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Clinical Trial Results:
A randomised, double-blind, double-dummy, placebo and active-controlled, three-way crossover study to evaluate the safety, tolerability and efficacy of 28-day inhaled CHF 6001 DPI (1200 microgrammes daily) in subjects with COPD.

Summary
EudraCT number	2012-001005-25
Trial protocol	GB
Global end of trial date	25 Oct 2013
Results information
Results version number	v1
This version publication date	12 Jul 2016
First version publication date	09 Aug 2015
Other versions	v2

Trial information Top of page
Trial identification
Sponsor protocol code	CCD-1201-PR-0079
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	Oriana Esposito, Chiesi Farmaceutici S.p.A., 39 05211689204, o.esposito@chiesi.com
Scientific contact	Oriana Esposito, Chiesi Farmaceutici S.p.A., 39 05211689204, o.esposito@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 steady-state in GOLD stage 2-3 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 follow-up 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 (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	43
From 65 to 84 years	12
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	-
Pre-assignment
Screening details	Fifty-five 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. Fifty-three 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	Subject, Investigator, Monitor, Data analyst, Carer, Assessor
Arms
Are arms mutually exclusive	Yes
Arm title	Sequence C--R--P
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 run-in 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 wash-out Period of 4-5 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 P--C--R
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 run-in 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 wash-out Period of 4-5 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 R--P--C
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 run-in 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 wash-out Period of 4-5 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 C--P--R
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 run-in 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 wash-out Period of 4-5 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 P--R--C
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 run-in 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 wash-out Period of 4-5 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 R--C--P
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 run-in 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 wash-out Period of 4-5 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
Number of subjects in period 1 Sequence C--R--P Sequence P--C--R Sequence R--P--C Sequence C--P--R Sequence P--R--C Sequence R--C--P Started 10 10 8 9 8 10 Completed 6 7 4 9 5 6 Not completed 4 3 4 0 3 4      Consent withdrawn by subject 1 1 - - 1 2      Adverse event, non-fatal 3 2 4 - 2 2

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Sequence C--R--P
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence P--C--R
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence R--P--C
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence C--P--R
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence P--R--C
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence R--C--P
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group values Sequence C--R--P Sequence P--C--R Sequence R--P--C Sequence C--P--R Sequence P--R--C Sequence R--C--P Total Number of subjects 10 10 8 9 8 10 55 Age categorical Units: Subjects     In utero 0     Preterm newborn infants (gestational age < 37 wks) 0     Newborns (0-27 days) 0     Infants and toddlers (28 days-23 months) 0     Children (2-11 years) 0     Adolescents (12-17 years) 0     Adults (18-64 years) 0     From 65-84 years 0     85 years and over 0 Age continuous Units: years     arithmetic mean (standard deviation) 59.5 ( 7.25 ) 61.7 ( 6.46 ) 59.4 ( 5.71 ) 55.2 ( 7.14 ) 60.5 ( 5.32 ) 59.3 ( 5.79 ) - Gender categorical Units: Subjects     Female 5 4 5 3 5 3 25     Male 5 6 3 6 3 7 30
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 intention-to-treat
Subject analysis set description	All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment
Subject analysis set title	Reference treatment - mITT population
Subject analysis set type	Modified intention-to-treat
Subject analysis set description	All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment.
Subject analysis set title	Placebo - mITT population
Subject analysis set type	Modified intention-to-treat
Subject analysis set description	All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment.
Subject analysis set title	Test treatment - PK population
Subject analysis set type	Sub-group 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
Subject analysis sets values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Test treatment - PK population Number of subjects 42 49 43 42 47 43 40 Age categorical Units: Subjects     In utero     Preterm newborn infants (gestational age < 37 wks)     Newborns (0-27 days)     Infants and toddlers (28 days-23 months)     Children (2-11 years)     Adolescents (12-17 years)     Adults (18-64 years)     From 65-84 years     85 years and over Age continuous Units: years     arithmetic mean (standard deviation) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Gender categorical Units: Subjects     Female 16 21 16 16 19 16 16     Male 26 28 27 26 28 27 24

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Sequence C--R--P
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence P--C--R
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence R--P--C
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence C--P--R
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence P--R--C
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 run-in 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 wash-out Period of 4-5 weeks.
Reporting group title	Sequence R--C--P
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 run-in 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 wash-out Period of 4-5 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 intention-to-treat
Subject analysis set description	All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment
Subject analysis set title	Reference treatment - mITT population
Subject analysis set type	Modified intention-to-treat
Subject analysis set description	All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment.
Subject analysis set title	Placebo - mITT population
Subject analysis set type	Modified intention-to-treat
Subject analysis set description	All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment.
Subject analysis set title	Test treatment - PK population
Subject analysis set type	Sub-group 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 Top of page

Primary: Total cell count Top of page
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.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: millions cells/g sputum     arithmetic mean (standard deviation) 2.7301 ( 8.58667 ) -0.6251 ( 17.58909 ) 1.0149 ( 13.52405 )
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	Pre-specified
Analysis type	other [1]
P-value	= 0.6544
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.912
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [2]
P-value	= 0.0835
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.673
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [3]
P-value	= 0.1875
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.355
Confidence interval
level	95%
sides	2-sided
lower limit	0.8571
upper limit	2.1422
Notes [3] - This is a "proof of concept" study: no statistical hypothesis is included

Primary: Total cell count Top of page

Secondary: Basophils Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: 10^9/L     arithmetic mean (standard deviation) -0.01 ( 0.028 ) 0 ( 0.03 ) 0 ( 0.023 )
No statistical analyses for this end point

Secondary: Basophils Top of page

Secondary: Basophils/Leukocytes Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 38 43 39 Units: percent     arithmetic mean (standard deviation) 0 ( 0.29 ) -0.1 ( 0.24 ) 0 ( 0.27 )
No statistical analyses for this end point

Secondary: Basophils/Leukocytes Top of page

Secondary: Eosinophils Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: 10^9/L     arithmetic mean (standard deviation) 0.01 ( 0.104 ) 0.02 ( 0.102 ) 0.07 ( 0.173 )
No statistical analyses for this end point

Secondary: Eosinophils Top of page

Secondary: Eosinophis/Leukocytes Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 38 43 39 Units: percent     arithmetic mean (standard deviation) 0.1 ( 1.39 ) 0 ( 1.27 ) 0.8 ( 2.06 )
No statistical analyses for this end point

Secondary: Eosinophis/Leukocytes Top of page

Secondary: Erythrocytes Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: 10^12/L     arithmetic mean (standard deviation) 0.015 ( 0.1844 ) 0.005 ( 0.2089 ) 0.022 ( 0.2293 )
No statistical analyses for this end point

Secondary: Erythrocytes Top of page

Secondary: Hematocrit Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: ratio     arithmetic mean (standard deviation) -0.001 ( 0.0177 ) -0.003 ( 0.0183 ) -0.001 ( 0.0201 )
No statistical analyses for this end point

Secondary: Hematocrit Top of page

Secondary: Hemoglobin Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: g/dL     arithmetic mean (standard deviation) -0.05 ( 0.567 ) -0.15 ( 0.607 ) -0.1 ( 0.669 )
No statistical analyses for this end point

Secondary: Hemoglobin Top of page

Secondary: Leukocytes Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: 10^9/L     arithmetic mean (standard deviation) 0.35 ( 1.673 ) 0.39 ( 1.345 ) 0.33 ( 1.517 )
No statistical analyses for this end point

Secondary: Leukocytes Top of page

Secondary: Lymphocytes Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: 10^9/L     arithmetic mean (standard deviation) 0.18 ( 0.439 ) 0.21 ( 0.457 ) 0.12 ( 0.453 )
No statistical analyses for this end point

Secondary: Lymphocytes Top of page

Secondary: Lymphocytes/Leukocytes Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 38 43 39 Units: percent     arithmetic mean (standard deviation) 1.5 ( 5.18 ) 1.3 ( 6.34 ) 0.6 ( 6.44 )
No statistical analyses for this end point

Secondary: Lymphocytes/Leukocytes Top of page

Secondary: Monocytes Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed Units: 10^9/L     arithmetic mean (standard deviation) -0.04 ( 0.183 ) 0 ( 0.121 ) -0.01 ( 0.176 )
No statistical analyses for this end point

Secondary: Monocytes Top of page

Secondary: Monocytes/Leukocytes Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 38 43 39 Units: percent     arithmetic mean (standard deviation) -0.8 ( 1.68 ) -0.5 ( 1.46 ) -0.6 ( 1.58 )
No statistical analyses for this end point

Secondary: Monocytes/Leukocytes Top of page

Secondary: Neutrophils Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: 10^9/L     arithmetic mean (standard deviation) 0.18 ( 1.479 ) 0.16 ( 1.237 ) 0.15 ( 1.325 )
No statistical analyses for this end point

Secondary: Neutrophils Top of page

Secondary: Neutrophils/Leukocytes Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 38 43 39 Units: percent     arithmetic mean (standard deviation) -0.8 ( 5.58 ) -0.6 ( 7.09 ) -0.8 ( 6.69 )
No statistical analyses for this end point

Secondary: Neutrophils/Leukocytes Top of page

Secondary: Platelets Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: 10^9/L     arithmetic mean (standard deviation) 2.25 ( 19.847 ) 13.44 ( 32.017 ) -1.46 ( 23.999 )
No statistical analyses for this end point

Secondary: Platelets Top of page

Secondary: Alanine aminotransferase Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 40 Units: U/L     arithmetic mean (standard deviation) -1.19 ( 7.895 ) -2.4 ( 6.13 ) -0.94 ( 9.66 )
No statistical analyses for this end point

Secondary: Alanine aminotransferase Top of page

Secondary: Albumin Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: g/L     arithmetic mean (standard deviation) -0.5 ( 2.192 ) -0.17 ( 2.533 ) -0.2 ( 2.131 )
No statistical analyses for this end point

Secondary: Albumin Top of page

Secondary: Akaline phosphatase Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 40 Units: U/L     arithmetic mean (standard deviation) -0.63 ( 9.352 ) 1.7 ( 9.028 ) 1.49 ( 7.882 )
No statistical analyses for this end point

Secondary: Akaline phosphatase Top of page

Secondary: Aspartate amintransferase Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 39 44 37 Units: U/L     arithmetic mean (standard deviation) 0.51 ( 8.583 ) -1.2 ( 5.03 ) 0.7 ( 6.479 )
No statistical analyses for this end point

Secondary: Aspartate amintransferase Top of page

Secondary: Bilirubin Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 40 Units: μmol/L     arithmetic mean (standard deviation) -0.51 ( 3.948 ) -0.48 ( 3.003 ) 0.01 ( 3.078 )
No statistical analyses for this end point

Secondary: Bilirubin Top of page

Secondary: Calcium Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 44 41 Units: mmol/L     arithmetic mean (standard deviation) -0.01 ( 0.1175 ) 0.016 ( 0.0957 ) -0.01 ( 0.0827 )
No statistical analyses for this end point

Secondary: Calcium Top of page

Secondary: Chloride Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 37 44 36 Units: mmol/L     arithmetic mean (standard deviation) -0.14 ( 2.702 ) -0.58 ( 2.281 ) -0.23 ( 2.496 )
No statistical analyses for this end point

Secondary: Chloride Top of page

Secondary: Creatinine Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: μmol/L     arithmetic mean (standard deviation) -0.9 ( 6.183 ) -0.18 ( 7.565 ) -1.32 ( 6.274 )
No statistical analyses for this end point

Secondary: Creatinine Top of page

Secondary: Gamma glutamyl transferase Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 39 44 40 Units: U/L     arithmetic mean (standard deviation) -1.44 ( 8.542 ) -0.76 ( 11.551 ) -1.37 ( 12.08 )
No statistical analyses for this end point

Secondary: Gamma glutamyl transferase Top of page

Secondary: Glucose Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 39 44 40 Units: mmol/L     arithmetic mean (standard deviation) 0.187 ( 0.6213 ) 0.167 ( 0.5524 ) 0.212 ( 0.9286 )
No statistical analyses for this end point

Secondary: Glucose Top of page

Secondary: Phosphate Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 40 Units: mmol/L     arithmetic mean (standard deviation) 0.039 ( 0.1867 ) 0.039 ( 0.1487 ) 0.028 ( 0.1309 )
No statistical analyses for this end point

Secondary: Phosphate Top of page

Secondary: Potassium Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 40 Units: mmol/L     arithmetic mean (standard deviation) -0.14 ( 0.3181 ) -0.049 ( 0.523 ) -0.124 ( 0.3382 )
No statistical analyses for this end point

Secondary: Potassium Top of page

Secondary: Protein Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 40 Units: g/L     arithmetic mean (standard deviation) -0.09 ( 3.775 ) 0.27 ( 3.547 ) 0.43 ( 3.083 )
No statistical analyses for this end point

Secondary: Protein Top of page

Secondary: Sodium Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 40 45 41 Units: mmol/L     arithmetic mean (standard deviation) 0 ( 2.1 ) -0.3 ( 2.09 ) -0.2 ( 2.06 )
No statistical analyses for this end point

Secondary: Sodium Top of page

Secondary: Urate Top of page
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.
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 35 40 36 Units: μmol/L     arithmetic mean (standard deviation) -2.94 ( 31.936 ) -12.15 ( 37.216 ) -11.09 ( 31.245 )
No statistical analyses for this end point

Secondary: Urate Top of page

Other pre-specified: Neutrophils - absolute count Top of page
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 pre-specified
End point timeframe	Neutrophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: millions neutrophils/g sputum     arithmetic mean (standard deviation) 2.6588 ( 8.28804 ) -0.647 ( 17.43528 ) 0.8679 ( 13.13533 )
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	Pre-specified
Analysis type	other [4]
P-value	= 0.565
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.879
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [5]
P-value	= 0.2238
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.358
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [6]
P-value	= 0.0815
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.647
Confidence interval
level	95%
sides	2-sided
lower limit	0.3958
upper limit	1.0587
Notes [6] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Neutrophils - absolute count Top of page

Other pre-specified: Neutrophils - differential count Top of page
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 pre-specified
End point timeframe	Neutrophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: percent     arithmetic mean (standard deviation) 0.4409 ( 14.89339 ) -5.5694 ( 13.66577 ) -1.0944 ( 16.06526 )
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	Pre-specified
Analysis type	other [7]
P-value	= 0.1779
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.953
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [8]
P-value	= 0.2549
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.957
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [9]
P-value	= 0.9277
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.996
Confidence interval
level	95%
sides	2-sided
lower limit	0.9208
upper limit	1.0783
Notes [9] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Neutrophils - differential count Top of page

Other pre-specified: Eosinophils - absolute count Top of page
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 pre-specified
End point timeframe	Eosinophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: millions eosinophils /g sputum     arithmetic mean (standard deviation) 0.0117 ( 1.19362 ) -0.0099 ( 0.08537 ) 0.0498 ( 0.30105 )
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	Pre-specified
Analysis type	other
P-value	= 0.1521
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.241
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [10]
P-value	= 0.5608
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.536
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [11]
P-value	= 0.4489
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.449
Confidence interval
level	95%
sides	2-sided
lower limit	0.0541
upper limit	3.7301
Notes [11] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Eosinophils - absolute count Top of page

Other pre-specified: Eosinophils - differential count Top of page
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 pre-specified
End point timeframe	Eosinophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: percent     arithmetic mean (standard deviation) -0.6263 ( 6.22173 ) 0.5386 ( 2.328 ) 1.3458 ( 4.51746 )
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	Pre-specified
Analysis type	other [12]
P-value	= 0.2485
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.238
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [13]
P-value	= 0.9687
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.949
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [14]
P-value	= 0.2957
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.251
Confidence interval
level	95%
sides	2-sided
lower limit	0.018
upper limit	3.5089
Notes [14] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Eosinophils - differential count Top of page

Other pre-specified: Macrophages - absolute count Top of page
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 pre-specified
End point timeframe	Macrophage count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: millions macrophages/g sputum     arithmetic mean (standard deviation) 0.1048 ( 0.70455 ) 0.0231 ( 0.77945 ) 0.0961 ( 1.01861 )
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	Pre-specified
Analysis type	other [15]
P-value	= 0.9379
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.983
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [16]
P-value	= 0.3588
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.808
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [17]
P-value	= 0.4097
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.218
Confidence interval
level	95%
sides	2-sided
lower limit	0.7549
upper limit	1.9643
Notes [17] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Macrophages - absolute count Top of page

Other pre-specified: Macrophages - differential count Top of page
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 pre-specified
End point timeframe	Macrophage count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: percent     arithmetic mean (standard deviation) 0.4879 ( 14.69496 ) 5.4444 ( 11.80631 ) -0.7194 ( 14.45761 )
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	Pre-specified
Analysis type	other [18]
P-value	= 0.9551
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.014
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [19]
P-value	= 0.3048
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.296
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [20]
P-value	= 0.3574
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.782
Confidence interval
level	95%
sides	2-sided
lower limit	0.4586
upper limit	1.3338
Notes [20] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Macrophages - differential count Top of page

Other pre-specified: Lymphocytes - absolute count Top of page
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 pre-specified
End point timeframe	Lymphocyte count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: millions lymphocytes/g sputum     arithmetic mean (standard deviation) -0.0017 ( 0.01046 ) 0.001 ( 0.00567 ) 0.0004 ( 0.00152 )
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	Pre-specified
Analysis type	other [21]
P-value	= 0.146
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	4.076
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [22]
P-value	= 0.2756
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	2.913
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [23]
P-value	= 0.741
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.399
Confidence interval
level	95%
sides	2-sided
lower limit	0.1817
upper limit	10.7785
Notes [23] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Lymphocytes - absolute count Top of page

Other pre-specified: Lymphocytes - differential count Top of page
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 pre-specified
End point timeframe	Lymphocyte count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: percent     arithmetic mean (standard deviation) -0.047 ( 0.21348 ) 0.0046 ( 0.08674 ) 0.0222 ( 0.09268 )
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	Pre-specified
Analysis type	other [24]
P-value	= 0.1235
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	8.409
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [25]
P-value	= 0.3513
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	3.701
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [26]
P-value	= 0.571
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	2.272
Confidence interval
level	95%
sides	2-sided
lower limit	0.1244
upper limit	41.5049
Notes [26] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Lymphocytes - differential count Top of page

Other pre-specified: IL-8 in sputum supernatant Top of page
End point title	IL-8 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 pre-specified
End point timeframe	The level of IL-8 in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: pg/mL     arithmetic mean (standard deviation) 152.9594 ( 2546.18 ) -923.286 ( 2862.978 ) 462.8729 ( 3054.962 )
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	Pre-specified
Analysis type	other [27]
P-value	= 0.0039
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.718
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [28]
P-value	= 0.0014
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.671
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [29]
P-value	= 0.602
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.07
Confidence interval
level	95%
sides	2-sided
lower limit	0.8228
upper limit	1.3915
Notes [29] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: IL-8 in sputum supernatant Top of page

Other pre-specified: IL-6 in sputum supernatant Top of page
End point title	IL-6 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 pre-specified
End point timeframe	The level of IL-6 in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: pg/mL     arithmetic mean (standard deviation) 54.1723 ( 212.7271 ) 17.2294 ( 137.5087 ) -20.7899 ( 92.10865 )
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	Pre-specified
Analysis type	other [30]
P-value	= 0.0801
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.373
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [31]
P-value	= 0.7928
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.952
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [32]
P-value	= 0.0724
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.442
Confidence interval
level	95%
sides	2-sided
lower limit	0.9652
upper limit	2.155
Notes [32] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: IL-6 in sputum supernatant Top of page

Other pre-specified: Neutrophil elastase in sputum supernatant Top of page
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 pre-specified
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.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: pg/mL     arithmetic mean (standard deviation) -215988 ( 1657361 ) -575067 ( 1738260 ) -473269 ( 1463202 )
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	Pre-specified
Analysis type	other [33]
P-value	= 0.0773
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.7
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [34]
P-value	= 0.0034
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.54
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [35]
P-value	= 0.2322
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.297
Confidence interval
level	95%
sides	2-sided
lower limit	0.8408
upper limit	1.9997
Notes [35] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Neutrophil elastase in sputum supernatant Top of page

Other pre-specified: Myeloperoxidase in sputum supernatant Top of page
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 pre-specified
End point timeframe	The level of myeloperoxidase in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: ng/mL     arithmetic mean (standard deviation) -4.2085 ( 1347.198 ) -402.997 ( 1347.198 ) -402.997 ( 1604.78 )
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	Pre-specified
Analysis type	other [36]
P-value	= 0.0368
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.676
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [37]
P-value	= 0.0086
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.589
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [38]
P-value	= 0.5117
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.149
Confidence interval
level	95%
sides	2-sided
lower limit	0.7517
upper limit	1.7561
Notes [38] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Myeloperoxidase in sputum supernatant Top of page

Other pre-specified: Change from baseline to Day 28 in serum fibrinogen Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: ug/L     arithmetic mean (standard deviation) 91.0237 ( 466.5769 ) 98.4042 ( 572.3796 ) 57.6753 ( 571.7863 )
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	Pre-specified
Analysis type	other [39]
P-value	= 0.0646
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.889
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [40]
P-value	= 0.4629
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.956
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [41]
P-value	= 0.2416
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.93
Confidence interval
level	95%
sides	2-sided
lower limit	0.8233
upper limit	1.051
Notes [41] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in serum fibrinogen Top of page

Other pre-specified: Change from baseline to Day 28 in serum CRP Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: nmol/L     arithmetic mean (standard deviation) 0.391 ( 44.4402 ) 15.331 ( 173.3361 ) -72.364 ( 381.2791 )
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	Pre-specified
Analysis type	other [42]
P-value	= 0.553
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.902
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [43]
P-value	= 0.5279
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.898
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [44]
P-value	= 0.9774
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.005
Confidence interval
level	95%
sides	2-sided
lower limit	0.7182
upper limit	1.4057
Notes [44] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in serum CRP Top of page

Other pre-specified: Change from baseline to Day 28 in blood IL-6 Top of page
End point title	Change from baseline to Day 28 in blood IL-6
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: pg/mL     arithmetic mean (standard deviation) 0.3074 ( 1.32279 ) 0.281 ( 1.79656 ) -1.0879 ( 2.77641 )
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	Pre-specified
Analysis type	other [45]
P-value	= 0.1517
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.13
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [46]
P-value	= 0.3013
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.091
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [47]
P-value	= 0.6741
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.035
Confidence interval
level	95%
sides	2-sided
lower limit	0.8783
upper limit	1.2208
Notes [47] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in blood IL-6 Top of page

Other pre-specified: Change from baseline to Day 28 in blood IL-8 Top of page
End point title	Change from baseline to Day 28 in blood IL-8
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: pg/mL     arithmetic mean (standard deviation) 0.0747 ( 4.90551 ) -2.7426 ( 10.89529 ) -3.8656 ( 7.08697 )
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	Pre-specified
Analysis type	other [48]
P-value	= 0.0556
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.157
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [49]
P-value	= 0.8286
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.015
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [50]
P-value	= 0.0736
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.14
Confidence interval
level	95%
sides	2-sided
lower limit	0.987
upper limit	1.3157
Notes [50] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in blood IL-8 Top of page

Other pre-specified: Change from baseline in pre-bronchodilator FEV1 Top of page
End point title	Change from baseline in pre-bronchodilator 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 pre-specified
End point timeframe	At Day 9, Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: liters     arithmetic mean (standard deviation) -0.054 ( 0.2149 ) 0.035 ( 0.1703 ) -0.044 ( 0.2219 )
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	Pre-specified
Analysis type	other [51]
P-value	= 0.6328
Method	ANCOVA
Parameter type	least square mean
Point estimate	0.014
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [52]
P-value	= 0.0631
Method	ANCOVA
Parameter type	least square mean
Point estimate	0.055
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [53]
P-value	= 0.1789
Method	ANCOVA
Parameter type	least square mean
Point estimate	-0.04
Confidence interval
level	95%
sides	2-sided
lower limit	-0.0996
upper limit	0.0189
Notes [53] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline in pre-bronchodilator FEV1 Top of page

Other pre-specified: Change from baseline in post-bronchodilator FEV1 Top of page
End point title	Change from baseline in post-bronchodilator FEV1
End point description	Only data on change from Day 1 (baseline) to Day 28 are reported here (sse tab.
End point type	Other pre-specified
End point timeframe	At Day 9, Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: liters     arithmetic mean (standard deviation) -0.067 ( 0.2459 ) 0.025 ( 0.1851 ) -0.068 ( 0.2136 )
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	Pre-specified
Analysis type	other [54]
P-value	= 0.8615
Method	ANCOVA
Parameter type	least square mean
Point estimate	-0.005
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [55]
P-value	= 0.6931
Method	ANCOVA
Parameter type	least square mean
Point estimate	0.012
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [56]
P-value	= 0.5734
Method	ANCOVA
Parameter type	least square mean
Point estimate	-0.017
Confidence interval
level	95%
sides	2-sided
lower limit	-0.078
upper limit	0.0435
Notes [56] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline in post-bronchodilator FEV1 Top of page

Other pre-specified: Change from baseline in pre-bronchodilator FVC Top of page
End point title	Change from baseline in pre-bronchodilator 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 pre-specified
End point timeframe	At Day 1, Day 9, Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: Liter     arithmetic mean (standard deviation) -0.079 ( 0.2833 ) 0.06 ( 0.3552 ) -0.109 ( 0.3519 )
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	Pre-specified
Analysis type	other [57]
P-value	= 0.2267
Method	ANCOVA
Parameter type	least square mean
Point estimate	0.058
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [58]
P-value	= 0.0292
Method	ANCOVA
Parameter type	least square mean
Point estimate	0.105
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [59]
P-value	= 0.3315
Method	ANCOVA
Parameter type	least square mean
Point estimate	-0.047
Confidence interval
level	95%
sides	2-sided
lower limit	-0.1421
upper limit	0.0486
Notes [59] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline in pre-bronchodilator FVC Top of page

Other pre-specified: Change from baseline in post-bronchodilator FVC Top of page
End point title	Change from baseline in post-bronchodilator 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 pre-specified
End point timeframe	At Day 9, Day 21, Day 24 and Day 28.
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: liters     arithmetic mean (standard deviation) -0.135 ( 0.3188 ) 0.007 ( 0.347 ) -0.128 ( 0.2882 )
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	Pre-specified
Analysis type	other [60]
P-value	= 0.6355
Method	ANCOVA
Parameter type	least square mean
Point estimate	0.023
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [61]
P-value	= 0.4213
Method	ANCOVA
Parameter type	least square mean
Point estimate	0.039
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [62]
P-value	= 0.7455
Method	ANCOVA
Parameter type	least square mean
Point estimate	-0.016
Confidence interval
level	95%
sides	2-sided
lower limit	-0.115
upper limit	0.0827
Notes [62] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline in post-bronchodilator FVC Top of page

Other pre-specified: Change from baseline to Day 28 in VC Top of page
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 pre-specified
End point timeframe	At Day 1 and Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: liters     arithmetic mean (standard deviation) 0.0013 ( 0.50406 ) 0.0612 ( 0.29528 ) 0.0853 ( 0.34144 )
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	Pre-specified
Analysis type	other [63]
P-value	= 0.3709
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.984
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [64]
P-value	= 0.243
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.021
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [65]
P-value	= 0.0311
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.964
Confidence interval
level	95%
sides	2-sided
lower limit	0.9321
upper limit	0.9965
Notes [65] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in VC Top of page

Other pre-specified: Change from baseline to Day 28 in IC Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: liters     arithmetic mean (standard deviation) 0.0354 ( 0.43351 ) 0.0312 ( 0.37439 ) 0.0017 ( 0.40019 )
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	Pre-specified
Analysis type	other [66]
P-value	= 0.5088
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.982
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [67]
P-value	= 0.5606
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.985
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [68]
P-value	= 0.9306
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.998
Confidence interval
level	95%
sides	2-sided
lower limit	0.9469
upper limit	1.0512
Notes [68] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in IC Top of page

Other pre-specified: Change from baseline to Day 28 in RV Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: liters     arithmetic mean (standard deviation) -0.0587 ( 1.08645 ) 0.016 ( 0.58512 ) 0.0097 ( 0.63798 )
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	Pre-specified
Analysis type	other [69]
P-value	= 0.6873
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.011
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [70]
P-value	= 0.1946
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.965
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [71]
P-value	= 0.0796
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.047
Confidence interval
level	95%
sides	2-sided
lower limit	0.9944
upper limit	1.1024
Notes [71] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in RV Top of page

Other pre-specified: Change from baseline to Day 28 in FRC Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: liters     arithmetic mean (standard deviation) -0.0726 ( 0.99242 ) 0.0607 ( 0.48505 ) 0.0867 ( 0.60328 )
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	Pre-specified
Analysis type	other [72]
P-value	= 0.9914
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [73]
P-value	= 0.9262
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.998
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [74]
P-value	= 0.9154
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.002
Confidence interval
level	95%
sides	2-sided
lower limit	0.9664
upper limit	1.0387
Notes [74] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in FRC Top of page

Other pre-specified: Change form baseline to Day 28 in TLC Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: liters     arithmetic mean (standard deviation) -0.0564 ( 0.79366 ) 0.0723 ( 0.53586 ) 0.0956 ( 0.62812 )
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	Pre-specified
Analysis type	other [75]
P-value	= 0.696
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.995
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other
P-value	= 0.3702 [76]
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.989
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [77]
P-value	= 0.6072
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.006
Confidence interval
level	95%
sides	2-sided
lower limit	0.9823
upper limit	1.0309
Notes [77] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change form baseline to Day 28 in TLC Top of page

Other pre-specified: Change from baseline to Day 28 in RV/TLC Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: percent     arithmetic mean (standard deviation) 0.1 ( 8.01 ) -0.2 ( 4.38 ) -0.4 ( 5.37 )
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	Pre-specified
Analysis type	other [78]
P-value	= 0.3623
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.018
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [79]
P-value	= 0.2407
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.978
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [80]
P-value	= 0.311
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.041
Confidence interval
level	95%
sides	2-sided
lower limit	1.0037
upper limit	1.0789
Notes [80] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in RV/TLC Top of page

Other pre-specified: Change from baseline to Day 28 in ITV Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: liters     arithmetic mean (standard deviation) -0.0267 ( 0.91372 ) -0.0112 ( 0.48576 ) 0.0822 ( 0.57956 )
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	Pre-specified
Analysis type	other [81]
P-value	= 0.7135
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.994
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [82]
P-value	= 0.5332
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.99
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [83]
P-value	= 0.8037
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.004
Confidence interval
level	95%
sides	2-sided
lower limit	0.9713
upper limit	1.0381
Notes [83] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in ITV Top of page

Other pre-specified: Change from baseline to Day 28 in sGAW Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: kPa/s     arithmetic mean (standard deviation) 0 ( 0.2071 ) 0.0302 ( 0.1805 ) 0.0086 ( 0.27717 )
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	Pre-specified
Analysis type	other [84]
P-value	= 0.4104
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.952
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [85]
P-value	= 0.2505
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.071
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [86]
P-value	= 0.0445
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.889
Confidence interval
level	95%
sides	2-sided
lower limit	0.7925
upper limit	0.997
Notes [86] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change from baseline to Day 28 in sGAW Top of page

Other pre-specified: Change form baseline to Day 28 in GAW Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: kPa*s/liters     arithmetic mean (standard deviation) -0.0003 ( 0.17315 ) -0.0388 ( 0.16972 ) -0.0051 ( 0.08507 )
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	Pre-specified
Analysis type	other [87]
P-value	= 0.3202
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.056
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [88]
P-value	= 0.3705
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.952
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [89]
P-value	= 0.0531
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.109
Confidence interval
level	95%
sides	2-sided
lower limit	0.9986
upper limit	1.2318
Notes [89] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Change form baseline to Day 28 in GAW Top of page

Other pre-specified: TDI scores on Day 28 Top of page
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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: integer     arithmetic mean (standard deviation) 0.2 ( 0.7 ) 0.2 ( 0.57 ) 0 ( 0.42 )
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	Pre-specified
Analysis type	other [90]
P-value	= 0.3202
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.056
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [91]
P-value	= 0.3705
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	0.952
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [92]
P-value	= 0.0531
Method	ANCOVA
Parameter type	geometric LSM
Point estimate	1.109
Confidence interval
level	95%
sides	2-sided
lower limit	0.9986
upper limit	1.2318
Notes [92] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: TDI scores on Day 28 Top of page

Other pre-specified: Rescue drug use over the 28-day period Top of page
End point title	Rescue drug use over the 28-day 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 pre-specified
End point timeframe	Throughout the 28-day period
End point values Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Number of subjects analysed 42 47 43 Units: puffs/day     arithmetic mean (standard deviation) 1.71 ( 2.244 ) 2.11 ( 2.667 ) 1.99 ( 2.583 )
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	Pre-specified
Analysis type	other [93]
P-value	= 0.1185
Method	ANOVA
Parameter type	least square mean
Point estimate	-0.23
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [94]
P-value	= 0.9173
Method	ANOVA
Parameter type	least square mean
Point estimate	0.01
Confidence interval
level	95%
sides	2-sided
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	Pre-specified
Analysis type	other [95]
P-value	= 0.0904
Method	ANOVA
Parameter type	least square mean
Point estimate	-0.25
Confidence interval
level	95%
sides	2-sided
lower limit	-0.53
upper limit	0.04
Notes [95] - This is a "proof of concept" study: no statistical hypothesis is included

Other pre-specified: Rescue drug use over the 28-day period Top of page

Other pre-specified: FEV1 on Day 1 Top of page
End point title	FEV1 on Day 1
End point description	FEV1, to assess potential occurrence of paradoxical bronchospasm on Day 1 (2-hour spirometry measurement). Absolute change values are reported here (sse table 14.3.9 of CSR)
End point type	Other pre-specified
End point timeframe	On Day 1 (2-hour spirometry measurement)
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: liters     arithmetic mean (standard deviation) 0.254 ( 0.1532 ) 0.246 ( 0.1853 ) 0.233 ( 0.158 )
No statistical analyses for this end point

Other pre-specified: FEV1 on Day 1 Top of page

Other pre-specified: Heart rate Top of page
End point title	Heart rate
End point description	Vital signs (HR and BP) were assessed after 5 min in supine position at pre-dose, 30 minutes, and 1, 2, 3, 6, 8 and 10 hours post-dose. Only data on Day 28, 10 hours post-dose are reported here (See tab. 14.3.6.1.1 of CSR).
End point type	Other pre-specified
End point timeframe	At Day 1 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: bpm     arithmetic mean (standard deviation) 73.9 ( 12.89 ) 76.6 ( 11.5 ) 74 ( 11.36 )
No statistical analyses for this end point

Other pre-specified: Heart rate Top of page

Other pre-specified: Systolic blood pressure Top of page
End point title	Systolic blood pressure
End point description	Vital signs (HR and BP) were assessed after 5 min in supine position at pre-dose, 30 minutes, and 1, 2, 3, 6, 8 and 10 hours post-dose. Only data from 10 hours post-dose measurement at Day 28 are reported here (sse table 14.3.6.2.1 of CSR).
End point type	Other pre-specified
End point timeframe	On Day 1 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: mmHg     arithmetic mean (standard deviation) 128.6 ( 18.99 ) 129.3 ( 16.73 ) 134.9 ( 16.47 )
No statistical analyses for this end point

Other pre-specified: Systolic blood pressure Top of page

Other pre-specified: Diastolic blood pressure Top of page
End point title	Diastolic blood pressure
End point description	Vital signs (HR and BP) were assessed after 5 min in supine position at pre-dose, 30 minutes, and 1, 2, 3, 6, 8 and 10 hours post-dose. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.6.3.1 of CSR).
End point type	Other pre-specified
End point timeframe	On Day 1 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: mmHg     arithmetic mean (standard deviation) 73.6 ( 12.37 ) 72.1 ( 11.04 ) 74.6 ( 10.95 )
No statistical analyses for this end point

Other pre-specified: Diastolic blood pressure Top of page

Other pre-specified: Body weight Top of page
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 pre-specified
End point timeframe	On Day 1 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: kg     arithmetic mean (standard deviation) 74.62 ( 16.446 ) 74.7 ( 15.971 ) 76.19 ( 16.868 )
No statistical analyses for this end point

Other pre-specified: Body weight Top of page

Other pre-specified: 12-lead ECG HR Top of page
End point title	12-lead ECG HR
End point description	Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.1.1 of CSR).
End point type	Other pre-specified
End point timeframe	At Day 1, Day 9, Day 21, Day 24 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: bpm     arithmetic mean (standard deviation) 74.4 ( 12.22 ) 76 ( 11.5 ) 74.8 ( 11.22 )
No statistical analyses for this end point

Other pre-specified: 12-lead ECG HR Top of page

Other pre-specified: 12-lead ECG PR Top of page
End point title	12-lead ECG PR
End point description	Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.2.1 of CSR).
End point type	Other pre-specified
End point timeframe	At Day 1, Day 9, Day 21, Day 24 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: msec     arithmetic mean (standard deviation) 155.9 ( 19.89 ) 153.3 ( 19.46 ) 157.9 ( 24.65 )
No statistical analyses for this end point

Other pre-specified: 12-lead ECG PR Top of page

Other pre-specified: 12-lead ECG QRS Top of page
End point title	12-lead ECG QRS
End point description	Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.3.1 of CSR).
End point type	Other pre-specified
End point timeframe	At Day 1, Day 9, Day 21, Day 24 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: msec     arithmetic mean (standard deviation) 91.1 ( 10.4 ) 92.4 ( 9.96 ) 91.4 ( 9.81 )
No statistical analyses for this end point

Other pre-specified: 12-lead ECG QRS Top of page

Other pre-specified: 12-lead ECG QT Top of page
End point title	12-lead ECG QT
End point description	Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.4.1 of CSR).
End point type	Other pre-specified
End point timeframe	At Day 1, Day 9, Day 21, Day 24 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: msec     arithmetic mean (standard deviation) 387.1 ( 25.61 ) 383.4 ( 25.29 ) 385.7 ( 26.75 )
No statistical analyses for this end point

Other pre-specified: 12-lead ECG QT Top of page

Other pre-specified: 12-lead ECG QTcB Top of page
End point title	12-lead ECG QTcB
End point description	Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.5.1 of CSR).
End point type	Other pre-specified
End point timeframe	At Day 1, Day 9, Day 21, Day 24 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: msec     arithmetic mean (standard deviation) 427.5 ( 18.06 ) 428.7 ( 15.91 ) 427.4 ( 18.25 )
No statistical analyses for this end point

Other pre-specified: 12-lead ECG QTcB Top of page

Other pre-specified: 12-lead ECG QTcF Top of page
End point title	12-lead ECG QTcF
End point description	Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.6.1 of CSR).
End point type	Other pre-specified
End point timeframe	At Day 1, Day 9, Day 21, Day 24 and Day 28
End point values Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Number of subjects analysed 42 49 43 Units: msec     arithmetic mean (standard deviation) 413.3 ( 14.05 ) 412.8 ( 14.24 ) 412.8 ( 15.65 )
No statistical analyses for this end point

Other pre-specified: 12-lead ECG QTcF Top of page

Other pre-specified: AUC0-t,ss of CHF6001 Top of page
End point title	AUC0-t,ss of CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 38 Units: pg*h/ml     geometric mean (geometric coefficient of variation) 16954 ( 42.1 )
No statistical analyses for this end point

Other pre-specified: AUC0-t,ss of CHF6001 Top of page

Other pre-specified: AUC0-t,ss of CHF5956 Top of page
End point title	AUC0-t,ss of CHF5956
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 39 Units: pg*h/mL     geometric mean (geometric coefficient of variation) 1097 ( 78.9 )
No statistical analyses for this end point

Other pre-specified: AUC0-t,ss of CHF5956 Top of page

Other pre-specified: AUC0-t,ss of CHF6095 Top of page
End point title	AUC0-t,ss of CHF6095
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 39 Units: pg*h/mL     geometric mean (geometric coefficient of variation) 322 ( 61.3 )
No statistical analyses for this end point

Other pre-specified: AUC0-t,ss of CHF6095 Top of page

Other pre-specified: AUC0-24h,ss of CHF6001 Top of page
End point title	AUC0-24h,ss of CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 33 Units: pg*h/mL     geometric mean (geometric coefficient of variation) 17344 ( 39.1 )
No statistical analyses for this end point

Other pre-specified: AUC0-24h,ss of CHF6001 Top of page

Other pre-specified: AUC0-24h,ss of CHF5956 Top of page
End point title	AUC0-24h,ss of CHF5956
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 34 Units: pg*h/mL     geometric mean (geometric coefficient of variation) 1193 ( 63.2 )
No statistical analyses for this end point

Other pre-specified: AUC0-24h,ss of CHF5956 Top of page

Other pre-specified: AUC0-24h,ss of CHF6095 Top of page
End point title	AUC0-24h,ss of CHF6095
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 27 Units: pg*h/mL     geometric mean (geometric coefficient of variation) 374 ( 49 )
No statistical analyses for this end point

Other pre-specified: AUC0-24h,ss of CHF6095 Top of page

Other pre-specified: Cmin,ss of CHF6001 Top of page
End point title	Cmin,ss of CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 38 Units: pg/mL     geometric mean (geometric coefficient of variation) 486 ( 48.4 )
No statistical analyses for this end point

Other pre-specified: Cmin,ss of CHF6001 Top of page

Other pre-specified: Cmax,ss of CHF6001 Top of page
End point title	Cmax,ss of CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 38 Units: pg/mL     geometric mean (geometric coefficient of variation) 1204 ( 35.4 )
No statistical analyses for this end point

Other pre-specified: Cmax,ss of CHF6001 Top of page

Other pre-specified: Cmax,ss of CHF5956 Top of page
End point title	Cmax,ss of CHF5956
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 39 Units: pg/mL     geometric mean (geometric coefficient of variation) 130 ( 60.1 )
No statistical analyses for this end point

Other pre-specified: Cmax,ss of CHF5956 Top of page

Other pre-specified: Cmax,ss of CHF6095 Top of page
End point title	Cmax,ss of CHF6095
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 39 Units: pg/mL     geometric mean (geometric coefficient of variation) 49.4 ( 45.4 )
No statistical analyses for this end point

Other pre-specified: Cmax,ss of CHF6095 Top of page

Other pre-specified: Cav,ss of CHF6001 Top of page
End point title	Cav,ss of CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 33 Units: pg/mL     geometric mean (geometric coefficient of variation) 723 ( 39.1 )
No statistical analyses for this end point

Other pre-specified: Cav,ss of CHF6001 Top of page

Other pre-specified: Cav,ss of CHF5956 Top of page
End point title	Cav,ss of CHF5956
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 34 Units: pg/mL     geometric mean (geometric coefficient of variation) 49.7 ( 63.2 )
No statistical analyses for this end point

Other pre-specified: Cav,ss of CHF5956 Top of page

Other pre-specified: Cav,ss of CHF6095 Top of page
End point title	Cav,ss of CHF6095
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 27 Units: pg/mL     geometric mean (geometric coefficient of variation) 15.6 ( 49 )
No statistical analyses for this end point

Other pre-specified: Cav,ss of CHF6095 Top of page

Other pre-specified: Tmax,ss for CHF6001 Top of page
End point title	Tmax,ss for CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 38 Units: hours     median (full range (min-max)) 1.78 (0.98 to 6.03)
No statistical analyses for this end point

Other pre-specified: Tmax,ss for CHF6001 Top of page

Other pre-specified: Tmax,ss for CHF5956 Top of page
End point title	Tmax,ss for CHF5956
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 39 Units: hours     median (full range (min-max)) 3 (0 to 8.02)
No statistical analyses for this end point

Other pre-specified: Tmax,ss for CHF5956 Top of page

Other pre-specified: Tmax,ss for CHF6095 Top of page
End point title	Tmax,ss for CHF6095
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 39 Units: hours     median (full range (min-max)) 2.98 (0 to 6.03)
No statistical analyses for this end point

Other pre-specified: Tmax,ss for CHF6095 Top of page

Other pre-specified: Tmin,ss for CHF6001 Top of page
End point title	Tmin,ss for CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 38 Units: hours     median (full range (min-max)) 24 (9.75 to 24.2)
No statistical analyses for this end point

Other pre-specified: Tmin,ss for CHF6001 Top of page

Other pre-specified: Tmin,ss for CHF5956 Top of page
End point title	Tmin,ss for CHF5956
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 39 Units: hours     median (full range (min-max)) 24 (8 to 24.2)
No statistical analyses for this end point

Other pre-specified: Tmin,ss for CHF5956 Top of page

Other pre-specified: Tmin,ss of CHF6095 Top of page
End point title	Tmin,ss of CHF6095
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 39 Units: hours     median (full range (min-max)) 24 (5.98 to 24.2)
No statistical analyses for this end point

Other pre-specified: Tmin,ss of CHF6095 Top of page

Other pre-specified: T1/2,ss for CHF6001 Top of page
End point title	T1/2,ss for CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 27 Units: hours     geometric mean (geometric coefficient of variation) 27.5 ( 43.9 )
No statistical analyses for this end point

Other pre-specified: T1/2,ss for CHF6001 Top of page

Other pre-specified: T1/2,ss for CHF5956 Top of page
End point title	T1/2,ss for CHF5956
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 30 Units: hours     geometric mean (geometric coefficient of variation) 11 ( 77.1 )
No statistical analyses for this end point

Other pre-specified: T1/2,ss for CHF5956 Top of page

Other pre-specified: T1/2,ss for CHF6095 Top of page
End point title	T1/2,ss for CHF6095
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 17 Units: hours     geometric mean (geometric coefficient of variation) 13.7 ( 128 )
No statistical analyses for this end point

Other pre-specified: T1/2,ss for CHF6095 Top of page

Other pre-specified: CL/F, ss for CHF6001 Top of page
End point title	CL/F, ss for CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 33 Units: mL/min     geometric mean (geometric coefficient of variation) 1153 ( 39.1 )
No statistical analyses for this end point

Other pre-specified: CL/F, ss for CHF6001 Top of page

Other pre-specified: CL/F, ss for CHF5956 Top of page
End point title	CL/F, ss for CHF5956
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 34 Units: mL/min     geometric mean (geometric coefficient of variation) 16758 ( 63.2 )
No statistical analyses for this end point

Other pre-specified: CL/F, ss for CHF5956 Top of page

Other pre-specified: Cl/F, ss for CHF6095 Top of page
End point title	Cl/F, ss for CHF6095
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 27 Units: mL/min     geometric mean (geometric coefficient of variation) 53466 ( 49 )
No statistical analyses for this end point

Other pre-specified: Cl/F, ss for CHF6095 Top of page

Other pre-specified: Vz/F,ss for CHF6001 Top of page
End point title	Vz/F,ss for CHF6001
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 38 Units: liters     geometric mean (geometric coefficient of variation) 2636 ( 69.8 )
No statistical analyses for this end point

Other pre-specified: Vz/F,ss for CHF6001 Top of page

Other pre-specified: Vz/F,ss for CHF5956 Top of page
End point title	Vz/F,ss for CHF5956
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 30 Units: liters     geometric mean (geometric coefficient of variation) 15537 ( 97.7 )
No statistical analyses for this end point

Other pre-specified: Vz/F,ss for CHF5956 Top of page

Other pre-specified: Vz/F,ss for CHF6095 Top of page
End point title	Vz/F,ss for CHF6095
End point description	PK blood collection will be performed on Day 28 at pre-dose 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 pre-specified
End point timeframe	At Day 28
End point values Test treatment - PK population Number of subjects analysed 17 Units: liters     geometric mean (geometric coefficient of variation) 53865 ( 123 )
No statistical analyses for this end point

Other pre-specified: Vz/F,ss for CHF6095 Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Throughout the study (from run-in to follow-up)
Adverse event reporting additional description	It was the responsibility of the Investigator to collect all AEs (both serious and non-serious), derived by spontaneous, unsolicited reports of patients, by observation and by routine open questioning
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	14.0
Reporting groups
Reporting group title	Period of treatment with CHF6001 - Safety population
Reporting group description	-
Reporting group title	Period of treatment with roflumilast - Safety population
Reporting group description	-
Reporting group title	Period of treatment with placebo - Safety population
Reporting group description	-
Reporting group title	Period of wash out - Safety population
Reporting group description	-
Reporting group title	Followp up - Safety population
Reporting group description	-
Serious adverse events Period of treatment with CHF6001 - Safety population Period of treatment with roflumilast - Safety population Period of treatment with placebo - Safety population Period of wash out - Safety population Followp up - Safety population Total subjects affected by serious adverse events      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      number of deaths (all causes) 0 0 0 0 0      number of deaths resulting from adverse events 0 0 0 0 0 Gastrointestinal disorders Peritonitis      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Infections and infestations Gallbladder empyema      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 1%
Non-serious adverse events Period of treatment with CHF6001 - Safety population Period of treatment with roflumilast - Safety population Period of treatment with placebo - Safety population Period of wash out - Safety population Followp up - Safety population Total subjects affected by non serious adverse events      subjects affected / exposed 32 / 42 (76.19%) 37 / 49 (75.51%) 30 / 43 (69.77%) 32 / 48 (66.67%) 9 / 46 (19.57%) Vascular disorders Hot flush      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 General disorders and administration site conditions Catheter site haematoma      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 3 / 43 (6.98%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 3 0 0 Chest discomfort      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 1 / 43 (2.33%) 0 / 48 (0.00%) 1 / 46 (2.17%)      occurrences all number 0 1 1 0 1 Exercise tolerance decreased      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Feeling hot      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Malaise      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Pain      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Pyrexia      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 1 / 46 (2.17%)      occurrences all number 0 0 0 0 1 Thirst      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 2 0 0 Vessel puncture site haematoma      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 0 0 0 Immune system disorders Seasonal allergy      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 1 / 42 (2.38%) 4 / 49 (8.16%) 6 / 43 (13.95%) 7 / 48 (14.58%) 0 / 46 (0.00%)      occurrences all number 1 4 7 7 0 Chronic obstructive pulmonary disease      subjects affected / exposed 3 / 42 (7.14%) 2 / 49 (4.08%) 4 / 43 (9.30%) 5 / 48 (10.42%) 1 / 46 (2.17%)      occurrences all number 3 2 4 5 1 Dyspnoea      subjects affected / exposed 4 / 42 (9.52%) 5 / 49 (10.20%) 3 / 43 (6.98%) 4 / 48 (8.33%) 1 / 46 (2.17%)      occurrences all number 6 5 3 4 1 Haemoptysis      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 1 / 46 (2.17%)      occurrences all number 1 0 1 0 1 Wheezing      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 2 / 43 (4.65%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 1 2 1 0 Dysphonia      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 1 0 0 Nasal congestion      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 1 0 0 Oropharyngeal pain      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 2 / 48 (4.17%) 0 / 46 (0.00%)      occurrences all number 0 0 0 3 0 Productive cough      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 1 1 0 Sputum increased      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 1 0 0 Dry throat      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Epistaxis      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Respiratory tract congestion      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Rhinorrhoea      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Synus congestion      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Sputum discoloured      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 1 0 0 Psychiatric disorders Anxiety      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Depressed mood      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Insomnia      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Panic attack      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Terminal insomnia      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Investigations Blood cholesterol increased      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Gamma-glutamyltransferase increased      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Sputum abnormal      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Injury, poisoning and procedural complications Contusion      subjects affected / exposed 1 / 42 (2.38%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 1 0 0 0 Muscle strain      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 1 0 0 Procedural site reaction      subjects affected / exposed 1 / 42 (2.38%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 1 0 0 0 Arthropod sting      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Foreign body      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Joint injury      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 2 0 0 0 0 Joint sprain      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Periorbital haematoma      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Post procedural swelling      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Procedural vomiting      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Sternal fracture      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Cardiac disorders Palpitations      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Nervous system disorders Headache      subjects affected / exposed 12 / 42 (28.57%) 17 / 49 (34.69%) 6 / 43 (13.95%) 4 / 48 (8.33%) 0 / 46 (0.00%)      occurrences all number 15 19 9 4 0 Migrane      subjects affected / exposed 1 / 42 (2.38%) 2 / 49 (4.08%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 2 0 0 0 Dizziness      subjects affected / exposed 0 / 42 (0.00%) 2 / 49 (4.08%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 2 0 0 0 Dysgeusia      subjects affected / exposed 1 / 42 (2.38%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 1 0 0 0 Lethargy      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Sciatica      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Ear and labyrinth disorders Cerumen impaction      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Gastrointestinal disorders Diarrhoea      subjects affected / exposed 5 / 42 (11.90%) 10 / 49 (20.41%) 2 / 43 (4.65%) 2 / 48 (4.17%) 0 / 46 (0.00%)      occurrences all number 8 10 2 2 0 Toothache      subjects affected / exposed 2 / 42 (4.76%) 2 / 49 (4.08%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 3 2 0 1 0 Vomiting      subjects affected / exposed 2 / 42 (4.76%) 2 / 49 (4.08%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 2 2 0 1 0 Nausea      subjects affected / exposed 1 / 42 (2.38%) 3 / 49 (6.12%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 3 0 0 0 Abdominal discomfort      subjects affected / exposed 0 / 42 (0.00%) 3 / 49 (6.12%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 3 0 0 0 Abdominal pain      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 2 / 48 (4.17%) 0 / 46 (0.00%)      occurrences all number 0 1 0 2 0 Constipation      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 3 / 48 (6.25%) 1 / 46 (2.17%)      occurrences all number 0 0 0 3 1 Dyspepsia      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 2 / 43 (4.65%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 2 0 0 Frequent bowel movements      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 1 0 0 Abdominal distension      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Abdominal pain lower      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Abdominal pain upper      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Food poisoning      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Gastrooesophageal reflux disease      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Lip dry      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Peritonitis      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Skin and subcutaneous tissue disorders Psoriasis      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 1 0 1 0 Rush      subjects affected / exposed 1 / 42 (2.38%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 1 0 0 0 Dermal cyst      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 1 / 46 (2.17%)      occurrences all number 0 0 0 0 1 Hyperhidrosis      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Skin discolouration      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Musculoskeletal and connective tissue disorders Back pain      subjects affected / exposed 1 / 42 (2.38%) 2 / 49 (4.08%) 1 / 43 (2.33%) 2 / 48 (4.17%) 1 / 46 (2.17%)      occurrences all number 1 3 1 2 1 Myalgia      subjects affected / exposed 1 / 42 (2.38%) 2 / 49 (4.08%) 0 / 43 (0.00%) 0 / 48 (0.00%) 1 / 46 (2.17%)      occurrences all number 1 2 0 0 1 Arthralgia      subjects affected / exposed 2 / 42 (4.76%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 2 0 0 0 0 Joint swelling      subjects affected / exposed 1 / 42 (2.38%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 1 0 0 0 Muscoloskeletal chest pain      subjects affected / exposed 2 / 42 (4.76%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 2 0 0 0 0 Muscoloskeletal pain      subjects affected / exposed 1 / 42 (2.38%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 1 0 0 0 Arthritis      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Coccydynia      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Muscle spasms      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Osteoarthritis      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Pain in extremity      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 1 0 1 0 Infections and infestations Nasopharyngitis      subjects affected / exposed 4 / 42 (9.52%) 4 / 49 (8.16%) 2 / 43 (4.65%) 2 / 48 (4.17%) 1 / 46 (2.17%)      occurrences all number 4 4 2 2 1 Upper respiratory tract infection      subjects affected / exposed 2 / 42 (4.76%) 2 / 49 (4.08%) 1 / 43 (2.33%) 3 / 48 (6.25%) 0 / 46 (0.00%)      occurrences all number 2 2 1 3 0 Lower respiratory tract infection      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 1 / 43 (2.33%) 0 / 48 (0.00%) 1 / 46 (2.17%)      occurrences all number 0 1 1 0 1 Oral candidiasis      subjects affected / exposed 2 / 42 (4.76%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 2 1 0 0 0 Rhinitis      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 2 / 48 (4.17%) 0 / 46 (0.00%)      occurrences all number 1 0 0 2 0 Urinary tract infection      subjects affected / exposed 1 / 42 (2.38%) 1 / 49 (2.04%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 1 1 0 1 0 Gallbladder empyema      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Gastroenteritis      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Gingival abscess      subjects affected / exposed 1 / 42 (2.38%) 0 / 49 (0.00%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 1 0 0 0 0 Gingival infection      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Sinusitis      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Skin infection      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Tooth abscess      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 1 / 43 (2.33%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 0 1 0 0 Tooth infection      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Viral infection      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 0 / 43 (0.00%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 0 0 0 Viral upper respiratory tract infection      subjects affected / exposed 0 / 42 (0.00%) 0 / 49 (0.00%) 0 / 43 (0.00%) 1 / 48 (2.08%) 0 / 46 (0.00%)      occurrences all number 0 0 0 1 0 Metabolism and nutrition disorders Decreased appetite      subjects affected / exposed 0 / 42 (0.00%) 1 / 49 (2.04%) 2 / 43 (4.65%) 0 / 48 (0.00%) 0 / 46 (0.00%)      occurrences all number 0 1 2 0 0

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Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
16 Jul 2012	Substantial Amendment 01 was written following a request from the Medicines and Healthcare products Regulatory Agency (MHRA) to modify the exclusion criteria such that patients with known contraindications or hypersensitivity to roflumilast, tiotropium bromide, or salbutamol, and patients with moderate or severe hepatic impairment, would not be considered eligible for the study. The MHRA also requested that rationale to justify both the selected dose of CHF 6001 and duration of its use in this study be added. Requests made by the IEC to amend the Information Sheet and Informed Consent Form ( II of the protocol) were also addressed in this amendment, as follows: 1. Information Sheet • the language and terminology used were simplified; • prohibited medications were included; • information on the National Health Service Patient Advice and Liaison Service was added; • it was included that patients should not donate blood during participation; • it was included that participants should be advised to use 2 forms of contraception during the course of the study and for 3 months later. 2. Informed Consent Form • the term ‘patients’ was amended to read ‘patients’ or ‘participants’. This amendment also added the evaluation of the systemic exposure to metabolite CHF 5956 to the pharmacokinetic assessments in this study. Preclinical studies and preliminary data from the human metabolic profiling of CHF 6001 suggest that its main metabolites are CHF 5956 and CHF 6095, though the investigation of systemic exposure to CHF 6001 metabolites had been focussed only on CHF 5956 which had appeared to be the most abundant compound. More recent preliminary toxicokinetic data had shown detectable concentrations of metabolite CHF 6095 in plasma samples from the rat and dog. Consequently, CHF 6095 was considered of interest and its evaluation was thus added to this protocol.
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
No limitations or caveats are reported in this study

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