  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.11 of CSR)


End point type 
Other prespecified


End point timeframe 
Macrophage count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF 6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[18]}  
Pvalue 
= 0.9551  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.6219  
upper limit 
1.6526  
Notes [18]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[19]}  
Pvalue 
= 0.3048  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.296


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7826  
upper limit 
2.1468  
Notes [19]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF 6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[20]}  
Pvalue 
= 0.3574  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.782


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.4586  
upper limit 
1.3338  
Notes [20]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Lymphocytes  absolute count  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table of 14.2.1.8 CSR)


End point type 
Other prespecified


End point timeframe 
Lymphocyte count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF 6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[21]}  
Pvalue 
= 0.146  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
4.076


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.6  
upper limit 
27.6916  
Notes [21]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[22]}  
Pvalue 
= 0.2756  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
2.913


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.4121  
upper limit 
20.5843  
Notes [22]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF 6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[23]}  
Pvalue 
= 0.741  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.399


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1817  
upper limit 
10.7785  
Notes [23]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Lymphocytes  differential count  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.12 of CSR)


End point type 
Other prespecified


End point timeframe 
Lymphocyte count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF 6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[24]}  
Pvalue 
= 0.1235  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
8.409


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.5454  
upper limit 
129.647  
Notes [24]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[25]}  
Pvalue 
= 0.3513  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
3.701


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.2237  
upper limit 
61.2316  
Notes [25]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF 6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[26]}  
Pvalue 
= 0.571  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
2.272


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1244  
upper limit 
41.5049  
Notes [26]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
IL8 in sputum supernatant  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.13 of CSR)


End point type 
Other prespecified


End point timeframe 
The level of IL8 in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[27]}  
Pvalue 
= 0.0039  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.718


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.5792  
upper limit 
0.8908  
Notes [27]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Placebo  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[28]}  
Pvalue 
= 0.0014  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.671


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.5333  
upper limit 
0.845  
Notes [28]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[29]}  
Pvalue 
= 0.602  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.07


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.8228  
upper limit 
1.3915  
Notes [29]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
IL6 in sputum supernatant  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.14 of CSR)


End point type 
Other prespecified


End point timeframe 
The level of IL6 in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[30]}  
Pvalue 
= 0.0801  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.373


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9604  
upper limit 
1.9617  
Notes [30]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[31]}  
Pvalue 
= 0.7928  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.952


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.6502  
upper limit 
1.3932  
Notes [31]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[32]}  
Pvalue 
= 0.0724  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.442


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9652  
upper limit 
2.155  
Notes [32]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Neutrophil elastase in sputum supernatant  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.15 of CSR)


End point type 
Other prespecified


End point timeframe 
The level of neutrophil elastase in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[33]}  
Pvalue 
= 0.0773  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.7


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.4706  
upper limit 
1.0418  
Notes [33]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[34]}  
Pvalue 
= 0.0034  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.54


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.3623  
upper limit 
0.8049  
Notes [34]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[35]}  
Pvalue 
= 0.2322  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.297


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.8408  
upper limit 
1.9997  
Notes [35]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Myeloperoxidase in sputum supernatant  
End point description 
Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.16 of CSR)


End point type 
Other prespecified


End point timeframe 
The level of myeloperoxidase in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Placebo  mITT population v Test treatment  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[36]}  
Pvalue 
= 0.0368  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.676


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.4693  
upper limit 
0.975  
Notes [36]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[37]}  
Pvalue 
= 0.0086  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.589


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.3997  
upper limit 
0.8672  
Notes [37]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[38]}  
Pvalue 
= 0.5117  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.149


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7517  
upper limit 
1.7561  
Notes [38]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in serum fibrinogen  
End point description 
Data on change from baseline to Day 28 were used in the analyses and are reported here (see Table 14.2.2.4 of CSR)


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[39]}  
Pvalue 
= 0.0646  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.889


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7846  
upper limit 
1.0073  
Notes [39]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[40]}  
Pvalue 
= 0.4629  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.956


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.8456  
upper limit 
1.0801  
Notes [40]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[41]}  
Pvalue 
= 0.2416  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.93


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.8233  
upper limit 
1.051  
Notes [41]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in serum CRP  
End point description 
Data on change from baseline to Day 28 were used in the analyses and are reported here (see Table 14.2.2.1 of CSR)


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[42]}  
Pvalue 
= 0.553  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.902


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.6382  
upper limit 
1.2746  
Notes [42]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[43]}  
Pvalue 
= 0.5279  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.898


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.6389  
upper limit 
1.2612  
Notes [43]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[44]}  
Pvalue 
= 0.9774  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.005


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7182  
upper limit 
1.4057  
Notes [44]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in blood IL6  
End point description 
Data on change from baseline to Day 28 were used in the analyses and are reported here (see Table 14.2.2.2 of CSR)


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[45]}  
Pvalue 
= 0.1517  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.13


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9549  
upper limit 
1.3375  
Notes [45]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[46]}  
Pvalue 
= 0.3013  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.091


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9229  
upper limit 
1.2908  
Notes [46]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[47]}  
Pvalue 
= 0.6741  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.035


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.8783  
upper limit 
1.2208  
Notes [47]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in blood IL8  
End point description 
Data on change from baseline to Day 28 were used in the analyses and are reported here (see Table 14.2.2.3 of CSR)


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[48]}  
Pvalue 
= 0.0556  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.157


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9964  
upper limit 
1.3435  
Notes [48]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[49]}  
Pvalue 
= 0.8286  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.015


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.882  
upper limit 
1.1688  
Notes [49]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[50]}  
Pvalue 
= 0.0736  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.14


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.987  
upper limit 
1.3157  
Notes [50]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline in prebronchodilator FEV1  
End point description 
Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.3.1. of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 9, Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[51]}  
Pvalue 
= 0.6328  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.014


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0447  
upper limit 
0.073  
Notes [51]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[52]}  
Pvalue 
= 0.0631  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.055


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0031  
upper limit 
0.1121  
Notes [52]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[53]}  
Pvalue 
= 0.1789  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.04


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0996  
upper limit 
0.0189  
Notes [53]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline in postbronchodilator FEV1  
End point description 
Only data on change from Day 1 (baseline) to Day 28 are reported here (sse tab.


End point type 
Other prespecified


End point timeframe 
At Day 9, Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[54]}  
Pvalue 
= 0.8615  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.005


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0652  
upper limit 
0.0547  
Notes [54]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[55]}  
Pvalue 
= 0.6931  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.012


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0483  
upper limit 
0.0723  
Notes [55]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[56]}  
Pvalue 
= 0.5734  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.017


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.078  
upper limit 
0.0435  
Notes [56]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline in prebronchodilator FVC  
End point description 
Only data on change from Day 1 (baseline) to Day 28 is reported here (see tab. 14.2.3.2 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 1, Day 9, Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[57]}  
Pvalue 
= 0.2267  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.058


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0371  
upper limit 
0.154  
Notes [57]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[58]}  
Pvalue 
= 0.0292  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.105


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0109  
upper limit 
0.1994  
Notes [58]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[59]}  
Pvalue 
= 0.3315  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.047


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1421  
upper limit 
0.0486  
Notes [59]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline in postbronchodilator FVC  
End point description 
Only data on change from Day 1 (baseline) to Day 28 is reported here (tab. 14.2.3.2 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 9, Day 21, Day 24 and Day 28.




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[60]}  
Pvalue 
= 0.6355  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.023


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0743  
upper limit 
0.121  
Notes [60]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[61]}  
Pvalue 
= 0.4213  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.039


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.0578  
upper limit 
0.1368  
Notes [61]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[62]}  
Pvalue 
= 0.7455  
Method 
ANCOVA  
Parameter type 
least square mean  
Point estimate 
0.016


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.115  
upper limit 
0.0827  
Notes [62]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in VC  
End point description 
Only data on change from baseline to Day 28 are reported here (see tab. 14.2.4..1 of CSR)


End point type 
Other prespecified


End point timeframe 
At Day 1 and Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[63]}  
Pvalue 
= 0.3709  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.984


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9494  
upper limit 
1.0198  
Notes [63]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[64]}  
Pvalue 
= 0.243  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.021


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9857  
upper limit 
1.0575  
Notes [64]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[65]}  
Pvalue 
= 0.0311  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.964


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9321  
upper limit 
0.9965  
Notes [65]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in IC  
End point description 
Only data on change from baseline to Day 28 are reported here (see tab 14.2.4.2).


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[66]}  
Pvalue 
= 0.5088  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.982


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9314  
upper limit 
1.0362  
Notes [66]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[67]}  
Pvalue 
= 0.5606  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.985


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9341  
upper limit 
1.038  
Notes [67]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[68]}  
Pvalue 
= 0.9306  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.998


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9469  
upper limit 
1.0512  
Notes [68]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in RV  
End point description 
Only data on change from baseline to Day 28 are reported here (see tab. 14.2.4.3 of CSR)


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[69]}  
Pvalue 
= 0.6873  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.011


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9583  
upper limit 
1.0664  
Notes [69]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[70]}  
Pvalue 
= 0.1946  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.965


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9152  
upper limit 
1.0186  
Notes [70]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[71]}  
Pvalue 
= 0.0796  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.047


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9944  
upper limit 
1.1024  
Notes [71]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in FRC  
End point description 
Data on change from baseline to Day 28 are reported here (see table 14.2.4.4 of CSR)


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[72]}  
Pvalue 
= 0.9914  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9635  
upper limit 
1.0383  
Notes [72]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[73]}  
Pvalue 
= 0.9262  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.998


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.962  
upper limit 
1.036  
Notes [73]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[74]}  
Pvalue 
= 0.9154  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.002


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9664  
upper limit 
1.0387  
Notes [74]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change form baseline to Day 28 in TLC  
End point description 
Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.5. of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[75]}  
Pvalue 
= 0.696  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.995


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9706  
upper limit 
1.0202  
Notes [75]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.3702 ^{[76]}  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.989


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9648  
upper limit 
1.0136  
Notes [76]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHf6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[77]}  
Pvalue 
= 0.6072  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.006


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9823  
upper limit 
1.0309  
Notes [77]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in RV/TLC  
End point description 
Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.6 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[78]}  
Pvalue 
= 0.3623  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.018


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9797  
upper limit 
1.057  
Notes [78]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[79]}  
Pvalue 
= 0.2407  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.978


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9416  
upper limit 
1.0155  
Notes [79]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[80]}  
Pvalue 
= 0.311  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.041


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.0037  
upper limit 
1.0789  
Notes [80]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in ITV  
End point description 
Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.7. of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[81]}  
Pvalue 
= 0.7135  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.994


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9604  
upper limit 
1.0282  
Notes [81]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[82]}  
Pvalue 
= 0.5332  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.99


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9572  
upper limit 
1.0231  
Notes [82]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[83]}  
Pvalue 
= 0.8037  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.004


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9713  
upper limit 
1.0381  
Notes [83]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change from baseline to Day 28 in sGAW  
End point description 
Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.8. of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[84]}  
Pvalue 
= 0.4104  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.952


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.845  
upper limit 
1.0721  
Notes [84]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
roflumilast vs placebo  
Comparison groups 
Placebo  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[85]}  
Pvalue 
= 0.2505  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.071


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9518  
upper limit 
1.2046  
Notes [85]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[86]}  
Pvalue 
= 0.0445  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.889


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7925  
upper limit 
0.997  
Notes [86]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Change form baseline to Day 28 in GAW  
End point description 
Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.9. of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[87]}  
Pvalue 
= 0.3202  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.056


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.947  
upper limit 
1.1782  
Notes [87]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[88]}  
Pvalue 
= 0.3705  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.952


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.855  
upper limit 
1.061  
Notes [88]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[89]}  
Pvalue 
= 0.0531  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.109


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9986  
upper limit 
1.2318  
Notes [89]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
TDI scores on Day 28  
End point description 
Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.5.1. of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 28




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[90]}  
Pvalue 
= 0.3202  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.056


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.947  
upper limit 
1.1782  
Notes [90]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[91]}  
Pvalue 
= 0.3705  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
0.952


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.855  
upper limit 
1.061  
Notes [91]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[92]}  
Pvalue 
= 0.0531  
Method 
ANCOVA  
Parameter type 
geometric LSM  
Point estimate 
1.109


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9986  
upper limit 
1.2318  
Notes [92]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
Rescue drug use over the 28day period  
End point description 
Rescue drug use was expressed as mean number of puffs/day of salbutamol resue medication. Data on table 14.2.6. of CSR are reported here.


End point type 
Other prespecified


End point timeframe 
Throughout the 28day period




Statistical analysis title 
CHF6001 vs placebo  
Comparison groups 
Test treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
85


Analysis specification 
Prespecified


Analysis type 
other ^{[93]}  
Pvalue 
= 0.1185  
Method 
ANOVA  
Parameter type 
least square mean  
Point estimate 
0.23


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.521  
upper limit 
0.06  
Notes [93]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
Roflumilast vs placebo  
Comparison groups 
Reference treatment  mITT population v Placebo  mITT population


Number of subjects included in analysis 
90


Analysis specification 
Prespecified


Analysis type 
other ^{[94]}  
Pvalue 
= 0.9173  
Method 
ANOVA  
Parameter type 
least square mean  
Point estimate 
0.01


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.269  
upper limit 
0.299  
Notes [94]  This is a "proof of concept" study: no statistical hypothesis is included 

Statistical analysis title 
CHF6001 vs Roflumilast  
Comparison groups 
Test treatment  mITT population v Reference treatment  mITT population


Number of subjects included in analysis 
89


Analysis specification 
Prespecified


Analysis type 
other ^{[95]}  
Pvalue 
= 0.0904  
Method 
ANOVA  
Parameter type 
least square mean  
Point estimate 
0.25


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.53  
upper limit 
0.04  
Notes [95]  This is a "proof of concept" study: no statistical hypothesis is included 


End point title 
FEV1 on Day 1  
End point description 
FEV1, to assess potential occurrence of paradoxical bronchospasm on Day 1 (2hour spirometry measurement). Absolute change values are reported here (sse table 14.3.9 of CSR)


End point type 
Other prespecified


End point timeframe 
On Day 1 (2hour spirometry measurement)




No statistical analyses for this end point 


End point title 
Heart rate  
End point description 
Vital signs (HR and BP) were assessed after 5 min in supine position at predose, 30 minutes, and 1, 2, 3, 6, 8 and 10 hours postdose.
Only data on Day 28, 10 hours postdose are reported here (See tab. 14.3.6.1.1 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 1 and Day 28




No statistical analyses for this end point 


End point title 
Systolic blood pressure  
End point description 
Vital signs (HR and BP) were assessed after 5 min in supine position at predose, 30 minutes, and 1, 2, 3, 6, 8 and 10 hours postdose.
Only data from 10 hours postdose measurement at Day 28 are reported here (sse table 14.3.6.2.1 of CSR).


End point type 
Other prespecified


End point timeframe 
On Day 1 and Day 28




No statistical analyses for this end point 


End point title 
Diastolic blood pressure  
End point description 
Vital signs (HR and BP) were assessed after 5 min in supine position at predose, 30 minutes, and 1, 2, 3, 6, 8 and 10 hours postdose.
Only data from 10 hours postdose measurement at Day 28 are reported here (see table 14.3.6.3.1 of CSR).


End point type 
Other prespecified


End point timeframe 
On Day 1 and Day 28




No statistical analyses for this end point 


End point title 
Body weight  
End point description 
Only data at Day 28 are reported here (see table 14.3.8 of CSR).


End point type 
Other prespecified


End point timeframe 
On Day 1 and Day 28




No statistical analyses for this end point 


End point title 
12lead ECG HR  
End point description 
Triplicate serial 12lead ECG was performed after 10 min in supine position at: predose, 30 min, 1, 2, 3, 6, 8 and 10 hrs postdose on Day 1 and Day 28.
Single 12lead ECG was performed at screening while triplicate 12lead ECG was performed after 10 min in supine position at predose on Day 9, 21, 24 of each Period.
Only data from 10 hours postdose measurement at Day 28 are reported here (see table 14.3.7.1.1 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 1, Day 9, Day 21, Day 24 and Day 28




No statistical analyses for this end point 


End point title 
12lead ECG PR  
End point description 
Triplicate serial 12lead ECG was performed after 10 min in supine position at: predose, 30 min, 1, 2, 3, 6, 8 and 10 hrs postdose on Day 1 and Day 28.
Single 12lead ECG was performed at screening while triplicate 12lead ECG was performed after 10 min in supine position at predose on Day 9, 21, 24 of each Period.
Only data from 10 hours postdose measurement at Day 28 are reported here (see table 14.3.7.2.1 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 1, Day 9, Day 21, Day 24 and Day 28




No statistical analyses for this end point 


End point title 
12lead ECG QRS  
End point description 
Triplicate serial 12lead ECG was performed after 10 min in supine position at: predose, 30 min, 1, 2, 3, 6, 8 and 10 hrs postdose on Day 1 and Day 28.
Single 12lead ECG was performed at screening while triplicate 12lead ECG was performed after 10 min in supine position at predose on Day 9, 21, 24 of each Period.
Only data from 10 hours postdose measurement at Day 28 are reported here (see table 14.3.7.3.1 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 1, Day 9, Day 21, Day 24 and Day 28




No statistical analyses for this end point 


End point title 
12lead ECG QT  
End point description 
Triplicate serial 12lead ECG was performed after 10 min in supine position at: predose, 30 min, 1, 2, 3, 6, 8 and 10 hrs postdose on Day 1 and Day 28.
Single 12lead ECG was performed at screening while triplicate 12lead ECG was performed after 10 min in supine position at predose on Day 9, 21, 24 of each Period.
Only data from 10 hours postdose measurement at Day 28 are reported here (see table 14.3.7.4.1 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 1, Day 9, Day 21, Day 24 and Day 28




No statistical analyses for this end point 


End point title 
12lead ECG QTcB  
End point description 
Triplicate serial 12lead ECG was performed after 10 min in supine position at: predose, 30 min, 1, 2, 3, 6, 8 and 10 hrs postdose on Day 1 and Day 28.
Single 12lead ECG was performed at screening while triplicate 12lead ECG was performed after 10 min in supine position at predose on Day 9, 21, 24 of each Period.
Only data from 10 hours postdose measurement at Day 28 are reported here (see table 14.3.7.5.1 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 1, Day 9, Day 21, Day 24 and Day 28




No statistical analyses for this end point 


End point title 
12lead ECG QTcF  
End point description 
Triplicate serial 12lead ECG was performed after 10 min in supine position at: predose, 30 min, 1, 2, 3, 6, 8 and 10 hrs postdose on Day 1 and Day 28.
Single 12lead ECG was performed at screening while triplicate 12lead ECG was performed after 10 min in supine position at predose on Day 9, 21, 24 of each Period.
Only data from 10 hours postdose measurement at Day 28 are reported here (see table 14.3.7.6.1 of CSR).


End point type 
Other prespecified


End point timeframe 
At Day 1, Day 9, Day 21, Day 24 and Day 28




No statistical analyses for this end point 


End point title 
AUC0t,ss of CHF6001  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
AUC0t,ss of CHF5956  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
AUC0t,ss of CHF6095  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
AUC024h,ss of CHF6001  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
AUC024h,ss of CHF5956  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
AUC024h,ss of CHF6095  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
Cmin,ss of CHF6001  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
Cmax,ss of CHF6001  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
Cmax,ss of CHF5956  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
Cmax,ss of CHF6095  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
Cav,ss of CHF6001  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
Cav,ss of CHF5956  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28




No statistical analyses for this end point 


End point title 
Cav,ss of CHF6095  
End point description 
PK blood collection will be performed on Day 28 at predose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose
(on Day 29) of each study Period.


End point type 
Other prespecified


End point timeframe 
At Day 28


