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Clinical Trial Results:
A RANDOMISED, DOUBLE-BLIND, PLACEBO CONTROLLED, REPEATED DOSE, THREE-WAY CROSSOVER STUDY TO EVALUATE THE PHARMACODYNAMICS, PHARMACOKINETICS AND SAFETY OF TWO DOSES OF CHF 6001 DPI IN SUBJECTS WITH MODERATE, SEVERE COPD.

Summary
EudraCT number	2015-005550-35
Trial protocol	GB DE
Global end of trial date	28 Dec 2017

Results information
Results version number	v1(current)
This version publication date	06 Jan 2019
First version publication date	06 Jan 2019
Other versions

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

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Trial information

Top of page

Sponsor protocol code

CCD-06001AA1-10

ISRCTN number

US NCT number

NCT03004417

WHO universal trial number (UTN)

Sponsor organisation name

Chiesi Farmaceutici S.p.A.

Sponsor organisation address

Via Palermo 26/A, Parma, Italy, 43122

Public contact

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com

Scientific contact

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com

Is trial part of an agreed paediatric investigation plan (PIP)

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

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

Analysis stage

Final

Date of interim/final analysis

19 Nov 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

28 Dec 2017

Global end of trial reached?

Yes

Global end of trial date

28 Dec 2017

Was the trial ended prematurely?

Main objective of the trial

The objectives of the study were: - To evaluate the effect of CHF 6001 on biomarkers of inflammation in induced sputum and in blood, on pulmonary function and on symptoms benefits in comparison with placebo; - To evaluate the safety and tolerability of CHF 6001; - To assess the PK profile of CHF 6001 and its metabolites at steady state in patients with moderate, severe COPD.

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinki, with the Good Clinical Practice (GCP) guidelines in force during study conduct and following all other requirements of local laws. At all visits from screening onwards, concomitant medications and adverse events (AEs) were recorded. Height and weight were measured at screening and weight was measured at Day 1 and Day 32 of each treatment period. Physical examinations were performed at screening, on Day 1 and Day 32 of each treatment period and at the follow-up visit. Additional physical examinations could have been performed on Day 20 and Day 26 of each treatment period, as needed. Vital signs and 12-lead electrocardiograms (ECGs) were recorded at screening and pre-dose on Day 1 and Day 32 of each treatment period. Patients were provided with salbutamol as rescue medication to use as needed throughout the study. Patients were maintained on their regular medication (triple therapy) throughout the study.

Background therapy

Patient's receiving daily maintenance with triple therapy (i.e. inhaled corticosteroid [ICS] plus long-acting beta-2 agonist [LABA] plus long-acting muscarinic anticholinergenic [LAMA]) at a stable dose and dosing regimen for at least 2 months prior to screening were enrolled in the study. Patients continued to receive this triple background medication throughout the study.

Evidence for comparator

Actual start date of recruitment

31 Oct 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 21

Country: Number of subjects enrolled

Germany: 40

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

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 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

140 patients were screened according to inclusion/exclusion criteria; 61 patients were randomised to 1 of 6 treatment sequences (Sequence CHF 6001 1600 µg [L]-CHF 6001 3200 µg [H]-placebo [P] [n=11], Sequence L-P-H [n=10], Sequence H-L-P [n=10], Sequence H-P-L [n=12], Sequence P-L-H [n=9], Sequence P-H-L [n=9]); 54 patients completed the study.

Screening details

The study comprised a pre-screening visit, occurring no more than 1 week prior to a screening visit. At the screening visit, inclusion/exclusion criteria were assessed. There were 79 screening failures (78 patients did not meet inclusion/exclusion criteria and 1 patient was lost to follow-up).

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

Blinding implementation details

At randomisation, patients were sequentially assigned to one of the six treatment sequences using a balanced block randomisation scheme and a pre-established randomisation list. The randomisation list was provided to the labelling facility and to the analytical and biomarker laboratories, but was not available to patients, investigators, monitors or employees of the centre involved in the management of the study before unblinding of the data, unless in case of emergency.

Are arms mutually exclusive

Yes

Sequence L-H-P

Arm description

Patients were randomised to receive three different treatments (total daily doses of 1600 µg and 3200 µg of CHF 6001 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted 32 (+2) days and were separated by two washout periods of 28 to 42 days. Treatment L = CHF 6001 1600 µg; Treatment H = CHF 6001 3200 µg; Treatment P = matched placebo.

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

CHF 6001

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained four inhalers (two inhalers for the morning administration and two inhalers for the evening administration). During each 32 (+2) day treatment period, the study medication was administered twice daily with patients taking two puffs from each "morning" inhaler and two puffs from each "evening" inhaler, adding up to eight puffs per day. Treatment L = CHF 6001 1600 µg; Treatment H = CHF 6001 3200 µg; Treatment P = placebo.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Sequence L-P-H

Arm description

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

CHF 6001

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Sequence H-L-P

Arm description

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

CHF 6001

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Sequence H-P-L

Arm description

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

CHF 6001

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Sequence P-L-H

Arm description

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

CHF 6001

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Sequence P-H-L

Arm description

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

CHF 6001

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Number of subjects in period 1	Sequence L-H-P	Sequence L-P-H	Sequence H-L-P	Sequence H-P-L	Sequence P-L-H	Sequence P-H-L
Started	11	10	10	12	9	9
Completed	10	9	9	10	8	8
Not completed	1	1	1	2	1	1
Adverse event, non-fatal	1	1	1	1	1	1
Lost to follow-up	-	-	-	1	-	-

Baseline characteristics

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Reporting group title

Sequence L-H-P

Reporting group description

Reporting group title

Sequence L-P-H

Reporting group description

Reporting group title

Sequence H-L-P

Reporting group description

Reporting group title

Sequence H-P-L

Reporting group description

Reporting group title

Sequence P-L-H

Reporting group description

Reporting group title

Sequence P-H-L

Reporting group description

Reporting group values	Sequence L-H-P	Sequence L-P-H	Sequence H-L-P	Sequence H-P-L	Sequence P-L-H	Sequence P-H-L	Total
Number of subjects	11	10	10	12	9	9	61
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	3	3	5	5	5	3	24
From 65-84 years	8	7	5	7	4	6	37
85 years and over	0	0	0	0	0	0	0
Gender categorical
Units: Subjects
Female	3	4	3	3	2	3	18
Male	8	6	7	9	7	6	43

End points

Top of page

Reporting group title

Sequence L-H-P

Reporting group description

Reporting group title

Sequence L-P-H

Reporting group description

Reporting group title

Sequence H-L-P

Reporting group description

Reporting group title

Sequence H-P-L

Reporting group description

Reporting group title

Sequence P-L-H

Reporting group description

Reporting group title

Sequence P-H-L

Reporting group description

Subject analysis set title

L: CHF 6001 1600 µg - PD

Subject analysis set type

Per protocol

Subject analysis set description

Treatment L: CHF 6001 1600 µg; the population was defined as all patients from the Safety population with available evaluation in at least two treatment periods excluding patients without any pharmacodynamic (PD) measurement and with major protocol deviations affecting the PD evaluations.

Subject analysis set title

H: CHF 6001 3200 µg - PD

Subject analysis set type

Per protocol

Subject analysis set description

Treatment H: CHF 6001 1600 µg; the population was defined as all patients from the Safety population with available evaluation in at least two treatment periods excluding patients without any pharmacodynamic (PD) measurement and with major protocol deviations affecting the PD evaluations.

Subject analysis set title

P: Placebo - PD

Subject analysis set type

Per protocol

Subject analysis set description

Treatment P : placebo; the population was defined as all patients from the Safety population with available evaluation in at least two treatment periods excluding patients without any pharmacodynamic (PD) measurement and with major protocol deviations affecting the PD evaluations.

Subject analysis set title

L: CHF 6001 1600 µg - PK

Subject analysis set type

Per protocol

Subject analysis set description

The PK population consisted of all patients from the Safety population excluding patients without any valid PK assessment and with major protocol deviations affecting the PK evaluations.

Subject analysis set title

H: CHF 6001 3200 µg - PK

Subject analysis set type

Per protocol

Subject analysis set description

The PK population consisted of all patients from the Safety population excluding patients without any valid PK assessment and with major protocol deviations affecting the PK evaluations.

Primary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in TNF-α in induced sputum

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End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in TNF-α in induced sputum

End point description

Note: all endpoints in this study were considered exploratory and none were defined as primary, secondary etc. In order to present results in the EudraCT system we have arbitrarily considered the change from baseline in TNF-α in induced sputum as the relevant endpoint to be labelled as the primary endpoint. All other endpoints were arbitrarily assigned as secondary endpoints.

End point type

Primary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	39	44	47
Units: pg/mL
geometric mean (confidence interval 95%)	0.488 (0.353 to 0.676)	0.658 (0.484 to 0.896)	1.012 (0.760 to 1.346)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

TNF-α level in induced sputum, obtained on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.001

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.482

Confidence interval

level

95%

sides

2-sided

lower limit

0.314

upper limit

0.741

Notes
[1] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

H: CHF 6001 3200 µg - PD v P: Placebo - PD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

= 0.049

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.651

Confidence interval

level

95%

sides

2-sided

lower limit

0.424

upper limit

0.998

Notes
[2] - Explorative

Secondary: Change from baseline to end to treatment (mean Day 20, 26 and 32 values) in absolute neutrophil count in induced sputum

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End point title

Change from baseline to end to treatment (mean Day 20, 26 and 32 values) in absolute neutrophil count in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	52	53	53
Units: 10^6/g
geometric mean (confidence interval 95%)	1.095 (0.901 to 1.331)	0.943 (0.777 to 1.144)	0.912 (0.753 to 1.103)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Absolute neutrophil count in induced sputum, obtained on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

P: Placebo - PD v L: CHF 6001 1600 µg - PD

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.183

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.201

Confidence interval

level

95%

sides

2-sided

lower limit

0.916

upper limit

1.575

Notes
[3] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

= 0.807

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.034

Confidence interval

level

95%

sides

2-sided

lower limit

0.789

upper limit

1.354

Notes
[4] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute eosinophil count in induced sputum

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End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute eosinophil count in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean of Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	52	53	53
Units: 10^6/g
geometric mean (confidence interval 95%)	0.829 (0.602 to 1.143)	0.875 (0.636 to 1.204)	1.016 (0.741 to 1.392)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Absolute eosinophil count in induced sputum, obtained on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.371

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.817

Confidence interval

level

95%

sides

2-sided

lower limit

0.522

upper limit

1.277

Notes
[5] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.508

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.862

Confidence interval

level

95%

sides

2-sided

lower limit

0.552

upper limit

1.345

Notes
[6] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute macrophage count in induced sputum

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End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute macrophage count in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	52	53	53
Units: 10^6/g
geometric mean (confidence interval 95%)	0.938 (0.774 to 1.135)	1.055 (0.874 to 1.275)	1.240 (1.029 to 1.495)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Absolute macrophage count in induced sputum, obtained on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.04

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.756

Confidence interval

level

95%

sides

2-sided

lower limit

0.579

upper limit

0.987

Notes
[7] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[8]

P-value

= 0.228

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.851

Confidence interval

level

95%

sides

2-sided

lower limit

0.653

upper limit

1.108

Notes
[8] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute lymphocyte count in induced sputum

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End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute lymphocyte count in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	52	53	53
Units: 10^6/g
geometric mean (confidence interval 95%)	1.378 (0.825 to 2.301)	1.450 (0.870 to 2.417)	2.026 (1.222 to 3.359)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Absolute lymphocyte count in induced sputum, obtained on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data was log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

other ^[9]

P-value

= 0.289

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

0.331

upper limit

1.395

Notes
[9] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Absolute lymphocyte count in induced sputum, obtained on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

= 0.357

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.716

Confidence interval

level

95%

sides

2-sided

lower limit

0.349

upper limit

1.466

Notes
[10] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of neutrophils in induced sputum

Top of page

End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of neutrophils in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	52	53	53
Units: percentage
geometric mean (confidence interval 95%)	1.013 (0.979 to 1.049)	0.999 (0.965 to 1.035)	0.957 (0.925 to 0.991)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

percentage of neutrophils in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

= 0.023

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.059

Confidence interval

level

95%

sides

2-sided

lower limit

1.008

upper limit

1.112

Notes
[11] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.087

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.044

Confidence interval

level

95%

sides

2-sided

lower limit

0.994

upper limit

1.097

Notes
[12] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of eosinophils in induced sputum

Top of page

End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of eosinophils in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean of Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	52	53	53
Units: percentage
geometric mean (confidence interval 95%)	0.746 (0.584 to 0.952)	0.888 (0.696 to 1.134)	0.989 (0.779 to 1.257)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

percentage of eosinophils in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

= 0.103

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.754

Confidence interval

level

95%

sides

2-sided

lower limit

0.536

upper limit

1.06

Notes
[13] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.53

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.898

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

1.26

Notes
[14] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of macrophages in induced sputum

Top of page

End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of macrophages in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	52	53	53
Units: percentage
geometric mean (confidence interval 95%)	1.001 (0.833 to 1.204)	1.226 (1.022 to 1.471)	1.414 (1.180 to 1.695)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

percentage of macrophages in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

= 0.009

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.708

Confidence interval

level

95%

sides

2-sided

lower limit

0.547

upper limit

0.916

Notes
[15] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

= 0.27

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.867

Confidence interval

level

95%

sides

2-sided

lower limit

0.671

upper limit

1.12

Notes
[16] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of lymphocytes in induced sputum

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End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of lymphocytes in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean of Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	52	53	53
Units: percentage
geometric mean (confidence interval 95%)	1.011 (0.818 to 1.250)	0.990 (0.802 to 1.224)	1.190 (0.966 to 1.465)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

percentage of lymphocytes in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

= 0.279

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.632

upper limit

1.143

Notes
[17] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.221

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.832

Confidence interval

level

95%

sides

2-sided

lower limit

0.619

upper limit

1.119

Notes
[18] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in IL-6 in induced sputum

Top of page

End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in IL-6 in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	48	53	54
Units: pg/mL
geometric mean (confidence interval 95%)	0.873 (0.754 to 1.011)	1.164 (1.015 to 1.335)	0.861 (0.754 to 0.984)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

IL-6 in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

other ^[19]

P-value

= 0.895

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.013

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.236

Notes
[19] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

= 0.002

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.351

Confidence interval

level

95%

sides

2-sided

lower limit

1.116

upper limit

1.636

Notes
[20] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in IL-8 in induced sputum

Top of page

End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in IL-8 in induced sputum

End point description

Note: all endpoints in this study were considered exploratory and none were defined as primary, secondary etc. In order to present results in the EudraCT system we have arbitrarily included the change from baseline in TNF-α in induced sputum as the primary endpoint. All other endpoints were arbitrarily assigned as secondary endpoints.

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	52	54	54
Units: pg/mL
geometric mean (confidence interval 95%)	0.54 (0.46 to 0.63)	0.64 (0.55 to 0.75)	0.81 (0.70 to 0.94)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

IL-8 in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

< 0.001

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

0.83

Notes
[21] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

= 0.035

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

0.98

Notes
[22] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MIP1β in induced sputum

Top of page

End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MIP1β in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	31	38	34
Units: pg/mL
geometric mean (confidence interval 95%)	0.510 (0.414 to 0.628)	0.508 (0.419 to 0.616)	0.813 (0.670 to 0.986)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

MIP1β in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.002

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.627

Confidence interval

level

95%

sides

2-sided

lower limit

0.471

upper limit

0.834

Notes
[23] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

< 0.001

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.625

Confidence interval

level

95%

sides

2-sided

lower limit

0.478

upper limit

0.818

Notes
[24] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MCP-1 in induced sputum

Top of page

End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MCP-1 in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	46	51	50
Units: pg/mL
geometric mean (confidence interval 95%)	0.667 (0.576 to 0.772)	0.796 (0.693 to 0.914)	0.933 (0.814 to 1.070)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

MCP-1 in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data werelog-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

= 0.001

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.715

Confidence interval

level

95%

sides

2-sided

lower limit

0.588

upper limit

0.87

Notes
[25] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

MCP-1 in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

other ^[26]

P-value

= 0.105

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.852

Confidence interval

level

95%

sides

2-sided

lower limit

0.702

upper limit

1.035

Notes
[26] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in leukotriene B4 in induced sputum

Top of page

End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in leukotriene B4 in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	49	53	54
Units: pg/mL
geometric mean (confidence interval 95%)	0.697 (0.544 to 0.892)	0.593 (0.470 to 0.749)	1.058 (0.843 to 1.328)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Leukotriene B4 in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

= 0.015

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.659

Confidence interval

level

95%

sides

2-sided

lower limit

0.472

upper limit

0.919

Notes
[27] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

other ^[28]

P-value

< 0.001

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.561

Confidence interval

level

95%

sides

2-sided

lower limit

0.405

upper limit

0.777

Notes
[28] - Explorative

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MMP9 in induced sputum

Top of page

End point title

Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MMP9 in induced sputum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (mean Day 20, 26 and 32 values)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	53	53	54
Units: ng/mL
geometric mean (confidence interval 95%)	0.779 (0.647 to 0.938)	0.771 (0.641 to 0.928)	1.017 (0.848 to 1.220)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

MMP9 in induced sputum on Days 20, 26 and 32 was averaged for each subject when receiving each treatment. The averaged values were used in the analysis. Mean change from baseline was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

= 0.043

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.766

Confidence interval

level

95%

sides

2-sided

lower limit

0.592

upper limit

0.992

Notes
[29] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

other ^[30]

P-value

= 0.038

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.759

Confidence interval

level

95%

sides

2-sided

lower limit

0.585

upper limit

0.985

Notes
[30] - Explorative

Secondary: PK sputum concentration for CHF 6001 at steady state

Top of page

End point title

PK sputum concentration for CHF 6001 at steady state

End point description

End point type

Secondary

End point timeframe

Measured on Day 20, Day 26 or Day 32 at 2 hours post-dose. Note: an aliquot of one of the sputum collections performed on Day 20, 26 or 32 was used for CHF 6001 determination.

End point values	L: CHF 6001 1600 µg - PK	H: CHF 6001 3200 µg - PK
Number of subjects analysed	57	58
Units: µg/mL
arithmetic mean (standard deviation)	4.87 ( 6.18 )	10.23 ( 12.47 )

No statistical analyses for this end point

Secondary: Change from baseline to end of treatment (Day 32) in IL-6 in serum

Top of page

End point title

Change from baseline to end of treatment (Day 32) in IL-6 in serum

End point description

Note: all endpoints in this study were considered exploratory and none were defined as primary, secondary etc. In order to present results in the EudraCT system we have arbitrarily included the change from baseline in TNF-α in induced sputum as the relevant endpoint to be labelled as the primary endpoint. All other endpoints were arbitrarily assigned as secondary endpoints.

End point type

Secondary

End point timeframe

Baseline to end of treatment (Day 32)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	46	48	44
Units: pg/mL
geometric mean (confidence interval 95%)	1.444 (1.222 to 1.707)	1.484 (1.261 to 1.747)	1.281 (1.080 to 1.521)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Mean change from baseline to Day 32 was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Data were log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[31]

P-value

= 0.323

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.127

Confidence interval

level

95%

sides

2-sided

lower limit

0.887

upper limit

1.432

Notes
[31] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[32]

P-value

= 0.224

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.158

Confidence interval

level

95%

sides

2-sided

lower limit

0.912

upper limit

1.47

Notes
[32] - Explorative

Secondary: Change from baseline to end of treatment (Day 32) in IL-8 in serum

Top of page

End point title

Change from baseline to end of treatment (Day 32) in IL-8 in serum

End point description

Note: all endpoints in this study were considered exploratory and none were defined as primary, secondary etc. In order to present results in the EudraCT system we have arbitrarily considered the change from baseline in TNF-α in sputum as the relevant endpoint to be labelled as the primary endpoint. All other endpoints were arbitrarily assigned as secondary endpoints.

End point type

Secondary

End point timeframe

Baseline to end of treatment (Day 32)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	53	52	53
Units: pg/mL
geometric mean (confidence interval 95%)	0.931 (0.855 to 1.014)	0.892 (0.818 to 0.972)	0.911 (0.837 to 0.992)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Mean change from baseline to Day 32 was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Non-normally distributed data was log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.726

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.022

Confidence interval

level

95%

sides

2-sided

lower limit

0.906

upper limit

1.152

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Mean change from baseline to Day 32 was compared between treatments using an analysis of covariance (ANCOVA), including treatment, subject and period as fixed effects and baseline values as covariate. Non-normally distributed data was log-transformed before analysis and results presented as ratio of geometric means.

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.721

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.979

Confidence interval

level

95%

sides

2-sided

lower limit

0.868

upper limit

1.103

Secondary: Change from baseline to end of treatment (Day 32) in TNF-α in vivo in serum

Top of page

End point title

Change from baseline to end of treatment (Day 32) in TNF-α in vivo in serum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (Day 32)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	55	55	53
Units: pg/mL
geometric mean (confidence interval 95%)	0.935 (0.867 to 1.008)	0.935 (0.867 to 1.008)	0.888 (0.821 to 0.960)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

= 0.344

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.052

Confidence interval

level

95%

sides

2-sided

lower limit

0.946

upper limit

1.171

Notes
[33] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

other ^[34]

P-value

= 0.354

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

1.052

Confidence interval

level

95%

sides

2-sided

lower limit

0.944

upper limit

1.173

Notes
[34] - Explorative

Secondary: Change from baseline to end of treatment (Day 32) in TNF-α ex vivo stimulated in plasma

Top of page

End point title

Change from baseline to end of treatment (Day 32) in TNF-α ex vivo stimulated in plasma

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (Day 32)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	56	57	55
Units: pg/mL
geometric mean (confidence interval 95%)	0.595 (0.439 to 0.806)	0.494 (0.366 to 0.665)	0.900 (0.662 to 1.224)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Comparison groups

L: CHF 6001 1600 µg - PD v P: Placebo - PD

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.057

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.661

Confidence interval

level

95%

sides

2-sided

lower limit

0.431

upper limit

1.013

Notes
[35] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

H: CHF 6001 3200 µg - PD v P: Placebo - PD

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

other ^[36]

P-value

= 0.006

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.548

Confidence interval

level

95%

sides

2-sided

lower limit

0.357

upper limit

0.841

Notes
[36] - Explorative

Secondary: Change from baseline to end of treatment (Day 32) in SP-D in serum

Top of page

End point title

Change from baseline to end of treatment (Day 32) in SP-D in serum

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (Day 32)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	54	55	53
Units: ng/mL
geometric mean (confidence interval 95%)	0.79 (0.74 to 0.83)	0.81 (0.77 to 0.86)	0.98 (0.92 to 1.03)

CHF 6001 1600 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v L: CHF 6001 1600 µg - PD

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

< 0.001

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

0.87

Notes
[37] - Explorative

CHF 6001 3200 µg vs. placebo

Statistical analysis description

Comparison groups

P: Placebo - PD v H: CHF 6001 3200 µg - PD

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

other ^[38]

P-value

< 0.001

Method

ANCOVA

Parameter type

ratio of geometric means

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

0.9

Notes
[38] - Explorative

Secondary: Area under the plasma concentration-time curve for CHF 6001 from 0 to 12 hours post-dose at steady-state

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End point title

Area under the plasma concentration-time curve for CHF 6001 from 0 to 12 hours post-dose at steady-state

End point description

End point type

Secondary

End point timeframe

Measured at Day 32 (steady-state). Blood samples were collected on Day 32 of each treatment period at 10 timepoints (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose).

End point values	L: CHF 6001 1600 µg - PK	H: CHF 6001 3200 µg - PK
Number of subjects analysed	55	58
Units: h.pg/mL
geometric mean (geometric coefficient of variation)	22116 ( 51.4 )	40814 ( 53.2 )

No statistical analyses for this end point

Secondary: Maximum plasma concentration of CHF 6001 at steady-state

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End point title

Maximum plasma concentration of CHF 6001 at steady-state

End point description

End point type

Secondary

End point timeframe

Measured on Day 32 (steady-state). Blood samples were collected on Day 32 of each treatment period at 10 timepoints (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose).

End point values	L: CHF 6001 1600 µg - PK	H: CHF 6001 3200 µg - PK
Number of subjects analysed	56	58
Units: pg/mL
geometric mean (geometric coefficient of variation)	2439 ( 50.0 )	4502 ( 50.8 )

No statistical analyses for this end point

Secondary: Change from baseline to end of treatment (pre-dose Day 32) in FEV1

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End point title

Change from baseline to end of treatment (pre-dose Day 32) in FEV1

End point description

End point type

Secondary

End point timeframe

Baseline to end of treatment (pre-dose Day 32)

End point values	L: CHF 6001 1600 µg - PD	H: CHF 6001 3200 µg - PD	P: Placebo - PD
Number of subjects analysed	55	57	56
Units: litre(s)
least squares mean (confidence interval 95%)	0.022 (-0.006 to 0.050)	-0.026 (-0.053 to 0.002)	0.009 (-0.018 to 0.037)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The reporting period for AEs was from the signature of the informed consent form until the patient's participation in the study ended.

Adverse event reporting additional description

All AEs starting on or after the time of first randomised study drug were classified as treatment-emergent adverse events (TEAEs) and were analysed in this study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

L: CHF 6001 1600 µg

Reporting group description

Treatment L = CHF 6001 1600 µg. The safety population was defined as all randomised patients who received at least one dose of the study medication.

Reporting group title

H: CHF 6001 3200 µg

Reporting group description

Treatment H = CHF 6001 3200 µg. The safety population was defined as all randomised patients who received at least one dose of the study medication.

Reporting group title

P: Placebo

Reporting group description

Treatment P = placebo. The safety population was defined as all randomised patients who received at least one dose of the study medication.

Serious adverse events	L: CHF 6001 1600 µg	H: CHF 6001 3200 µg	P: Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 58 (3.45%)	2 / 59 (3.39%)	2 / 58 (3.45%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Investigations
Blood immunoglobulin A increased
subjects affected / exposed	1 / 58 (1.72%)	0 / 59 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma
subjects affected / exposed	1 / 58 (1.72%)	0 / 59 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 58 (0.00%)	1 / 59 (1.69%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 58 (0.00%)	1 / 59 (1.69%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrospinal fistula
subjects affected / exposed	0 / 58 (0.00%)	1 / 59 (1.69%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 58 (0.00%)	0 / 59 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 58 (0.00%)	0 / 59 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 58 (0.00%)	0 / 59 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 58 (0.00%)	0 / 59 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Endocarditis
subjects affected / exposed	0 / 58 (0.00%)	1 / 59 (1.69%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection staphylococcal
subjects affected / exposed	0 / 58 (0.00%)	1 / 59 (1.69%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	L: CHF 6001 1600 µg	H: CHF 6001 3200 µg	P: Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 58 (51.72%)	32 / 59 (54.24%)	24 / 58 (41.38%)
Nervous system disorders
Headache
subjects affected / exposed	1 / 58 (1.72%)	7 / 59 (11.86%)	1 / 58 (1.72%)
occurrences all number	1	7	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 58 (1.72%)	3 / 59 (5.08%)	0 / 58 (0.00%)
occurrences all number	1	3	0
Chest pain
subjects affected / exposed	2 / 58 (3.45%)	1 / 59 (1.69%)	0 / 58 (0.00%)
occurrences all number	2	1	0
Chest discomfort
subjects affected / exposed	2 / 58 (3.45%)	0 / 59 (0.00%)	0 / 58 (0.00%)
occurrences all number	2	0	0
Gastrointestinal disorders
Toothache
subjects affected / exposed	3 / 58 (5.17%)	1 / 59 (1.69%)	2 / 58 (3.45%)
occurrences all number	4	1	2
Diarrhoea
subjects affected / exposed	3 / 58 (5.17%)	1 / 59 (1.69%)	0 / 58 (0.00%)
occurrences all number	3	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 58 (1.72%)	3 / 59 (5.08%)	1 / 58 (1.72%)
occurrences all number	1	3	1
Oropharyngeal pain
subjects affected / exposed	3 / 58 (5.17%)	2 / 59 (3.39%)	0 / 58 (0.00%)
occurrences all number	3	2	0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 58 (1.72%)	2 / 59 (3.39%)	0 / 58 (0.00%)
occurrences all number	1	2	0
Dyspnoea
subjects affected / exposed	1 / 58 (1.72%)	0 / 59 (0.00%)	2 / 58 (3.45%)
occurrences all number	1	0	2
Psychiatric disorders
Sleep disorder
subjects affected / exposed	2 / 58 (3.45%)	0 / 59 (0.00%)	0 / 58 (0.00%)
occurrences all number	2	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	4 / 58 (6.90%)	1 / 59 (1.69%)	2 / 58 (3.45%)
occurrences all number	4	1	2
Muscle spasms
subjects affected / exposed	1 / 58 (1.72%)	1 / 59 (1.69%)	2 / 58 (3.45%)
occurrences all number	1	1	2
Osteoarthritis
subjects affected / exposed	0 / 58 (0.00%)	2 / 59 (3.39%)	0 / 58 (0.00%)
occurrences all number	0	2	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 58 (8.62%)	6 / 59 (10.17%)	8 / 58 (13.79%)
occurrences all number	5	6	8
Lower respiratory tract infection
subjects affected / exposed	0 / 58 (0.00%)	2 / 59 (3.39%)	0 / 58 (0.00%)
occurrences all number	0	2	0
Respiratory tract infection
subjects affected / exposed	2 / 58 (3.45%)	0 / 59 (0.00%)	0 / 58 (0.00%)
occurrences all number	2	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

25 Aug 2016

Protocol v 2.0. was issued on 25 August 2016 to implement comments raised by the authority MHRA to monitor specifically psychiatric adverse events. It was submitted to both MHRA and EC on the 26th of August 2016 and approved by both on the 09th of September 2016. It was also submitted to both BfArM and EC on the 19th and the 21st of September 2016 respectively, and approved by BfArM on the 5th of October and by the EC on the 01st of December 2016.

29 Sep 2016

Protocol v 3.0 was issued on 29 Sep 2016 to implement a smoking diary to monitor the change in the patients smoking habits. It was submitted to both EC and BfArM on the 26 and 27 October 2016 respectively and approved by the EC the 1st December 2016 alongside the approval of the version 2.0 of the protocol, while BfArM considered it as non-substantial amendment. It was also submitted to both MHRA and EC on the 21st of October 2016 and approved by both, the 25th of November 2016.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A RANDOMISED, DOUBLE-BLIND, PLACEBO CONTROLLED, REPEATED DOSE, THREE-WAY CROSSOVER STUDY TO EVALUATE THE PHARMACODYNAMICS, PHARMACOKINETICS AND SAFETY OF TWO DOSES OF CHF 6001 DPI IN SUBJECTS WITH MODERATE, SEVERE COPD.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in TNF-α in induced sputum

Primary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in TNF-α in induced sputum

Secondary: Change from baseline to end to treatment (mean Day 20, 26 and 32 values) in absolute neutrophil count in induced sputum

Secondary: Change from baseline to end to treatment (mean Day 20, 26 and 32 values) in absolute neutrophil count in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute eosinophil count in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute eosinophil count in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute macrophage count in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute macrophage count in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute lymphocyte count in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in absolute lymphocyte count in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of neutrophils in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of neutrophils in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of eosinophils in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of eosinophils in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of macrophages in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of macrophages in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of lymphocytes in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in percentage of lymphocytes in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in IL-6 in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in IL-6 in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in IL-8 in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in IL-8 in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MIP1β in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MIP1β in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MCP-1 in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MCP-1 in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in leukotriene B4 in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in leukotriene B4 in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MMP9 in induced sputum

Secondary: Change from baseline to end of treatment (mean Day 20, 26 and 32 values) in MMP9 in induced sputum

Secondary: PK sputum concentration for CHF 6001 at steady state

Secondary: PK sputum concentration for CHF 6001 at steady state

Secondary: Change from baseline to end of treatment (Day 32) in IL-6 in serum

Secondary: Change from baseline to end of treatment (Day 32) in IL-6 in serum

Secondary: Change from baseline to end of treatment (Day 32) in IL-8 in serum

Secondary: Change from baseline to end of treatment (Day 32) in IL-8 in serum

Secondary: Change from baseline to end of treatment (Day 32) in TNF-α in vivo in serum

Secondary: Change from baseline to end of treatment (Day 32) in TNF-α in vivo in serum

Secondary: Change from baseline to end of treatment (Day 32) in TNF-α ex vivo stimulated in plasma

Secondary: Change from baseline to end of treatment (Day 32) in TNF-α ex vivo stimulated in plasma

Secondary: Change from baseline to end of treatment (Day 32) in SP-D in serum

Secondary: Change from baseline to end of treatment (Day 32) in SP-D in serum

Secondary: Area under the plasma concentration-time curve for CHF 6001 from 0 to 12 hours post-dose at steady-state

Secondary: Area under the plasma concentration-time curve for CHF 6001 from 0 to 12 hours post-dose at steady-state

Secondary: Maximum plasma concentration of CHF 6001 at steady-state

Secondary: Maximum plasma concentration of CHF 6001 at steady-state

Secondary: Change from baseline to end of treatment (pre-dose Day 32) in FEV1

Secondary: Change from baseline to end of treatment (pre-dose Day 32) in FEV1

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A RANDOMISED, DOUBLE-BLIND, PLACEBO CONTROLLED, REPEATED DOSE, THREE-WAY CROSSOVER STUDY TO EVALUATE THE PHARMACODYNAMICS, PHARMACOKINETICS AND SAFETY OF TWO DOSES OF CHF 6001 DPI IN SUBJECTS WITH MODERATE, SEVERE COPD.