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Clinical Trial Results:
A 24-WEEK, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO AND ACTIVE CONTROLLED, PARALLEL GROUP, DOSE RANGING STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 4 DOSES OF CHF 6001 DPI IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ON A BACKGROUND THERAPY.

Summary
EudraCT number	2015-005548-32
Trial protocol	GB DE HU PL BG
Global end of trial date	09 Jan 2018

Results information
Results version number	v1(current)
This version publication date	25 Jan 2019
First version publication date	25 Jan 2019
Other versions

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

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Trial information

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Sponsor protocol code

CCD-06001AA1-01

ISRCTN number

US NCT number

NCT02986321

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., +39 0521 2791, clinicaltrials_info@chiesi.com

Scientific contact

Clinical Trial Transparency, 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

22 Oct 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Jan 2018

Global end of trial reached?

Yes

Global end of trial date

09 Jan 2018

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this trial was to investigate the dose-response relationship of 4 doses of CHF 6001 dry powder inhaler (DPI) with respect to pre-dose forced expiratory volume in the 1st second (FEV1) after 12 weeks of treatment and to identify the optimal dose of CHF 6001 for further development in patients with moderate to severe COPD already treated with background therapy.

Protection of trial subjects

The trial was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines, and following all other requirements of local laws. At all visits from screening onwards, concomitant medications and adverse events were recorded and physical examination of subjects was carried out. Vital signs were recorded pre-dose and pre-dose spirometry (including inspiratory capacity [IC], FEV1 and forced vital capacity [FVC]) was performed at screening, randomisation and all post-randomisation visits until the last treatment visit. Baseline Dyspnoea Index (BDI) was recorded at randomisation and Transition Dyspnoea Index (TDI) was recorded at all post-randomisation visits until the last treatment visit. COPD exacerbations were assessed at all post-randomisation visits. Subjects were provided with salbutamol as rescue medication. From screening, the electronic diary (eDiary) was completed by patients from home on a daily basis to record rescue medication use, compliance with background medication and study treatment, and COPD exacerbation-related outcomes (using the EXAcerbations of Chronic pulmonary disease Tool - Patient Reported Outcome [EXACT-PRO]/Respiratory Symptoms [E-RS] questionnaire). Health related quality of life was assessed at all visits over the randomised treatment period using the St. George's Respiratory Questionnaire (SGRQ). Blood collection for routine haematology and blood chemistry was performed at screening, randomisation, Week 12 and last treatment visits; thyroid functions were tested at screening. From screening, 12-lead electrocardiogram (ECG) parameters (heart rate [HR], Fridericia-corrected QT interval [QTcF], PR interval [PR] and QRS interval [QRS]) were recorded.

Background therapy

Patients received formoterol fumarate 12 µg (one inhalation twice daily, total daily dose 24 µg) as background medication during the two-week run-in period, which was continued at the same dose throughout the study. Patients also received salbutamol as rescue medication (dose of 100 µg pressured metered dose inhaler [pMDI] as needed [PRN], maximum of 8 puffs/day), to be used throughout the study.

Evidence for comparator

Budesonide (ICS)

Actual start date of recruitment

15 Dec 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 210

Country: Number of subjects enrolled

United Kingdom: 1

Country: Number of subjects enrolled

Bulgaria: 126

Country: Number of subjects enrolled

Germany: 18

Country: Number of subjects enrolled

Hungary: 87

Country: Number of subjects enrolled

Russian Federation: 263

Country: Number of subjects enrolled

Ukraine: 425

Worldwide total number of subjects

1130

EEA total number of subjects

442

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)

554

From 65 to 84 years

573

85 years and over

Subject disposition

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Recruitment details

Overall, 1593 patients were screened according to inclusion and exclusion criteria; of these, 1130 patients were randomised.

Screening details

At screening, not more than 7 days after a pre-screening visit, inclusion/exclusion criteria were assessed. There were 463 screening failures (failure to meet randomisation criteria [418 patients], consent withdrawal [31 patients] , other reasons [5 patients], AEs [4 patients], protocol deviations [3 patients], lost to follow-up [2 patients]).

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Data analyst, Subject, Carer, Assessor

Blinding implementation details

An Interactive Response Technology (IRT) system was used to generate the randomisation list.

Are arms mutually exclusive

Yes

CHF 6001 800 μg

Arm description

Patients were randomised to receive CHF 6001 800 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period.

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Test product: CHF 6001 DPI NEXThaler®100 µg/actuation. Double-blind double-dummy design: During study visits patients in the CHF 6001 800 µg group received two boxes, each with two NEXThaler®s with CHF 6001 100 µg/actuation and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 100 µg/actuation plus 2 inhalations of CHF 6001 100 µg/actuation plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: CHF 6001 800 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

CHF 6001 1600 μg

Arm description

Patients were randomised to receive CHF 6001 1600 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Test product: CHF 6001 DPI NEXThaler®400 µg/actuation. Double-blind double-dummy design: During study visits patients in the CHF 6001 1600 µg group received two boxes, each with a NEXThaler® with CHF 6001 400 µg/actuation, a NEXThaler® with CHF 6001 matched Placebo and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other box to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 400 µg/actuation plus 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: CHF 6001 1600 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

CHF 6001 2400 µg

Arm description

Patients were randomised to receive CHF 6001 2400 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Test product: CHF 6001 DPI NEXThaler®300 µg/actuation. Double-blind double-dummy design: During study visits patients in the CHF 6001 2400 µg group received two boxes, each with two NEXThaler®s with CHF 6001 300 µg/actuation and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 300 µg/actuation plus 2 inhalations of CHF 6001 300 µg/actuation plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: CHF 6001 2400 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

CHF 6001 3200 µg

Arm description

Patients were randomised to receive CHF 6001 3200 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

Arm type

Experimental

Investigational medicinal product name

CHF 6001

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Test product: CHF 6001 DPI NEXThaler®400 µg/actuation. Double-blind double-dummy design: During study visits patients in the CHF 6001 3200 µg group received two boxes, each with two NEXThaler®s with CHF 6001 400 µg/actuation and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 400 µg/actuation plus 2 inhalations of CHF 6001 400 µg/actuation plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: CHF 6001 3200 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

Budesonide 800 µg

Arm description

Patients were randomised to receive Budesonide 800 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

Arm type

Active comparator

Investigational medicinal product name

Budesonide

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Test product: Budesonide DPI Pulmicort® Turbohaler® 200 µg/actuation. Double-blind double-dummy design: During study visits, patients in the Budesonide 800 µg group received two boxes, each with two NEXThaler®s with CHF 6001 matched Placebo and a Budesonide DPI (Pulmicort® Turbohaler®) 200 µg/actuation, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of Budesonide DPI 200 µg/actuation, all twice daily (BID). Total daily dose: Budesonide 800 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

Placebo

Arm description

Patients were randomised to receive Placebo for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

Arm type

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

Test product: Matched Placebo. Double-blind double-dummy design: During study visits patients in the Placebo group received two boxes, each with two CHF 6001 DPI NEXThaler® matched Placebos and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: Not applicable. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

Number of subjects in period 1	CHF 6001 800 μg	CHF 6001 1600 μg	CHF 6001 2400 µg	CHF 6001 3200 µg	Budesonide 800 µg	Placebo
Started	190	179	188	193	187	193
Completed	175	162	176	173	175	177
Not completed	15	17	12	20	12	16
Adverse event, serious fatal	1	1	1	2	-	-
Consent withdrawn by subject	7	10	5	5	4	7
No reason specified	2	1	1	4	1	3
Adverse event, non-fatal	3	2	3	6	2	5
Lost to follow-up	-	-	-	-	1	-
Lack of efficacy	2	1	2	3	4	1
Protocol deviation	-	2	-	-	-	-

Baseline characteristics

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Reporting group title

CHF 6001 800 μg

Reporting group description

Reporting group title

CHF 6001 1600 μg

Reporting group description

Reporting group title

CHF 6001 2400 µg

Reporting group description

Reporting group title

CHF 6001 3200 µg

Reporting group description

Reporting group title

Budesonide 800 µg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	CHF 6001 800 μg	CHF 6001 1600 μg	CHF 6001 2400 µg	CHF 6001 3200 µg	Budesonide 800 µg	Placebo	Total
Number of subjects	190	179	188	193	187	193	1130
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)	94	80	90	104	91	95	554
From 65-84 years	96	98	98	89	95	97	573
85 years and over	0	1	0	0	1	1	3
Gender categorical
Units: Subjects
Female	57	50	57	58	55	60	337
Male	133	129	131	135	132	133	793

End points

Top of page

Reporting group title

CHF 6001 800 μg

Reporting group description

Reporting group title

CHF 6001 1600 μg

Reporting group description

Reporting group title

CHF 6001 2400 µg

Reporting group description

Reporting group title

CHF 6001 3200 µg

Reporting group description

Reporting group title

Budesonide 800 µg

Reporting group description

Reporting group title

Placebo

Reporting group description

Subject analysis set title

CHF 6001 800 μg - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study medication and with at least one available evaluation of efficacy after the baseline.

Subject analysis set title

CHF 6001 1600 μg - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

CHF 6001 2400 μg - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

CHF 6001 3200 μg - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Budesonide 800 μg - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Placebo - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Change from baseline in morning pre-dose FEV1 at Week 12

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End point title

Change from baseline in morning pre-dose FEV1 at Week 12

End point description

Morning pre-dose forced expiratory volume in the first second (FEV1).

End point type

Primary

End point timeframe

Baseline (pre-dose at the randomisation visit, Week 0) to Week 12.

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	177 ^[1]	166 ^[2]	178 ^[3]	178 ^[4]	178 ^[5]	176 ^[6]
Units: Litres
least squares mean (confidence interval 95%)	-0.004 (-0.037 to 0.028)	0.011 (-0.022 to 0.044)	0.004 (-0.029 to 0.036)	-0.024 (-0.057 to 0.008)	-0.002 (-0.035 to 0.030)	-0.006 (-0.039 to 0.026)

Notes
[1] - Number of patients in the ITT population = 190, number of patients with available data = 177
[2] - Number of patients in the ITT population = 179, number of patients with available data = 166
[3] - Number of patients in the ITT population = 188, number of patients with available data = 178
[4] - Number of patients in the ITT population = 193, number of patients with available data = 178
[5] - Number of patients in the ITT population = 187, number of patients with available data = 178
[6] - Number of patients in the ITT population = 193, number of patients with available data = 176

Adjusted mean difference in CFB FEV1 at Week 12

Statistical analysis description

The CFB in pre-dose morning FEV1 was analysed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction and sites pooled by country as effects and baseline FEV1 value and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo were estimated by the model. Comparisons with Budesonide were also provided.

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

353

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.932

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-0.044

upper limit

0.048

Adjusted mean difference in CFB FEV1 at Week 12

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

342

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.47

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.029

upper limit

0.064

Adjusted mean difference in CFB FEV1 at Week 12

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

354

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.673

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.036

upper limit

0.056

Adjusted mean difference in CFB FEV1 at Week 12

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

354

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.433

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.064

upper limit

0.027

Secondary: TDI score at Week 3

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End point title

TDI score at Week 3

End point description

The Baseline Dyspnoea Index (BDI)/Transition Dyspnoea Index (TDI) is a clinical rating used to measure the impact of dyspnoea on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI focal scores were recorded at the randomisation visit (Week 0) and TDI focal scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). A TDI focal score ≥ 1 is considered the minimal clinically important difference (MCID) for this instrument.

End point type

Secondary

End point timeframe

Week 3

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	181 ^[7]	172 ^[8]	183 ^[9]	185 ^[10]	181 ^[11]	187 ^[12]
Units: TDI focal scores
least squares mean (confidence interval 95%)	0.84 (0.51 to 1.17)	0.74 (0.39 to 1.08)	0.65 (0.32 to 0.98)	0.58 (0.25 to 0.91)	0.89 (0.56 to 1.22)	0.73 (0.40 to 1.06)

Notes
[7] - Number of patients in the ITT population = 190, number of patients with available data = 181
[8] - Number of patients in the ITT population = 179, number of patients with available data = 172
[9] - Number of patients in the ITT population = 188, number of patients with available data = 183
[10] - Number of patients in the ITT population = 193, number of patients with available data = 185
[11] - Number of patients in the ITT population = 187, number of patients with available data = 181
[12] - Number of patients in the ITT population = 193, number of patients with available data = 187

Adjusted mean difference in TDI focal scores

Statistical analysis description

The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

368

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.645

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

0.57

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

359

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.968

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

0.48

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

370

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.753

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.54

upper limit

0.39

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.537

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.62

upper limit

0.32

Secondary: TDI score at Week 6

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End point title

TDI score at Week 6

End point description

End point type

Secondary

End point timeframe

Week 6

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	183 ^[13]	168 ^[14]	181 ^[15]	184 ^[16]	179 ^[17]	186 ^[18]
Units: TDI focal scores
least squares mean (confidence interval 95%)	1.28 (0.96 to 1.61)	1.14 (0.79 to 1.48)	1.17 (0.83 to 1.50)	1.09 (0.75 to 1.42)	1.44 (1.11 to 1.77)	1.15 (0.82 to 1.48)

Notes
[13] - Number of patients in the ITT population = 190, number of patients with available data = 183
[14] - Number of patients in the ITT population = 179, number of patients with available data = 168
[15] - Number of patients in the ITT population = 188, number of patients with available data = 181
[16] - Number of patients in the ITT population = 193, number of patients with available data = 184
[17] - Number of patients in the ITT population = 187, number of patients with available data = 179
[18] - Number of patients in the ITT population = 193, number of patients with available data = 186

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

369

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.574

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.33

upper limit

0.6

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

354

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.957

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.49

upper limit

0.46

Adjusted mean difference in TDI focal score

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

367

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.945

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.45

upper limit

0.49

Adjusted mean difference in TDI focal score

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

370

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.793

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.41

Secondary: TDI score at Week 12

Top of page

End point title

TDI score at Week 12

End point description

End point type

Secondary

End point timeframe

Week 12

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	179 ^[19]	164 ^[20]	178 ^[21]	182 ^[22]	180 ^[23]	178 ^[24]
Units: TDI focal scores
least squares mean (confidence interval 95%)	1.23 (0.88 to 1.57)	1.21 (0.84 to 1.57)	1.15 (0.80 to 1.50)	0.99 (0.64 to 1.34)	1.03 (0.68 to 1.37)	1.21 (0.86 to 1.56)

Notes
[19] - Number of patients in the ITT population = 190, number of patients with available data = 179
[20] - Number of patients in the ITT population = 179, number of patients with available data = 164
[21] - Number of patients in the ITT population = 188, number of patients with available data = 178
[22] - Number of patients in the ITT population = 193, number of patients with available data = 182
[23] - Number of patients in the ITT population = 187, number of patients with available data = 180
[24] - Number of patients in the ITT population = 193, number of patients with available data = 178

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

357

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.948

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.48

upper limit

0.51

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

342

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.988

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

0.5

Adjusted mean difference in TDI focal score

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.82

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.55

upper limit

0.44

Adjusted mean difference in TDI focal score

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.387

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

0.28

Secondary: TDI score at Week 18

Top of page

End point title

TDI score at Week 18

End point description

End point type

Secondary

End point timeframe

Week 18

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	178 ^[25]	164 ^[26]	178 ^[27]	172 ^[28]	177 ^[29]	178 ^[30]
Units: TDI focal scores
least squares mean (confidence interval 95%)	1.09 (0.74 to 1.45)	1.14 (0.76 to 1.52)	1.07 (0.71 to 1.43)	1.11 (0.73 to 1.48)	1.19 (0.83 to 1.55)	0.96 (0.60 to 1.32)

Notes
[25] - Number of patients in the ITT population = 190, number of patients with available data = 178
[26] - Number of patients in the ITT population = 179, number of patients with available data = 164
[27] - Number of patients in the ITT population = 188, number of patients with available data = 178
[28] - Number of patients in the ITT population = 193, number of patients with available data = 172
[29] - Number of patients in the ITT population = 187, number of patients with available data = 177
[30] - Number of patients in the ITT population = 193, number of patients with available data = 178

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.606

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

0.64

Adjusted mean difference in TDI focal score

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

342

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.496

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.34

upper limit

0.7

Adjusted mean difference in TDI focal score

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.678

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

0.62

Adjusted mean difference in TDI focal score

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

350

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.582

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

0.66

Secondary: TDI score at Week 24

Top of page

End point title

TDI score at Week 24

End point description

End point type

Secondary

End point timeframe

Week 24

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	175 ^[31]	159 ^[32]	175 ^[33]	172 ^[34]	174 ^[35]	177 ^[36]
Units: TDI focal scores
least squares mean (confidence interval 95%)	1.54 (1.19 to 1.90)	1.28 (0.90 to 1.65)	1.49 (1.13 to 1.85)	1.44 (1.08 to 1.81)	1.49 (1.13 to 1.84)	1.46 (1.11 to 1.82)

Notes
[31] - Number of patients in the ITT population = 190, number of patients with available data = 175
[32] - Number of patients in the ITT population = 179, number of patients with available data = 159
[33] - Number of patients in the ITT population = 188, number of patients with available data = 175
[34] - Number of patients in the ITT population = 193, number of patients with available data = 172
[35] - Number of patients in the ITT population = 187, number of patients with available data = 174
[36] - Number of patients in the ITT population = 193, number of patients with available data = 177

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.758

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

0.58

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.484

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.33

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.922

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.48

upper limit

0.53

Adjusted mean difference in TDI focal scores

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

349

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.939

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.49

Secondary: TDI response

Top of page

End point title

TDI response

End point description

TDI focal scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24) . A TDI response is defined as TDI focal score ≥ 1 unit. TDI response was assessed at each post-randomisation visit. Patients with TDI focal score < 1 unit or with missing data at any visit were classed as non-responders.

End point type

Secondary

End point timeframe

Week 3, Week 6, Week 12, Week 18, Week 24.

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	190 ^[37]	179 ^[38]	188 ^[39]	193 ^[40]	187 ^[41]	193 ^[42]
Units: Patients
number (not applicable)
Week 3	85	74	70	84	85	80
Week 6	94	83	83	94	95	88
Week 12	90	78	84	80	86	93
Week 18	83	81	81	80	85	86
Week 24	96	77	90	88	95	100

Notes
[37] - ITT population
[38] - ITT population
[39] - ITT population
[40] - ITT population
[41] - ITT population
[42] - ITT population

No statistical analyses for this end point

Secondary: Change from baseline to Week 3 in SGRQ total score

Top of page

End point title

Change from baseline to Week 3 in SGRQ total score

End point description

The St. George's Respiratory Questionnaire (SGRQ) is used to measure health-related quality of life. Decrease in SGRQ total scores indicates improvement. Baseline SGRQ total score was recorded at the randomisation visit (Week 0) and SGRQ total scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). The minimal clinically important difference (MCID) for this instrument is a decrease from baseline of ≥ 4 units.

End point type

Secondary

End point timeframe

Baseline to Week 3.

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	184 ^[43]	173 ^[44]	185 ^[45]	186 ^[46]	183 ^[47]	189 ^[48]
Units: SGRQ total scores
least squares mean (confidence interval 95%)	-1.49 (-3.08 to 0.10)	-2.90 (-4.53 to -1.26)	-2.37 (-3.95 to -0.79)	-2.87 (-4.44 to -1.30)	-3.46 (-5.05 to -1.87)	-3.51 (-5.07 to -1.94)

Notes
[43] - Number of patients in the ITT population = 190, number of patients with available data = 184
[44] - Number of patients in the ITT population = 179, number of patients with available data = 173
[45] - Number of patients in the ITT population = 188, number of patients with available data = 185
[46] - Number of patients in the ITT population = 193, number of patients with available data = 186
[47] - Number of patients in the ITT population = 187, number of patients with available data = 183
[48] - Number of patients in the ITT population = 193, number of patients with available data = 189

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.075

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

2.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.21

upper limit

4.25

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

The changes from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

362

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.594

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-1.65

upper limit

2.88

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.314

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

-1.08

upper limit

3.37

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.572

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

-1.58

upper limit

2.86

Secondary: Change from baseline to Week 6 in SGRQ total score

Top of page

End point title

Change from baseline to Week 6 in SGRQ total score

End point description

End point type

Secondary

End point timeframe

Baseline to Week 6

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	181 ^[49]	170 ^[50]	184 ^[51]	182 ^[52]	182 ^[53]	184 ^[54]
Units: SGRQ total scores
least squares mean (confidence interval 95%)	-2.21 (-3.92 to -0.50)	-5.21 (-6.96 to -3.45)	-4.12 (-5.82 to -2.43)	-4.82 (-6.52 to -3.12)	-5.32 (-7.03 to -3.62)	-5.42 (-7.11 to -3.73)

Notes
[49] - Number of patients in the ITT population = 190, number of patients with available data = 181
[50] - Number of patients in the ITT population = 179, number of patients with available data = 170
[51] - Number of patients in the ITT population = 188, number of patients with available data = 184
[52] - Number of patients in the ITT population = 193, number of patients with available data = 182
[53] - Number of patients in the ITT population = 187, number of patients with available data = 182
[54] - Number of patients in the ITT population = 193, number of patients with available data = 184

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

365

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

3.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

5.61

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

354

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.865

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-2.23

upper limit

2.65

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

368

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.289

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

3.69

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

366

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.624

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

2.99

Secondary: Change from baseline to Week 12 in SGRQ total score

Top of page

End point title

Change from baseline to Week 12 in SGRQ total score

End point description

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	176 ^[55]	167 ^[56]	179 ^[57]	180 ^[58]	180 ^[59]	179 ^[60]
Units: SGRQ total scores
least squares mean (confidence interval 95%)	-4.53 (-6.43 to -2.62)	-6.62 (-8.57 to -4.66)	-4.58 (-6.47 to -2.69)	-6.38 (-8.26 to -4.50)	-5.56 (-7.45 to -3.67)	-6.17 (-8.06 to -4.29)

Notes
[55] - Number of patients in the ITT population = 190, number of patients with available data = 176
[56] - Number of patients in the ITT population = 179, number of patients with available data = 167
[57] - Number of patients in the ITT population = 188, number of patients with available data = 179
[58] - Number of patients in the ITT population = 193, number of patients with available data = 180
[59] - Number of patients in the ITT population = 187, number of patients with available data = 180
[60] - Number of patients in the ITT population = 193, number of patients with available data = 179

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

355

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.227

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

1.65

Confidence interval

level

95%

sides

2-sided

lower limit

-1.03

upper limit

4.33

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

346

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.75

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.44

Confidence interval

level

95%

sides

2-sided

lower limit

-3.15

upper limit

2.27

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

358

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.241

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

1.59

Confidence interval

level

95%

sides

2-sided

lower limit

-1.07

upper limit

4.26

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

359

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.879

Method

Linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-2.87

upper limit

2.46

Secondary: Change from baseline to Week 18 in SGRQ total score

Top of page

End point title

Change from baseline to Week 18 in SGRQ total score

End point description

End point type

Secondary

End point timeframe

Baseline to Week 18

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	176 ^[61]	163 ^[62]	179 ^[63]	176 ^[64]	176 ^[65]	178 ^[66]
Units: SGRQ total scores
least squares mean (confidence interval 95%)	-6.04 (-7.98 to -4.09)	-7.93 (-9.94 to -5.92)	-5.18 (-7.11 to -3.25)	-6.09 (-8.02 to -4.15)	-5.91 (-7.85 to -3.97)	-6.50 (-8.42 to -4.57)

Notes
[61] - Number of patients in the ITT population = 190, number of patients with available data = 176
[62] - Number of patients in the ITT population = 179, number of patients with available data = 163
[63] - Number of patients in the ITT population = 188, number of patients with available data = 179
[64] - Number of patients in the ITT population = 193, number of patients with available data = 176
[65] - Number of patients in the ITT population = 187, number of patients with available data = 176
[66] - Number of patients in the ITT population = 193, number of patients with available data = 178

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

354

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.742

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-2.28

upper limit

3.2

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

341

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.313

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-1.43

Confidence interval

level

95%

sides

2-sided

lower limit

-4.22

upper limit

1.35

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

357

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.344

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

-1.41

upper limit

4.05

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

354

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.769

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-2.32

upper limit

3.14

Secondary: Change from baseline to Week 24 in SGRQ total score

Top of page

End point title

Change from baseline to Week 24 in SGRQ total score

End point description

End point type

Secondary

End point timeframe

Baseline to Week 24

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	172 ^[67]	162 ^[68]	175 ^[69]	173 ^[70]	176 ^[71]	177 ^[72]
Units: SGRQ total scores
least squares mean (confidence interval 95%)	-5.54 (-7.64 to -3.43)	-8.06 (-10.24 to -5.89)	-5.95 (-8.04 to -3.86)	-6.96 (-9.06 to -4.87)	-7.11 (-9.20 to -5.02)	-7.48 (-9.57 to -5.40)

Notes
[67] - Number of patients in the ITT population = 190, number of patients with available data = 172
[68] - Number of patients in the ITT population = 179, number of patients with available data = 162
[69] - Number of patients in the ITT population = 188, number of patients with available data = 175
[70] - Number of patients in the ITT population = 193, number of patients with available data = 173
[71] - Number of patients in the ITT population = 187, number of patients with available data = 176
[72] - Number of patients in the ITT population = 193, number of patients with available data = 177

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

349

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.198

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

1.95

Confidence interval

level

95%

sides

2-sided

lower limit

-1.02

upper limit

4.91

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

339

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.705

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.58

Confidence interval

level

95%

sides

2-sided

lower limit

-3.59

upper limit

2.43

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.307

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

1.54

Confidence interval

level

95%

sides

2-sided

lower limit

-1.42

upper limit

4.49

Adjusted mean difference in CFB, SGRQ total score

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

350

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.73

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-2.43

upper limit

3.47

Secondary: SGRQ response

Top of page

End point title

SGRQ response

End point description

SGRQ response is defined as a decrease from baseline in SGRQ total score ≥ 4 units. Baseline SGRQ total scores were recorded at the randomisation visit (Week 0), and SGRQ total scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). Patients with decrease from baseline in SGRQ score ≥ 4 units at any visit were classed as responders. Patients with a decrease from baseline in SGRQ total score < 4 units or with missing data at any visit, were classed as non-responders.

End point type

Secondary

End point timeframe

Week 3, Week 6, Week 12, Week 18 and Week 24.

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	190 ^[73]	179 ^[74]	188 ^[75]	193 ^[76]	187 ^[77]	193 ^[78]
Units: Patients
number (not applicable)
Week 3	83	71	81	74	92	88
Week 6	80	90	90	92	93	95
Week 12	93	96	87	97	95	90
Week 18	98	95	101	102	92	97
Week 24	91	98	94	90	93	92

Notes
[73] - ITT population
[74] - ITT population
[75] - ITT population
[76] - ITT population
[77] - ITT population
[78] - ITT population

No statistical analyses for this end point

Secondary: CFB to the entire treatment period in average E-RS total score

Top of page

End point title

CFB to the entire treatment period in average E-RS total score

End point description

The EXAcerbations of Chronic pulmonary disease Tool (EXACT) collects patient-reported outcomes (PRO) data in order to capture frequency, severity and time course of COPD exacerbations. Digital platform technology was used for data collection in this study. Average EXACT-Respiratory Symptoms (E-RS) scores were recorded during the 2-week run-in period (baseline) and over the entire treatment period of 24 weeks. Change from baseline (CFB) over the entire treatment period was analysed. A decrease from baseline in average E-RS scores ≥ 2.0 is the minimal clinically important difference (MCID) for this instrument.

End point type

Secondary

End point timeframe

Baseline (run-in period) to 24 weeks treatment period.

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	187 ^[79]	176 ^[80]	186 ^[81]	187 ^[82]	184 ^[83]	193 ^[84]
Units: Average E-RS total scores
least squares mean (confidence interval 95%)	-1.53 (-2.21 to -0.94)	-2.41 (-3.01 to -1.80)	-1.89 (-2.48 to -1.31)	-2.07 (-2.66 to -1.48)	-2.35 (-2.94 to -1.76)	-2.12 (-2.79 to -1.63)

Notes
[79] - Number of patients in the ITT population = 190, number of patients with available data = 187
[80] - Number of patients in the ITT population = 179, number of patients with available data = 176
[81] - Number of patients in the ITT population = 188, number of patients with available data = 186
[82] - Number of patients in the ITT population = 193, number of patients with available data = 187
[83] - Number of patients in the ITT population = 187, number of patients with available data = 184
[84] - Number of patients in the ITT population = 193, number of patients with available data = 193

Adjusted mean difference in CFB, E-RS total score

Statistical analysis description

Analysis of change from baseline (CFB) to the entire treatment period in average E-RS total scores was based on a linear mixed model for repeated measures (MMRM) including treatment, inter-Visit period, treatment by inter-Visit period interaction and Pooled Country as fixed effects, and baseline value and baseline by inter-Visit period interaction as covariates. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo are presented.

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

380

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.105

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

1.5

Adjusted mean difference in CFB, E-RS total score

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

369

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.647

Method

lnear MMRM

Parameter type

Adjusted mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.03

upper limit

0.64

Adjusted mean difference in CFB, E-RS total score

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

379

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.451

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

1.14

Adjusted mean difference in CFB, E-RS total score

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

380

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.737

Method

linear MMRM

Parameter type

Adjusted mean difference

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

0.97

Secondary: E-RS response

Top of page

End point title

E-RS response

End point description

Average E-RS total scores were recorded during the run-in period (baseline) and for each inter-visit period over the treatment period of 24 weeks. The proportion of patients with a decrease from baseline in average E-RS total score ≥ 2.0 were classed as responders; patients with a decrease from baseline in average E-RS total score < 2.0 units or with missing data for any inter-visit period were classed as non-responders.

End point type

Secondary

End point timeframe

Baseline (two-week run-in period) and inter-visit periods Week 1 to Week 3, Week 4 to Week 6, Week 7 to Week 12, Week 13 to Week 18 and Week 19 to Week 24.

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	190 ^[85]	179 ^[86]	188 ^[87]	193 ^[88]	187 ^[89]	193 ^[90]
Units: Patients
number (not applicable)
Week 1 to Week 3	58	65	54	58	60	62
Week 4 to Week 6	73	82	62	82	76	73
Week 7 to Week 12	78	86	72	87	89	81
Week 13 to Week 18	74	84	83	77	90	93
Week 19 to Week 24	79	94	80	82	86	89

Notes
[85] - ITT population
[86] - ITT population
[87] - ITT population
[88] - ITT population
[89] - ITT population
[90] - ITT population

No statistical analyses for this end point

Secondary: Moderate and severe COPD exacerbation rate over 24 weeks of treatment

Top of page

End point title

Moderate and severe COPD exacerbation rate over 24 weeks of treatment

End point description

The rate of moderate or severe COPD exacerbations was evaluated over 24 weeks of treatment. Exacerbations were classified as moderate or severe as per European Medicines Agency (EMA)/Committee for Medicinal Products for Human Use (CHMP) guideline definitions. A moderate exacerbation was defined as a sustained worsening of the patient's condition that required treatment with systemic (oral/IV/IM) corticosteroids and/or antibiotics. A severe exacerbation was defined as one that required hospitalisation or resulted in death. The recognition of potential COPD exacerbations was optimised by the daily reporting of worsened symptoms through the EXAcerbations of Chronic pulmonary disease Tool - Patient Reported Outcome (EXACT-PRO) questionnaire.

End point type

Secondary

End point timeframe

Baseline to 24 weeks.

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	190 ^[91]	179 ^[92]	188 ^[93]	193 ^[94]	187 ^[95]	193 ^[96]
Units: Adjusted exacerbation rate/patient/year
number (confidence interval 95%)	0.563 (0.414 to 0.764)	0.585 (0.428 to 0.799)	0.593 (0.440 to 0.801)	0.487 (0.351 to 0.675)	0.415 (0.292 to 0.589)	0.681 (0.514 to 0.902)

Notes
[91] - ITT population
[92] - ITT population
[93] - ITT population
[94] - ITT population
[95] - ITT population
[96] - ITT population

Adjusted exacerbation rate ratio

Statistical analysis description

The rate of moderate and severe COPD exacerbations over 24 weeks of treatment was analysed using a negative binomial model including treatment and sites pooled by country as factors and logarithm of time into the study as an offset. Adjusted rate ratios (95% CIs) for CHF 6001 treatments over Placebo estimated by the model are presented.

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.367

Method

Negative binomial model

Parameter type

Adjusted rate ratio

Point estimate

0.826

Confidence interval

level

95%

sides

2-sided

lower limit

0.546

upper limit

1.251

Adjusted exacerbation rate ratio

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.479

Method

Negative binomial model

Parameter type

Adjusted rate ratio

Point estimate

0.859

Confidence interval

level

95%

sides

2-sided

lower limit

0.565

upper limit

1.307

Adjusted exacerbation rate ratio

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

381

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.51

Method

Negative binomial model

Parameter type

Adjusted rate ratio

Point estimate

0.871

Confidence interval

level

95%

sides

2-sided

lower limit

0.578

upper limit

1.313

Adjusted exacerbation rate ratio

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

386

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.127

Method

Negative binomial model

Parameter type

Adjusted rate ratio

Point estimate

0.715

Confidence interval

level

95%

sides

2-sided

lower limit

0.465

upper limit

1.1

Secondary: Time to first moderate or severe COPD exacerbation

Top of page

End point title

Time to first moderate or severe COPD exacerbation

End point description

The number of patients at risk of a moderate or severe COPD exacerbation is presented.

End point type

Secondary

End point timeframe

Baseline to 24 weeks

End point values	CHF 6001 800 μg - ITT	CHF 6001 1600 μg - ITT	CHF 6001 2400 μg - ITT	CHF 6001 3200 μg - ITT	Budesonide 800 μg - ITT	Placebo - ITT
Number of subjects analysed	190 ^[97]	179 ^[98]	188 ^[99]	193 ^[100]	187 ^[101]	193 ^[102]
Units: Patients
number (not applicable)	37	36	42	35	32	49

Notes
[97] - ITT population
[98] - ITT population
[99] - ITT population
[100] - ITT population
[101] - ITT population
[102] - ITT population

Hazard ratio - time to first exacerbation

Statistical analysis description

The time to first moderate or severe COPD exacerbation was analysed using Cox proportional hazard regression model including treatment and sites pooled by country as factors. The hazard ratios (95% CIs) for the CHF 6001 treatment groups (versus Placebo) are presented.

Comparison groups

CHF 6001 800 μg - ITT v Placebo - ITT

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

superiority

Method

Cox proportional hazard regression model

Parameter type

Hazard ratio (HR)

Point estimate

0.731

Confidence interval

level

95%

sides

2-sided

lower limit

0.477

upper limit

1.12

Hazard ratio - time to first exacerbation

Statistical analysis description

Comparison groups

CHF 6001 1600 μg - ITT v Placebo - ITT

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

Method

Cox proportional hazard regression model

Parameter type

Hazard ratio (HR)

Point estimate

0.768

Confidence interval

level

95%

sides

2-sided

lower limit

0.499

upper limit

1.181

Hazard ratio - time to first exacerbation

Statistical analysis description

Comparison groups

CHF 6001 2400 μg - ITT v Placebo - ITT

Number of subjects included in analysis

381

Analysis specification

Pre-specified

Analysis type

superiority

Method

Cox proportional hazard regression model

Parameter type

Hazard ratio (HR)

Point estimate

0.829

Confidence interval

level

95%

sides

2-sided

lower limit

0.549

upper limit

1.252

Hazard ratio - time to first exacerbation

Statistical analysis description

Comparison groups

CHF 6001 3200 μg - ITT v Placebo - ITT

Number of subjects included in analysis

386

Analysis specification

Pre-specified

Analysis type

superiority

Method

Cox proportional hazard regression model

Parameter type

Hazard ratio (HR)

Point estimate

0.693

Confidence interval

level

95%

sides

2-sided

lower limit

0.449

upper limit

1.07

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events (AEs) were reported from the time of patient informed consent to study completion or discontinuation.

Adverse event reporting additional description

Treatment-emergent adverse events (TEAEs) were defined as AEs starting on or after the first randomised study medication intake.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

CHF 6001 800 μg - Safety

Reporting group description

The Safety population was defined as all randomised patients who received at least one dose of study medication.

Reporting group title

CHF 6001 1600 μg - Safety

Reporting group description

The Safety population was defined as all randomised patients who received at least one dose of the study medication.

Reporting group title

CHF 6001 2400 µg - Safety

Reporting group description

The Safety population was defined as all randomised patients who received at least one dose of the study medication.

Reporting group title

CHF 6001 3200 µg - Safety

Reporting group description

The Safety population was defined as all randomised patients who received at least one dose of the study medication.

Reporting group title

Budesonide 800 µg - Safety

Reporting group description

The Safety population was defined as all randomised patients who received at least one dose of the study medication.

Reporting group title

Placebo - Safety

Reporting group description

The Safety population was defined as all randomised patients who received at least one dose of the study medication.

Serious adverse events	CHF 6001 800 μg - Safety	CHF 6001 1600 μg - Safety	CHF 6001 2400 µg - Safety	CHF 6001 3200 µg - Safety	Budesonide 800 µg - Safety	Placebo - Safety
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 190 (5.79%)	13 / 179 (7.26%)	12 / 188 (6.38%)	7 / 193 (3.63%)	10 / 187 (5.35%)	7 / 193 (3.63%)
number of deaths (all causes)	1	1	1	2	0	0
number of deaths resulting from adverse events	1	1	1	2	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant
subjects affected / exposed	1 / 190 (0.53%)	0 / 179 (0.00%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	1 / 188 (0.53%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Humerus fracture
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	0 / 188 (0.00%)	0 / 193 (0.00%)	1 / 187 (0.53%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Meniscus injury
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	0 / 188 (0.00%)	1 / 193 (0.52%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	0 / 188 (0.00%)	1 / 193 (0.52%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	0 / 188 (0.00%)	0 / 193 (0.00%)	1 / 187 (0.53%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Vascular disorders
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	1 / 188 (0.53%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 190 (0.00%)	1 / 179 (0.56%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 190 (0.00%)	1 / 179 (0.56%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 190 (0.53%)	0 / 179 (0.00%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	1 / 188 (0.53%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	0 / 188 (0.00%)	1 / 193 (0.52%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 190 (0.00%)	1 / 179 (0.56%)	0 / 188 (0.00%)	1 / 193 (0.52%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 190 (0.00%)	1 / 179 (0.56%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	1 / 190 (0.53%)	0 / 179 (0.00%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 190 (0.00%)	1 / 179 (0.56%)	0 / 188 (0.00%)	1 / 193 (0.52%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 190 (0.53%)	0 / 179 (0.00%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Duodenal stenosis
subjects affected / exposed	1 / 190 (0.53%)	0 / 179 (0.00%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	1 / 188 (0.53%)	0 / 193 (0.00%)	1 / 187 (0.53%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 190 (0.00%)	1 / 179 (0.56%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 190 (0.00%)	1 / 179 (0.56%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 190 (0.00%)	1 / 179 (0.56%)	0 / 188 (0.00%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	6 / 190 (3.16%)	7 / 179 (3.91%)	7 / 188 (3.72%)	2 / 193 (1.04%)	5 / 187 (2.67%)	5 / 193 (2.59%)
occurrences causally related to treatment / all	0 / 6	0 / 7	0 / 7	0 / 2	0 / 5	0 / 6
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Infections and infestations
Infectious pleural effusion
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	0 / 188 (0.00%)	0 / 193 (0.00%)	1 / 187 (0.53%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Pneumonia
subjects affected / exposed	1 / 190 (0.53%)	1 / 179 (0.56%)	1 / 188 (0.53%)	0 / 193 (0.00%)	1 / 187 (0.53%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia escherichia
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	1 / 188 (0.53%)	0 / 193 (0.00%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 190 (0.00%)	0 / 179 (0.00%)	0 / 188 (0.00%)	1 / 193 (0.52%)	0 / 187 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3.5%

Non-serious adverse events	CHF 6001 800 μg - Safety	CHF 6001 1600 μg - Safety	CHF 6001 2400 µg - Safety	CHF 6001 3200 µg - Safety	Budesonide 800 µg - Safety	Placebo - Safety
Total subjects affected by non serious adverse events
subjects affected / exposed	86 / 190 (45.26%)	90 / 179 (50.28%)	91 / 188 (48.40%)	83 / 193 (43.01%)	89 / 187 (47.59%)	101 / 193 (52.33%)
Nervous system disorders
Headache
subjects affected / exposed	10 / 190 (5.26%)	7 / 179 (3.91%)	7 / 188 (3.72%)	11 / 193 (5.70%)	10 / 187 (5.35%)	8 / 193 (4.15%)
occurrences all number	14	8	8	15	12	10
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	42 / 190 (22.11%)	41 / 179 (22.91%)	54 / 188 (28.72%)	43 / 193 (22.28%)	39 / 187 (20.86%)	58 / 193 (30.05%)
occurrences all number	68	58	66	60	56	75
Infections and infestations
Nasopharyngitis
subjects affected / exposed	7 / 190 (3.68%)	14 / 179 (7.82%)	11 / 188 (5.85%)	12 / 193 (6.22%)	9 / 187 (4.81%)	13 / 193 (6.74%)
occurrences all number	10	16	11	15	10	13

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Were there any global substantial amendments to the protocol? Yes

27 Oct 2016

There were three versions of the clinical study protocol. Version 1.0 was never used, and initial submissions were done with Version 2.0. Based on the Medicines and Healthcare products Regulatory Agency (MHRA) comments, there was one substantial protocol amendment, with the following main changes implemented further to the initial protocol version: - The thyroid function tests were added at the screening visit to confirm the exclusion of the uncontrolled thyroid disease as per exclusion criterion #16; - Monitoring of psychiatric adverse events was specified (including update of the physical examination section). The first Competent Authority approval of Version 3.0 was received on 27 October 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in morning pre-dose FEV1 at Week 12

Primary: Change from baseline in morning pre-dose FEV1 at Week 12

Secondary: TDI score at Week 3

Secondary: TDI score at Week 3

Secondary: TDI score at Week 6

Secondary: TDI score at Week 6

Secondary: TDI score at Week 12

Secondary: TDI score at Week 12

Secondary: TDI score at Week 18

Secondary: TDI score at Week 18

Secondary: TDI score at Week 24

Secondary: TDI score at Week 24

Secondary: TDI response

Secondary: TDI response

Secondary: Change from baseline to Week 3 in SGRQ total score

Secondary: Change from baseline to Week 3 in SGRQ total score

Secondary: Change from baseline to Week 6 in SGRQ total score

Secondary: Change from baseline to Week 6 in SGRQ total score

Secondary: Change from baseline to Week 12 in SGRQ total score

Secondary: Change from baseline to Week 12 in SGRQ total score

Secondary: Change from baseline to Week 18 in SGRQ total score

Secondary: Change from baseline to Week 18 in SGRQ total score

Secondary: Change from baseline to Week 24 in SGRQ total score

Secondary: Change from baseline to Week 24 in SGRQ total score

Secondary: SGRQ response

Secondary: SGRQ response

Secondary: CFB to the entire treatment period in average E-RS total score

Secondary: CFB to the entire treatment period in average E-RS total score

Secondary: E-RS response

Secondary: E-RS response

Secondary: Moderate and severe COPD exacerbation rate over 24 weeks of treatment

Secondary: Moderate and severe COPD exacerbation rate over 24 weeks of treatment

Secondary: Time to first moderate or severe COPD exacerbation

Secondary: Time to first moderate or severe COPD exacerbation

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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