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Clinical Trial Results:
A first in human randomised, double-blind, placebo-controlled study of single ascending doses in healthy male volunteers and repeated ascending dose in asthmatic patients followed by a 3-way cross-over, placebo-controlled, single-dose in COPD patients to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of CHF6366

Summary
EudraCT number	2015-005551-27
Trial protocol	GB
Global end of trial date	18 Apr 2019

Results information
Results version number	v1(current)
This version publication date	03 May 2020
First version publication date	03 May 2020
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-06366AA1-01

ISRCTN number

US NCT number

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., clinicaltrials_info@chiesi.com

Scientific contact

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., 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

10 Feb 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Apr 2019

Was the trial ended prematurely?

Main objective of the trial

Assess the safety and tolerability of single ascending doses of CHF 6366 in healthy male volunteers, of repeated ascending doses in male and female patients with asthma , and of a single dose in male patients with COPD. CHF 6366 is a new chemical entity with muscarinic antagonist and β2 receptor agonist (MABA) properties, which is being developed by Chiesi for treatment of asthma and COPD. The parent compound CHF 6366 is metabolised to the metabolites CHF 6387 and CHF 6361. The study consisted of 3 independent parts: Part 1: Randomised, placebo-controlled, double-blind, single dose-escalation, alternating cross-over design, in 3 cohorts of healthy male subjects. Part 2: Randomised, placebo-controlled, double-blind, repeated dose-escalation, parallel group design, in 4 cohorts of subjects with asthma. Part 3: Randomised, placebo-controlled (double-blind), active-controlled (open-label), single-dose, 3-way cross-over design, in subjects with COPD.

Protection of trial subjects

The study was conducted according to the clinical study protocol, according with the principles of the Declaration of Helsinki, and local regulations, as well as according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) notes for guidance on Good Clinical Practice (GCP) (ICH/CPMP/135/95). AEs and vital signs were recorded at all visits (from screening onward). Based on the medical opinion of the Investigator, all new clinically relevant abnormalities or significant changes at the study visits were reported as AEs in the electronic case report form (eCRF). All PK and safety assessments were performed according to accepted methods. Part 1: The dose-escalation was alternated between the 3 cohorts (Cohorts A, B, and H). Eight of 12 subjects in each treatment period received CHF 6366 and 4 subjects received placebo. A sentinel/staggered dosing was followed to ensure additional safety of the subjects. A sentinel group of 2 subjects (1 active and 1 placebo) were initially dosed at least 24 hours in advance of the other subjects in each cohort. The other 10 subjects of the cohort were dosed only after a safety review of data from the sentinels by the Safety Advisory Committee (SAC). From Dose 2 to Dose 7 (i.e., 10 μg to 360 μg), the administered doses could be modified based on safety and PK data review. Stopping rules were in place. Part 2: Started only after completion and review of the safety data from Part 1. A similar approach as for Part 1 was used ( sentinel/staggered dosing), to ensure additional safety of the subjects. Rules for increasing the dose followed a defined criterion. Stopping rules were in place. SAC reviewed the safety and available PK data before next dose increase. Part 3: Drug administration started after the completion and review of the safety data of the entire Part 1 of the study.

Background therapy

There was no background therapy used in this trial. Abbreviations used in this database entry: AE=Adverse event Anoro=ANORO ELLIPTA 55 micrograms/22 micrograms inhalation powder, pre-dispensed AUC(0-12h)=The area under the plasma concentration curve observed from 0 to 12 hours post-dose was computed using the linear trapezoidal rule bid=Twice daily BLQ=Below the limit of quantification BP=Blood pressure bpm=Beats per minute Cmax=Maximum plasma concentration DB=Double-blind DPI=Dry-powder inhaler Cmax=Maximum plasma concentration COPD=Chronic obstructive pulmonary disease CSR=Clinical study report DBP=Diastolic blood pressure eCRF=Electronic case report form ECG=Electrocardiogram FEV1=Forced expiratory volume in 1 second HR=Heart rate IMP=Investigational medicinal product MABA=Muscarinic antagonist and β2 receptor agonist MAPK=Mitogen-activated protein kinases MD=Multiple Dose Level (as in MD1, MD2, MD3, MD4) mg=Milligram ms=Millisecond µg=Microgram N=Number of subjects ND=Not determined PBO-controlled=Placebo-controlled PI=Principle investigator PK=Pharmacokinetic QTcF=QT interval, corrected using Fridericia’s formula SAC=Safety Advisory Committee SAE=Serious adverse event SBP=Systolic blood pressure SD1=Single Dose Level 1 SD2=Single Dose Level 2 TEAEs=Treatment-emergent adverse events t½ =Terminal (apparent elimination) half-life Tmax=Time of the maximum plasma concentration

Evidence for comparator

Actual start date of recruitment

28 Dec 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 106

Worldwide total number of subjects

106

EEA total number of subjects

106

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

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Recruitment details

Healthy adult male subjects (N=34), male and female patients diagnosed with asthma (N=48) or with COPD (N=24) were screened according to the study inclusion and exclusion criteria. Signed Informed Consent Form was obtained prior to any study-related procedures.

Screening details

Screening visit was 3 - 28 days (depending on the part of the study), before the first administration of the study treatment. For healthy subjects, none of the vital signs, ECG results, or lung function data, and physical examination were considered abnormal or clinically relevant. For asthma and COPD inclusion and exclusion criteria were observed.

Period 1 title

Treatment Study Parts 1, 2, 3 (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

Blinding was as follows: Part 1: Placebo-controlled, double-blind, healthy subjects Part 2: Placebo-controlled, double-blind, subjects with asthma Part 3: Placebo-controlled (double-blind), active-controlled (open-label), subjects with COPD

Are arms mutually exclusive

Yes

Part 1 - Cohort A - Healthy subjects

Arm description

Part 1: Single ascending dose in healthy subjects. Randomised, placebo-controlled, double blind, single dose-escalation, alternating cross-over design in 3 cohorts (A, B, and H) of healthy male subjects. During Part 1, seven single doses of CHF 6366 were administered according to an escalation scheme. The dose-escalation was alternated between the 3 cohorts (Cohorts A, B, and H). Subjects in Cohort A received 3 ascending doses of CHF 6366: 5 μg (Dose 1), 20 μg (Dose 3), and 80 μg (Dose 5). Cohort H: consisted of 3 subjects from Cohort A and 9 subjects from Cohort B. Subjects in Cohort H received 1 ascending dose: 360 μg (Dose 7).

Arm type

Experimental

Investigational medicinal product name

CHF 6366

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 1: Single ascending dose – Healthy subjects CHF 6366 was a colourless, aqueous, isotonic solution, administered as oral inhalation in the morning through e-Flow Rapid (PARI) nebuliser. Seven single doses of CHF 6366 were administered according to an escalation scheme. Study Part 1 was run according to an alternating crossover design with 3 cohorts of healthy male subjects (cohort A, cohort B, cohort H), with an alternating crossover design, for a given subject. Each subject participated in 3 or 4 treatment periods (alternating dose levels). The washout between 2 consecutive treatments was at least 14 days. • Subjects in Cohort A received 3 ascending doses of CHF 6366: 5 μg (Dose 1), 20 μg (Dose 3), and 80 μg (Dose 5) • Subjects in Cohort B received 3 ascending doses of CHF 6366: 10 μg (Dose 2), 40 μg (Dose 4), and 160 μg (Dose 6) • Subjects in Cohort H received 1 ascending dose of CHF 6366: 360 μg (Dose 7)

Investigational medicinal product name

CHF 6366 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 1, Part 2, Part 3 -- Placebo CHF 6366 placebo was a colourless, aqueous, isotonic solution, administered as oral inhalation in the morning through e-Flow Rapid (PARI) nebuliser, according to the randomisation scheme.

Part 1 - Cohort B - Healthy subjects

Arm description

Part 1: Single ascending dose in healthy subjects. Randomised, placebo-controlled, double blind, single dose-escalation, alternating cross-over design in 3 cohorts (A, B, and H) of healthy male subjects. During Part 1, seven single doses of CHF 6366 were administered according to an escalation scheme. The dose-escalation was alternated between the 3 cohorts (Cohorts A, B, and H). Subjects in Cohort B received 3 ascending doses of CHF 6366: 10 μg (Dose 2), 40 μg (Dose 4), and 160 μg (Dose 6). Cohort H: consisted of 3 subjects from Cohort A and 9 subjects from Cohort B. Subjects in Cohort H received 1 ascending dose: 360 μg (Dose 7).

Arm type

Experimental

Investigational medicinal product name

CHF 6366

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

CHF 6366 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 2 - Cohort C - Asthma - CHF 6366 - 40 µg

Arm description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort C received 40 µg of CHF 6366, once daily for 7 days.

Arm type

Experimental

Investigational medicinal product name

CHF 6366

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 2: Multiple ascending dose of CHF 6366 – Subjects with asthma CHF 6366 was a colourless, aqueous, isotonic solution, administered as oral inhalation in the morning through e-Flow Rapid (PARI) nebuliser. Four multiple doses of CHF 6366 were administered once daily for 7 days, according to an escalation scheme. In study Part 2, subjects were divided into 4 dose cohorts (Cohorts C, D, E, and F) and randomised to receive either CHF 6366 or placebo once daily for 7 days. • Subjects in Cohort C received: 40 μg (MD1) total daily dose • Subjects in Cohort D received: 80 μg (MD2) total daily dose • Subjects in Cohort E received: 160 μg (MD3) total daily dose • Subjects in Cohort F received: 240 μg (MD4) total daily dose

Investigational medicinal product name

CHF 6366 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 2 - Cohort D - Asthma - CHF 6366 - 80 µg

Arm description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort D received 80 µg of CHF 6366, once daily for 7 days.

Arm type

Experimental

Investigational medicinal product name

CHF 6366

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

CHF 6366 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 2 - Cohort E - Asthma - CHF 6366 - 160 µg

Arm description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort E received 160 µg of CHF 6366, once daily for 7 days.

Arm type

Experimental

Investigational medicinal product name

CHF 6366

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

CHF 6366 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 2 - Cohort F - Asthma - CHF 6366 - 240 µg

Arm description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort F received 240 µg of CHF 6366, once daily for 7 days.

Arm type

Experimental

Investigational medicinal product name

CHF 6366

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

CHF 6366 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 2 - Subjects with asthma - Placebo

Arm description

Part 2 of the study. Subjects with asthma who received placebo for 7 days.

Arm type

Placebo

Investigational medicinal product name

CHF 6366 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 3 - Subjects with COPD

Arm description

Part 3 – Single dose in subjects with COPD. Randomised, placebo-controlled (double-blind), active-controlled (open-label), single-dose, 3-way crossover design. After completion and review of the safety data of the entire Part 1 of the study, one dose of the study drug was administered to a cohort of subjects with COPD, according to a randomised, placebo controlled, active-controlled*, single-dose, 3-way cross-over design. The washout time between the 3 treatments was at least 7 days. *The active control was Anoro [Anoro Ellipta (umeclidinium and vilanterol dry powder inhaler, 55/22 μg)].

Arm type

Experimental

Investigational medicinal product name

CHF 6366

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Part 3: Single dose of CHF 6366 – Subjects with COPD CHF 6366 was a colourless, aqueous, isotonic solution, administered as oral inhalation in the morning through e-Flow Rapid (PARI) nebuliser. In study Part 3, subjects with COPD received a single dose of either 240 µg CHF 6366, Anoro (active comparator), or placebo, according to a randomisation scheme.

Investigational medicinal product name

CHF 6366 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

Anoro Ellipta

Investigational medicinal product code

ATC code: R03AL03

Other name

Umeclidinium and Vilanterol dry powder inhaler, 55/22 μg

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Part 3: Single dose of Anoro Ellipta – Subjects with COPD In part 3, a single dose of anoro ellipta (umeclidinium and vilanterol dry powder inhaler, 55/22 μg) was administered as oral inhalation in the morning through Ellipta inhaler, according to the randomisation scheme.

Number of subjects in period 1	Part 1 - Cohort A - Healthy subjects	Part 1 - Cohort B - Healthy subjects	Part 2 - Cohort C - Asthma - CHF 6366 - 40 µg	Part 2 - Cohort D - Asthma - CHF 6366 - 80 µg	Part 2 - Cohort E - Asthma - CHF 6366 - 160 µg	Part 2 - Cohort F - Asthma - CHF 6366 - 240 µg	Part 2 - Subjects with asthma - Placebo	Part 3 - Subjects with COPD
Started	18	16	9	9	9	9	12	24
Completed	12	12	8	8	9	9	12	21
Not completed	6	4	1	1	0	0	0	3
Consent withdrawn by subject	6	-	1	1	-	-	-	-
Physician decision	-	-	-	-	-	-	-	1
Adverse event, non-fatal	-	-	-	-	-	-	-	2
Lost to follow-up	-	1	-	-	-	-	-	-
CHF provide brief reason for disont	-	3	-	-	-	-	-	-

Baseline characteristics

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Reporting group title

Part 1 - Cohort A - Healthy subjects

Reporting group description

Reporting group title

Part 1 - Cohort B - Healthy subjects

Reporting group description

Part 1: Single ascending dose in healthy subjects. Randomised, placebo-controlled, double blind, single dose-escalation, alternating cross-over design in 3 cohorts (A, B, and H) of healthy male subjects. During Part 1, seven single doses of CHF 6366 were administered according to an escalation scheme. The dose-escalation was alternated between the 3 cohorts (Cohorts A, B, and H). Subjects in Cohort B received 3 ascending doses of CHF 6366: 10 μg (Dose 2), 40 μg (Dose 4), and 160 μg (Dose 6). Cohort H: consisted of 3 subjects from Cohort A and 9 subjects from Cohort B. Subjects in Cohort H received 1 ascending dose: 360 μg (Dose 7).

Reporting group title

Part 2 - Cohort C - Asthma - CHF 6366 - 40 µg

Reporting group description

Reporting group title

Part 2 - Cohort D - Asthma - CHF 6366 - 80 µg

Reporting group description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort D received 80 µg of CHF 6366, once daily for 7 days.

Reporting group title

Part 2 - Cohort E - Asthma - CHF 6366 - 160 µg

Reporting group description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort E received 160 µg of CHF 6366, once daily for 7 days.

Reporting group title

Part 2 - Cohort F - Asthma - CHF 6366 - 240 µg

Reporting group description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort F received 240 µg of CHF 6366, once daily for 7 days.

Reporting group title

Part 2 - Subjects with asthma - Placebo

Reporting group description

Part 2 of the study. Subjects with asthma who received placebo for 7 days.

Reporting group title

Part 3 - Subjects with COPD

Reporting group description

Reporting group values	Part 1 - Cohort A - Healthy subjects	Part 1 - Cohort B - Healthy subjects	Part 2 - Cohort C - Asthma - CHF 6366 - 40 µg	Part 2 - Cohort D - Asthma - CHF 6366 - 80 µg	Part 2 - Cohort E - Asthma - CHF 6366 - 160 µg	Part 2 - Cohort F - Asthma - CHF 6366 - 240 µg	Part 2 - Subjects with asthma - Placebo	Part 3 - Subjects with COPD	Total
Number of subjects	18	16	9	9	9	9	12	24	106
Age categorical
Units: Subjects
Adults (18-64 years)	18	16	9	9	9	9	12	13	95
From 65-84 years	0	0	0	0	0	0	0	11	11
Age continuous
Units: years
arithmetic mean (standard deviation)	36.9 ( 9.6 )	32.9 ( 9.2 )	39.9 ( 17.9 )	38.3 ( 11.4 )	34.6 ( 10.0 )	36.2 ( 9.2 )	41.4 ( 9.4 )	61.9 ( 8.0 )	-
Gender categorical
Units: Subjects
Female	0	0	3	4	3	4	3	10	27
Male	18	16	6	5	6	5	9	14	79
Body mass index
Units: kg/m2
arithmetic mean (standard deviation)	26.50 ( 3.2 )	25.92 ( 3.02 )	25.69 ( 3.31 )	29.08 ( 4.89 )	26.74 ( 5.20 )	29.62 ( 7.06 )	25.39 ( 2.23 )	27.40 ( 3.91 )	-

End points

Top of page

Reporting group title

Part 1 - Cohort A - Healthy subjects

Reporting group description

Reporting group title

Part 1 - Cohort B - Healthy subjects

Reporting group description

Part 1: Single ascending dose in healthy subjects. Randomised, placebo-controlled, double blind, single dose-escalation, alternating cross-over design in 3 cohorts (A, B, and H) of healthy male subjects. During Part 1, seven single doses of CHF 6366 were administered according to an escalation scheme. The dose-escalation was alternated between the 3 cohorts (Cohorts A, B, and H). Subjects in Cohort B received 3 ascending doses of CHF 6366: 10 μg (Dose 2), 40 μg (Dose 4), and 160 μg (Dose 6). Cohort H: consisted of 3 subjects from Cohort A and 9 subjects from Cohort B. Subjects in Cohort H received 1 ascending dose: 360 μg (Dose 7).

Reporting group title

Part 2 - Cohort C - Asthma - CHF 6366 - 40 µg

Reporting group description

Reporting group title

Part 2 - Cohort D - Asthma - CHF 6366 - 80 µg

Reporting group description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort D received 80 µg of CHF 6366, once daily for 7 days.

Reporting group title

Part 2 - Cohort E - Asthma - CHF 6366 - 160 µg

Reporting group description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort E received 160 µg of CHF 6366, once daily for 7 days.

Reporting group title

Part 2 - Cohort F - Asthma - CHF 6366 - 240 µg

Reporting group description

Part 2 – Multiple ascending dose in subjects with asthma. Randomised, placebo-controlled, double blind, repeated dose-escalation, parallel group design in 4 dose cohorts (Cohorts C, D, E, and F). Subjects were randomised to receive either CHF 6366 or placebo, once daily for 7 days. Subjects in cohort F received 240 µg of CHF 6366, once daily for 7 days.

Reporting group title

Part 2 - Subjects with asthma - Placebo

Reporting group description

Part 2 of the study. Subjects with asthma who received placebo for 7 days.

Reporting group title

Part 3 - Subjects with COPD

Reporting group description

Subject analysis set title

Part 1 - Cohort A - Healthy subjects

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in Cohort A recieved 3 ascending doses of CHF 6366: 5 μg (Dose 1), 20 μg (Dose 3), and 80 μg (Dose 5), or placebo.

Subject analysis set title

Part 1 - Cohort B - Healthy subjects

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in Cohort B received 3 ascending doses CHF 6366: 10 μg (Dose 2), 40 μg (Dose 4), and 160 μg (Dose 6), or placebo.

Subject analysis set title

Part 1 - Cohort H - Healthy subjects

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in Cohort H recieved 1 ascending dose: 360 μg (Dose 7) or placebo.

Subject analysis set title

Part 1 - Healthy subjects - CHF 6366, 5 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 5 µg. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 1 - Healthy subjects - CHF 6366, 10 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 10 µg. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 1 - Healthy subjects - CHF 6366, 20 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 20 µg. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 1 - Healthy subjects - CHF 6366, 40 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 40 µg. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 1 - Healthy subjects - CHF 6366, 80 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 80 µg. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 1 - Healthy subjects - CHF 6366, 160 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 160 µg. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 1 - Healthy subjects - CHF 6366, 360 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 360 µg. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 1 - Healthy subjects - Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1 of the study. Healthy subjects who received placebo. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 2 - Subjects with asthma - CHF 6366, 40 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 2 of the study. Subjects with asthma who received multiple ascending dose of CHF 6366, 40 µg for 7 days, according to the escalation scheme. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 2 - Subjects with asthma - CHF 6366, 80 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 2 of the study. Subjects with asthma who received multiple ascending dose of CHF 6366, 80 µg for 7 days, according to the escalation scheme. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 2 - Subjects with asthma - CHF 6366, 160 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 2 of the study. Subjects with asthma who received multiple ascending dose of CHF 6366, 160 µg for 7 days, according to the escalation scheme. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 2 - Subjects with asthma - CHF 6366, 240 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 2 of the study. Subjects with asthma who received multiple ascending dose of CHF 6366, 240 µg for 7 days, according to the escalation scheme. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 2 - Subjects with asthma - Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Part 2 of the study. Subjects with asthma who received placebo for 7 days. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 3 - Subjects with COPD - CHF 6366, 240 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 3 of the study. Subjects with COPD who received a single dose of CHF 6366, 240 µg, according to the randomisation scheme. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 3 - Subjects with COPD - Anoro, 55/22 µg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 3 of the study. Subjects with COPD who received a single dose of Anoro, 55/22 µg, according to the randomisation scheme. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Subject analysis set title

Part 3 - Subjects with COPD - Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Part 3 of the study. Subjects with COPD who received a single dose of Placebo, according to the randomisation scheme. For pragmatic reasons to complete this database entry, this subject analysis set was also used to represent the Pharmacodynamic population and Pharmacokinetic population.

Primary: 1_Part 1 - SBP and DBP - Single ascending dose - Healthy subjects - Any post-dose timepoint

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End point title

1_Part 1 - SBP and DBP - Single ascending dose - Healthy subjects - Any post-dose timepoint ^[1]

End point description

2_Part 1 - SBP and DBP - Healthy subjects Cohorts A, B, H - Any post-dose timepoint. Data were derived from manual measurements by the study staff. Baseline is defined as pre-dose value on Day 1 of each treatment for Cohorts A and B and last non-missing schedule value prior to dosing with study medication for Cohort H. Presented are representative results of the time points. The number of subjects from contributing to the data is indicated (Cohort A, B, and H). In Cohort H, 3 subjects were from Cohort A and 9 subjects were from Cohort B; thus, in the Placebo column, the same subject was counted twice.

End point type

Primary

End point timeframe

On Day 1, at pre-dose and 15 min, 30 min, 1, 2, 4, 8, and 12 h post-dose. On Day 2, at 24 h post-dose. On Day 3, at 48 h post-dose, and at Follow-up.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 1 - Healthy subjects - CHF 6366, 5 µg	Part 1 - Healthy subjects - CHF 6366, 10 µg	Part 1 - Healthy subjects - CHF 6366, 20 µg	Part 1 - Healthy subjects - CHF 6366, 40 µg	Part 1 - Healthy subjects - CHF 6366, 80 µg	Part 1 - Healthy subjects - CHF 6366, 160 µg	Part 1 - Healthy subjects - CHF 6366, 360 µg	Part 1 - Healthy subjects - Placebo
Number of subjects analysed	8 ^[2]	8	8	8	8	8	8	24 ^[3]
Units: subjects
SBP change >20 mmHg	1	0	0	0	0	1	1	2
SBP change <-20 mmHg	0	0	0	0	0	0	0	2
DBP change >10 mmHg	2	0	1	0	1	2	0	4
DBP change <-10 mmHg	3	4	2	1	1	4	1	4

Notes
[2] - Safety population was used for the analysis of each group.
[3] - N=28 see explanation in the endpoint description

No statistical analyses for this end point

Primary: 2_Part 1 - Heart rate (0-24h) - Single ascending dose - Healthy subjects - Change from baseline

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End point title

2_Part 1 - Heart rate (0-24h) - Single ascending dose - Healthy subjects - Change from baseline ^[4]

End point description

Part 1 - Heart rate (0-24h) - Healthy subjects - Change from baseline. Data were derived from measurements using 12-lead ECG, extracted from 24 h Holter monitoring. Baseline is defined as the average HR of the 24 hours preceding the study drug administration on Day 1 of each treatment period. Results show the value obtained for the adjusted difference vs placebo. Adjusted mean difference and 90% CI based on a linear model with terms for treatment, period and sequence and subject within sequence as random effects and Baseline value as a covariate. Presented are values extracted from Holter at pre-defined timepoints. The number of subjects contributing to the data is indicated (Cohort A, B, and H).

End point type

Primary

End point timeframe

24h Holter ECG recording.

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 1 - Healthy subjects - CHF 6366, 5 µg	Part 1 - Healthy subjects - CHF 6366, 10 µg	Part 1 - Healthy subjects - CHF 6366, 20 µg	Part 1 - Healthy subjects - CHF 6366, 40 µg	Part 1 - Healthy subjects - CHF 6366, 80 µg	Part 1 - Healthy subjects - CHF 6366, 160 µg	Part 1 - Healthy subjects - CHF 6366, 360 µg
Number of subjects analysed	8 ^[5]	8	8	8	8	8	8
Units: bpm
number (confidence interval 90%)	-0.8 (-4.0 to 2.4)	-0.4 (-3.4 to 2.5)	-2.7 (-5.4 to -0.1)	0.4 (-2.3 to 3.0)	1.3 (-1.4 to 4.1)	2.4 (-0.6 to 5.4)	-0.1 (-6.0 to 5.7)

Notes
[5] - Safety population was used for the analysis of each group. Adjusted mean difference vs placebo.

No statistical analyses for this end point

Primary: 3_Part 1 - QTcF - Single ascending dose - Healthy subjects - Any post-dose timepoint

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End point title

3_Part 1 - QTcF - Single ascending dose - Healthy subjects - Any post-dose timepoint ^[6]

End point description

Part 1 - QTcF - Single ascending dose - Healthy subjects - Any post-dose timepoint. Data were derived from measurements using 12-lead ECG, extracted from 24 h Holter monitoring. Baseline is defined as the time-matched measurement taken prior to the study drug administration on Day 1 (of each period for Cohorts A, B, and H). Presented are values extracted from Holter at pre-defined timepoints. The number of subjects contributing to the data is indicated. In Cohort H, 3 subjects were from Cohort A and 9 from Cohort B, and thus in the Placebo column the same subject was counted twice.

End point type

Primary

End point timeframe

On Day 1 at pre-dose and 5, 15, 30, 45 min and 1, 1.5, 2, 4, 8, and 12 h post-dose. On Day 2 at 24 h post-dose. On Day 3 at 48 h post-dose and at Follow-up (if required).

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 1 - Healthy subjects - CHF 6366, 5 µg	Part 1 - Healthy subjects - CHF 6366, 10 µg	Part 1 - Healthy subjects - CHF 6366, 20 µg	Part 1 - Healthy subjects - CHF 6366, 40 µg	Part 1 - Healthy subjects - CHF 6366, 80 µg	Part 1 - Healthy subjects - CHF 6366, 160 µg	Part 1 - Healthy subjects - CHF 6366, 360 µg	Part 1 - Healthy subjects - Placebo
Number of subjects analysed	8 ^[7]	8	8	8	8	8	8	24 ^[8]
Units: subjects
450 < QTcF <= 480 msec	0	0	0	0	0	0	0	0
480 < QTcF <= 500 msec	0	0	0	0	0	0	0	0
QTcF > 500 msec	0	0	0	0	0	0	0	0
30 <= QTcF Increase from Baseline <= 60 msec	0	0	0	0	0	0	0	0
QTcF Increase from Baseline > 60 msec	0	0	0	0	0	0	0	0

Notes
[7] - Safety population was used for the analysis of each group.
[8] - N=28 (see explanation in the end point description)

No statistical analyses for this end point

Primary: 4_Part 1 - FEV1 - Single ascending dose - Healthy subjects - Decrease from baseline

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End point title

4_Part 1 - FEV1 - Single ascending dose - Healthy subjects - Decrease from baseline ^[9]

End point description

Part 1 - FEV1 - Single ascending dose - Healthy subjects - Decrease from baseline FEV1 ≥ 20% Data were derived from lung function measurements. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (Cohort A, B, and H).

End point type

Primary

End point timeframe

On Day 1, at pre-dose, 15, 30, 45 min and 1, 2, 6, and 12 h post-dose. On Day 2, at 24 h post-dose. On Day 3, at 48 h post-dose.

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 1 - Healthy subjects - CHF 6366, 5 µg	Part 1 - Healthy subjects - CHF 6366, 10 µg	Part 1 - Healthy subjects - CHF 6366, 20 µg	Part 1 - Healthy subjects - CHF 6366, 40 µg	Part 1 - Healthy subjects - CHF 6366, 80 µg	Part 1 - Healthy subjects - CHF 6366, 160 µg	Part 1 - Healthy subjects - CHF 6366, 360 µg	Part 1 - Healthy subjects - Placebo
Number of subjects analysed
Units: subjects
Decrease from baseline FEV1 ≥ 20%	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Primary: 5_Part 2 - SBP and DBP - Multiple ascending dose - Subjects with Asthma - Any post-dose timepoint

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End point title

5_Part 2 - SBP and DBP - Multiple ascending dose - Subjects with Asthma - Any post-dose timepoint ^[10]

End point description

SBP and DBP - Multiple ascending dose - Subjects with Asthma Cohorts C, D, E, F - Any post-dose timepoint. Data were derived from manual measurements by the study staff. Baseline is defined as pre-dose value on Day 1. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (Cohort C, D, E, F).

End point type

Primary

End point timeframe

On Day 1 and on Day 7, at pre-dose and 15 and 30 min, 1, 2, 4, 8, and 12 h post-dose. From Day 2, to Day 6 at pre-dose only. On Day 8, at 24 h post-dose and at Follow-up.

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg	Part 2 - Subjects with asthma - Placebo
Number of subjects analysed	9 ^[11]	9	9	9	12
Units: subjects
SBP change >20 mmHg	0	1	0	0	1
SBP change <-20 mmHg	1	1	1	1	0
DBP change >10 mmHg	1	1	0	1	1
DBP change <-10 mmHg	2	3	4	7	3

Notes
[11] - Safety population was used for the analysis of each group.

No statistical analyses for this end point

Primary: 6_Part 2 - Heart rate (0-24h) - Multiple ascending dose - Subjects with asthma - Change from baseline

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End point title

6_Part 2 - Heart rate (0-24h) - Multiple ascending dose - Subjects with asthma - Change from baseline ^[12]

End point description

Part 2 - Heart rate (0-24h) - Multiple ascending dose -Subjects with asthma - Change from baseline Data were derived from measurements using 12-lead ECG, extracted from 24 h Holter monitoring. Baseline is defined as the average heart rate (in bpm) of the 24 hours preceding the study drug administration on Day 1. Results show the value obtained for the adjusted difference vs placebo on Day 1 and Day 7. Adjusted mean difference and 90% CI based on a linear model with terms for treatment, period and sequence and subject within sequence as random effects and baseline value as a covariate. Presented are values extracted from Holter at pre-defined timepoints. The number of subjects contributing to the data is indicated (Cohort C, D, E, F).

End point type

Primary

End point timeframe

24h Holter ECG recording.

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg
Number of subjects analysed	9 ^[13]	9	9	9
Units: bpm
number (confidence interval 90%)
Day 1	4.5 (0.9 to 8.0)	0.3 (-3.5 to 4.1)	1.3 (-2.3 to 4.9)	1.9 (-1.7 to 5.6)
Day 7	4.3 (0.8 to 7.7)	0.6 (-3.1 to 4.2)	4.3 (0.9 to 7.7)	3.2 (-0.2 to 6.6)

Notes
[13] - Safety population was used for the analysis of each group.

No statistical analyses for this end point

Primary: 7_Part 2 - QTcF - Multiple ascending dose - Subjects with asthma - Any post-dose timepoint

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End point title

7_Part 2 - QTcF - Multiple ascending dose - Subjects with asthma - Any post-dose timepoint ^[14]

End point description

Part 2 - QTcF - Multiple ascending dose - Subjects with asthma - Any post-dose timepoint Data were derived from measurements using 12-lead ECG, extracted from 24 h Holter monitoring. Baseline for a particular post-baseline time point on Day X is defined as the time-matched measurement taken X days prior to the treatment administration. Presented are values extracted from Holter at pre-defined timepoints. The number of subjects contributing to the data is indicated (Cohort C, D, E, F).

End point type

Primary

End point timeframe

On Day 1, at pre-dose, 5, 15, 30, 45 min and 1, 1.5, 2, 4, 8, 12 h post-dose. On Day 2, at 24 h after Day 1 dose. On Day 7, at pre-dose, 15, 30 and 45 min and 1, 1.5, 2, 4, 8, 12 h post-dose. On Day 8, 24-hours post-dose and at Follow-up.

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg	Part 2 - Subjects with asthma - Placebo
Number of subjects analysed	8 ^[15]	9	9	9	12
Units: subjects
450 < QTcF <= 480 msec	0	0	0	0	0
480 < QTcF <= 500 msec	0	0	0	0	0
QTcF > 500 msec	0	0	0	0	0
30 <= QTcF Increase from Baseline <= 60 msec	1	0	0	2	1
QTcF Increase from Baseline > 60 msec	0	0	0	0	0

Notes
[15] - Safety population was used for the analysis of each group.

No statistical analyses for this end point

Primary: 8_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Change from baseline - Day 1

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End point title

8_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Change from baseline - Day 1 ^[16]

End point description

Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - FEV1 Change from baseline - Day 1 Data were derived from lung function measurements. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (Cohort C, D, E, and F).

End point type

Primary

End point timeframe

On Day 1 and Day 7, at pre-dose, 15, 30, and 45 min and 1, 2, 6, 12, and 24 h post-dose (Day 2). On Day 8, at 24 h post-Day 7 dose.

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg	Part 2 - Subjects with asthma - Placebo
Number of subjects analysed	9 ^[17]	9 ^[18]	9	9	12
Units: litre(s)
arithmetic mean (confidence interval 95%)
Day 1, 15 min	0.180 (0.070 to 0.290)	0.219 (0.014 to 0.424)	0.426 (0.120 to 0.731)	0.304 (0.022 to 0.587)	-0.020 (-0.141 to 0.101)
Day 1, 30 min	0.179 (0.023 to 0.335)	0.381 (0.168 to 0.595)	0.552 (0.248 to 0.856)	0.284 (0.019 to 0.550)	0.004 (-0.146 to 0.154)
Day 1, 45 min	0.369 (0.219 to 0.519)	0.259 (0.058 to 0.460)	0.617 (0.309 to 0.925)	0.397 (0.176 to 0.618)	0.034 (-0.056 to 0.124)
Day 1, 1 h	0.239 (0.067 to 0.411)	0.262 (0.037 to 0.488)	0.666 (0.357 to 0.974)	0.448 (0.204 to 0.691)	0.043 (-0.044 to 0.129)
Day 1, 2 h	0.309 (0.154 to 0.464)	0.406 (0.193 to 0.618)	0.608 (0.360 to 0.855)	0.400 (0.129 to 0.671)	0.118 (0.003 to 0.234)
Day 1, 6 h	0.102 (-0.051 to 0.256)	0.243 (0.010 to 0.476)	0.558 (0.259 to 0.856)	0.350 (0.102 to 0.598)	0.045 (-0.074 to 0.164)

Notes
[17] - Safety population was used for the analysis of each group.
[18] - N=9 N=8 N=9 N=9 N=9 N=9

No statistical analyses for this end point

Primary: 9_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Change from pre-dose - Day 7

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End point title

9_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Change from pre-dose - Day 7 ^[19]

End point description

Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Change from pre-dose - Day 7. Data were derived from lung function measurements. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (Cohort C, D, E, and F).

End point type

Primary

End point timeframe

On Day 1 and Day 7, at pre-dose, 15, 30, and 45 min and 1, 2, 6, 12, and 24 h post-dose (Day 2). On Day 8, at 24 h post-Day 7 dose.

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg	Part 2 - Subjects with asthma - Placebo
Number of subjects analysed	8 ^[20]	8	9 ^[21]	9 ^[22]	12
Units: litre(s)
arithmetic mean (confidence interval 95%)
Day 7, 15 min	0.441 (0.132 to 0.715)	0.371 (0.094 to 0.649)	0.412 (0.046 to 0.779)	0.260 (0.081 to 0.439)	0.106 (-0.055 to 0.267)
Day 7, 30 min	0.410 (0.097 to 0.723)	0.540 (0.221 to 0.859)	0.443 (0.035 to 0.852)	0.376 (0.170 to 0.581)	0.064 (-0.043 to 0.171)
Day 7, 45 min	0.480 (0.132 to 0.828)	0.575 (0.257 to 0.893)	0.468 (0.057 to 0.878)	0.464 (0.235 to 0.693)	0.125 (0.008 to 0.242)
Day 7, 1 h	0.466 (0.163 to 0.770)	0.688 (0.328 to 1.047)	0.488 (0.060 to 0.916)	0.379 (0.181 to 0.577)	0.163 (0.031 to 0.294)
Day 7, 2 h	0.561 (0.173 to 0.949)	0.685 (0.311 to 1.059)	0.450 (0.144 to 0.756)	0.415 (0.306 to 0.524)	0.208 (0.070 to 0.345)
Day 7, 6 h	0.384 (0.074 to 0.694)	0.439 (0.087 to 0.790)	0.288 (-0.057 to 0.632)	0.186 (0.066 to 0.305)	0.132 (-0.000 to 0.264)

Notes
[20] - Safety population was used for the analysis of each group.
[21] - N=9 N=9 N=9 N=9 N=9 N=8
[22] - N=9 N=9 N=8 N=9 N=8 N=9

No statistical analyses for this end point

Primary: 10_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from pre-dose ≥ 20% - Day 7

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End point title

10_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from pre-dose ≥ 20% - Day 7 ^[23]

End point description

Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from pre-dose ≥ 20% - Day 7. Data were derived from lung function measurements. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (Cohort C, D, E, and F).

End point type

Primary

End point timeframe

On Day 1 and Day 7, at pre-dose, 15, 30, and 45 min and 1, 2, 6, 12, and 24 h post-dose (Day 2). On Day 8, at 24 h post-Day 7 dose.

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg	Part 2 - Subjects with asthma - Placebo
Number of subjects analysed	9 ^[24]	9	9	9	12
Units: subjects	0	0	0	0	0

Notes
[24] - Safety population was used for the analysis of each group.

No statistical analyses for this end point

Primary: 11_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from baseline ≥ 20% - Any post-dose timepoint

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End point title

11_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from baseline ≥ 20% - Any post-dose timepoint ^[25]

End point description

Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from baseline ≥ 20% - Any post-dose timepoint Data were derived from lung function measurements. Baseline is defined as pre-dose value on Day 1. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (Cohort C, D, E, and F).

End point type

Primary

End point timeframe

On Day 1 and Day 7, at pre-dose, 15, 30, and 45 min and 1, 2, 6, 12, and 24 h post-dose (Day 2). On Day 8, at 24 h post-Day 7 dose.

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg	Part 2 - Subjects with asthma - Placebo
Number of subjects analysed	9 ^[26]	9	9	9	12
Units: subjects
Day 1, 15 min	0	0	0	0	0
Day 1, 30 min	0	0	0	0	0
Day 1, 45 min	0	0	0	0	0
Day 1, 1 h	0	0	0	0	0
Day 1, 2 h	0	0	0	0	0
Day 1, 6 h	0	0	0	0	0

Notes
[26] - Safety population was used for the analysis of each group.

No statistical analyses for this end point

Primary: 12_Part 3 - SBP and DBP - Single dose - Subjects with COPD - Any post-dose timepoint

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End point title

12_Part 3 - SBP and DBP - Single dose - Subjects with COPD - Any post-dose timepoint ^[27]

End point description

Part 3 - SBP and DBP - Multiple ascending dose - Subjects with COPD - Any post-dose timepoint. Data were derived from manual measurements by the study staff. Baseline is defined as pre-dose value on Day 1 of each treatment. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (subjects receiving CHF 6366, Anoro, Placebo).

End point type

Primary

End point timeframe

On Day 1, at pre-dose, and at 15, 30 min, 1, 2, 4, 8, 12 h post-dose. On Day 2, at 24 h post-dose. Day 3, at 48 h post-dose and at Follow-up.

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg	Part 3 - Subjects with COPD - Anoro, 55/22 µg	Part 3 - Subjects with COPD - Placebo
Number of subjects analysed	21 ^[28]	23	24
Units: subjects
SBP change > 20 mmHg	1	2	1
SBP change < -20 mmHg	5	4	2
DBP change > 10 mmHg	1	2	2
DBP change < -10 mmHg	12	10	5

Notes
[28] - Safety population was used for the analysis of each group.

No statistical analyses for this end point

Primary: 13_Part 3 - Heart rate (0-24h) - Single dose - Subjects with COPD - Change from baseline

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End point title

13_Part 3 - Heart rate (0-24h) - Single dose - Subjects with COPD - Change from baseline

End point description

Part 3 - Heart rate (0-24h) - Single dose - Subjects with COPD - Change from baseline. Data were derived from measurements using 12-lead ECG, extracted from 24 h Holter monitoring. Baseline is defined as the average HR of the 24 hours preceding the study drug administration on Day 1 of each treatment period. Results show the value obtained as adjusted mean and 95% CI. Presented are values extracted from Holter at pre-defined timepoints. The number of subjects contributing to the data is indicated (subjects receiving CHF 6366, Anoro, Placebo).

End point type

Primary

End point timeframe

24h Holter ECG recording.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg	Part 3 - Subjects with COPD - Anoro, 55/22 µg	Part 3 - Subjects with COPD - Placebo
Number of subjects analysed	21 ^[29]	22	24
Units: bpm
arithmetic mean (confidence interval 95%)	1.6 (0.4 to 2.8)	-1.5 (-2.6 to -0.3)	-0.0 (-1.1 to 1.0)

Notes
[29] - Safety population was used for the analysis of each group.

1_CHF 6366 vs Placebo

Statistical analysis description

Adjusted mean difference and 90% CI based on a linear model with terms for treatment, period and subject as fixed effects and Baseline value as a covariate. The value N=45, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=21 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - CHF 6366, 240 µg v Part 3 - Subjects with COPD - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[30]

Method

Parameter type

Mean difference (final values)

Point estimate

1.6

Confidence interval

level

90%

sides

2-sided

lower limit

0.3

upper limit

Notes
[30] - Model was carried out to estimate CIs.

2_Anoro vs Placebo

Statistical analysis description

Adjusted mean difference and 90% CI based on a linear model with terms for treatment, period and subject as fixed effects and Baseline value as a covariate. The value N=46, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=22 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - Anoro, 55/22 µg v Part 3 - Subjects with COPD - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[31]

Method

Parameter type

Mean difference (final values)

Point estimate

-1.4

Confidence interval

level

90%

sides

2-sided

lower limit

-2.7

upper limit

-0.1

Notes
[31] - Model was carried out to estimate CIs.

Primary: 14_Part 3 - QTcF - Single dose - Subjects with COPD - Any post-dose timepoint

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End point title

14_Part 3 - QTcF - Single dose - Subjects with COPD - Any post-dose timepoint ^[32]

End point description

Part 3 - QTcF - Single dose - Subjects with COPD - Any post-dose timepoint. Data were derived from measurements using 12-lead ECG, extracted from 24 h Holter monitoring. Baseline is defined as the time-matched measurement taken prior to the study drug administration on Day 1 of each treatment. Presented are values extracted from Holter at pre-defined timepoints. The number of subjects contributing to the data is indicated (subjects receiving CHF 6366, Anoro, Placebo).

End point type

Primary

End point timeframe

On Day 1, at pre-dose and 5, 15, 30 and 45 min and 1, 1.5, 2, 4, 8 and 12 h post-dose. On Day 2, at 24 h post-dose. Day 3, at 48 h post-dose and at Follow-up.

Notes
[32] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg	Part 3 - Subjects with COPD - Anoro, 55/22 µg	Part 3 - Subjects with COPD - Placebo
Number of subjects analysed	21 ^[33]	22	24
Units: subjects
450 < QTcF <= 480 msec	0	0	1
480 < QTcF <= 500 msec	0	0	0
QTcF > 500 msec	0	0	0
30 <= QTcF Increase from Baseline <= 60 msec	2	1	2
QTcF Increase from Baseline > 60 msec	0	0	0

Notes
[33] - Safety population was used for the analysis of each group.

No statistical analyses for this end point

Primary: 15_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1(0-24h)/24 h

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End point title

15_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1(0-24h)/24 h

End point description

Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1(0-24h)/24 h. Data were derived from lung function measurements. Results show the statistical comparison of FEV1(0-24h)/24 h for CHF 6366 vs Placebo, CHF 6366 vs Anoro, and Anoro vs Placebo. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (subjects receiving CHF 6366, Anoro, Placebo).

End point type

Primary

End point timeframe

On Day 1, at pre-dose and 15, 30 and 45 min and 1, 2, 6, 12, 23 and 24 h post-dose (Day 2). On Day 3, and at Follow-up.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg	Part 3 - Subjects with COPD - Anoro, 55/22 µg	Part 3 - Subjects with COPD - Placebo
Number of subjects analysed	21 ^[34]	23	21
Units: litre(s)
arithmetic mean (confidence interval 95%)	1.498 (1.449 to 1.547)	1.617 (1.572 to 1.662)	1.350 (1.301 to 1.399)

Notes
[34] - Pharmacodynamic population was used for the analysis of each group.

1_CHF 6366 vs Placebo

Statistical analysis description

Results are based on an analysis of covariance model with treatment, period, and subject as fixed effects and corresponding Baseline value (Day 1 pre dose FEV1 value of each period) as a covariate. The value N=42, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=21 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - CHF 6366, 240 µg v Part 3 - Subjects with COPD - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[35]

Method

Parameter type

Mean difference (final values)

Point estimate

0.1478

Confidence interval

level

95%

sides

2-sided

lower limit

0.07913

upper limit

0.2165

Notes
[35] - Model was carried out to estimate CIs.

2_CHF 6366 vs Anoro

Statistical analysis description

Results are based on an analysis of covariance model with treatment, period, and subject as fixed effects and corresponding Baseline value (Day 1 pre dose FEV1 value of each period) as a covariate. The value N=44, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=23 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - Anoro, 55/22 µg v Part 3 - Subjects with COPD - CHF 6366, 240 µg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[36]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.1188

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1853

upper limit

-0.05235

Notes
[36] - Model was carried out to estimate CIs.

3_Anoro vs Placebo

Statistical analysis description

Results are based on an analysis of covariance model with treatment, period, and subject as fixed effects and corresponding Baseline value (Day 1 pre dose FEV1 value of each period) as a covariate. The value N=44, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=21 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - Anoro, 55/22 µg v Part 3 - Subjects with COPD - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[37]

Method

Parameter type

Mean difference (final values)

Point estimate

0.2666

Confidence interval

level

95%

sides

2-sided

lower limit

0.2002

upper limit

0.3331

Notes
[37] - Model was carried out to estimate CIs.

Primary: 16_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Through

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End point title

16_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Through

End point description

Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Through. Data were derived from lung function measurements. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (subjects receiving CHF 6366, Anoro, Placebo).

End point type

Primary

End point timeframe

On Day 1 at pre-dose and 15, 30 and 45 min and at 1, 2, 6, 12, 23 and 24 h post-dose (Day 2). On Day 3 and at Follow-up.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg	Part 3 - Subjects with COPD - Anoro, 55/22 µg	Part 3 - Subjects with COPD - Placebo
Number of subjects analysed	21 ^[38]	23	22
Units: litre(s)
arithmetic mean (confidence interval 95%)	1.397 (1.344 to 1.451)	1.597 (1.548 to 1.646)	1.350 (1.299 to 1.402)

Notes
[38] - Pharmacodynamic population was used for the analysis of each group.

1_CHF 6366 vs Placebo

Statistical analysis description

Results are based on an analysis of covariance model with treatment, period, and subject as fixed effects and corresponding Baseline value (Day 1 pre dose FEV1 value of each period) as a covariate. The value N=43, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=21 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - CHF 6366, 240 µg v Part 3 - Subjects with COPD - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[39]

Method

Parameter type

Mean difference (final values)

Point estimate

0.047

Confidence interval

level

95%

sides

2-sided

lower limit

-0.027

upper limit

0.121

Notes
[39] - Model was carried out to estimate CIs.

2_CHF 6366 vs Anoro

Statistical analysis description

Results are based on an analysis of covariance model with treatment, period, and subject as fixed effects and corresponding Baseline value (Day 1 pre dose FEV1 value of each period) as a covariate. The value N=44, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=21 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - CHF 6366, 240 µg v Part 3 - Subjects with COPD - Anoro, 55/22 µg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[40]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.273

upper limit

-0.127

Notes
[40] - Model was carried out to estimate CIs.

3_Anoro vs Placebo

Statistical analysis description

Results are based on an analysis of covariance model with treatment, period, and subject as fixed effects and corresponding Baseline value (Day 1 pre dose FEV1 value of each period) as a covariate. The value N=45, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=21 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - Anoro, 55/22 µg v Part 3 - Subjects with COPD - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[41]

Method

Parameter type

Mean difference (final values)

Point estimate

0.247

Confidence interval

level

95%

sides

2-sided

lower limit

0.175

upper limit

0.318

Notes
[41] - Model was carried out to estimate CIs.

Primary: 17_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Peak

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End point title

17_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Peak

End point description

Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Peak. Data were derived from lung function measurements. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (subjects receiving CHF 6366, Anoro, Placebo).

End point type

Primary

End point timeframe

On Day 1 at pre-dose and 15, 30 and 45 min and at 1, 2, 6, 12, 23 and 24 h post-dose (Day 2). On Day 3 and at Follow-up.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg	Part 3 - Subjects with COPD - Anoro, 55/22 µg	Part 3 - Subjects with COPD - Placebo
Number of subjects analysed	21 ^[42]	23	22
Units: litre(s)
arithmetic mean (confidence interval 95%)	1.740 (1.682 to 1.798)	1.743 (1.690 to 1.795)	1.478 (1.422 to 1.534)

Notes
[42] - Pharmacodynamic population was used for the analysis of each group.

1_CHF 6366 vs Placebo

Statistical analysis description

Results are based on an analysis of covariance model with treatment, period, and subject as fixed effects and corresponding Baseline value (Day 1 pre dose FEV1 value of each period) as a covariate. The value N=43, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=21 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - CHF 6366, 240 µg v Part 3 - Subjects with COPD - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[43]

Method

Parameter type

Mean difference (final values)

Point estimate

0.262

Confidence interval

level

95%

sides

2-sided

lower limit

0.183

upper limit

0.341

Notes
[43] - Model was carried out to estimate CIs.

2_CHF 6366 vs Anoro

Statistical analysis description

Results are based on an analysis of covariance model with treatment, period, and subject as fixed effects and corresponding Baseline value (Day 1 pre dose FEV1 value of each period) as a covariate. The value N=44, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=21 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - CHF 6366, 240 µg v Part 3 - Subjects with COPD - Anoro, 55/22 µg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[44]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-0.08

upper limit

0.075

Notes
[44] - Model was carried out to estimate CIs.

3_Anoro vs Placebo

Statistical analysis description

Results are based on an analysis of covariance model with treatment, period, and subject as fixed effects and corresponding Baseline value (Day 1 pre dose FEV1 value of each period) as a covariate. The value N=45, shown below, is generated automatically and is due to innate error of the EudraCT database system. The correct value for subjects in the analysis is N=21 (cross-over study design).

Comparison groups

Part 3 - Subjects with COPD - Anoro, 55/22 µg v Part 3 - Subjects with COPD - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[45]

P-value

< 0.0001

Method

CHF pls specify method

Parameter type

Mean difference (final values)

Point estimate

0.265

Confidence interval

level

95%

sides

2-sided

lower limit

0.188

upper limit

0.341

Notes
[45] - Model was carried out to estimate CIs.

Primary: 18_Part 3 - FEV1 - Single dose - Subjects with COPD - Decrease from baseline ≥ 20%

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End point title

18_Part 3 - FEV1 - Single dose - Subjects with COPD - Decrease from baseline ≥ 20% ^[46]

End point description

FEV1 - Single dose - Subjects with COPD - Decrease from baseline ≥ 20% by scheduled time by treatment Data were derived from lung function measurements. Presented are representative results of the time points. The number of subjects contributing to the data is indicated (subjects receiving CHF 6366, Anoro, Placebo).

End point type

Primary

End point timeframe

On Day 1 at pre-dose and 15, 30 and 45 min and at 1, 2, 6, 12, 23 and 24 h post-dose (Day 2). On Day 3 and at Follow-up.

Notes
[46] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg	Part 3 - Subjects with COPD - Anoro, 55/22 µg	Part 3 - Subjects with COPD - Placebo
Number of subjects analysed	21 ^[47]	23	24 ^[48]
Units: subjects
15 min	0	0	1
30 min	0	0	1
45 min	0	0	1
1 h	0	0	1
2 h	0	0	1
6 h	0	0	0

Notes
[47] - N=21 N=19 N=21 N=21 N=21 N=21
[48] - N=23 N=23 N=23 N=24 N=24 N=24

No statistical analyses for this end point

Secondary: 19_Part 1 - Tmax - Single ascending dose - Healthy subjects

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End point title

19_Part 1 - Tmax - Single ascending dose - Healthy subjects

End point description

Part 1 - Tmax - Single ascending dose - Healthy subjects. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

On Day 1, at pre-dose, 5, 10, 15, 30 and 45 mi, at 1, 1.5, 2, 4, 6, 8, 12, and 18 h post-dose. On Day 2, at 24 h post-dose. On Day 3, at 48 h post-dose.

End point values	Part 1 - Healthy subjects - CHF 6366, 10 µg	Part 1 - Healthy subjects - CHF 6366, 20 µg	Part 1 - Healthy subjects - CHF 6366, 40 µg	Part 1 - Healthy subjects - CHF 6366, 80 µg	Part 1 - Healthy subjects - CHF 6366, 160 µg	Part 1 - Healthy subjects - CHF 6366, 360 µg
Number of subjects analysed	3 ^[49]	6	8	7	8 ^[50]	8 ^[51]
Units: hour
median (full range (min-max))
CHF 6361	1.0000 (0.933 to 1.017)	0.8750 (0.500 to 1.00)	1.0000 (0.750 to 1.000)	0.7500 (0.500 to 1.500)	0.8835 (0.500 to 1.600)	1.1335 (0.733 to 1.500)

Notes
[49] - Pharmacokinetic population was used for the analysis of each group.
[50] - Results for Tmax: CHF 6366: ND CHF 6387: N=5; 0.7500 (0.750 – 1.000) h
[51] - Results for Tmax: CHF 6366: N=3; 0.5000 (0.500 - 1.017) h CHF 6387: N=8; 1.5085 (1.017 – 8.000) h

No statistical analyses for this end point

Secondary: 20_Part 1 - T1/2 - Single ascending dose - Healthy subjects

Top of page

End point title

20_Part 1 - T1/2 - Single ascending dose - Healthy subjects

End point description

Part 1 - T1/2 - Single ascending dose - Healthy subjects. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

On Day 1, at pre-dose, 5, 10, 15, 30 and 45 mi, at 1, 1.5, 2, 4, 6, 8, 12, and 18 h post-dose. On Day 2, at 24 h post-dose. On Day 3, at 48 h post-dose.

End point values	Part 1 - Healthy subjects - CHF 6366, 40 µg	Part 1 - Healthy subjects - CHF 6366, 80 µg	Part 1 - Healthy subjects - CHF 6366, 160 µg	Part 1 - Healthy subjects - CHF 6366, 360 µg
Number of subjects analysed	4 ^[52]	7	3	7 ^[53]
Units: hour
geometric mean (geometric coefficient of variation)
CHF 6361	2.071 ( 25.39 )	8.139 ( 152.2 )	6.710 ( 132.2 )	31.46 ( 23.38 )

Notes
[52] - Pharmacokinetic population was used for the analysis of each group.
[53] - Results for T1/2: CHF 6366: ND CHF 6387: N=2; 2.460 (0.5749) h

No statistical analyses for this end point

Secondary: 21_Part 1 - Cmax - Single ascending dose - Healthy subjects

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End point title

21_Part 1 - Cmax - Single ascending dose - Healthy subjects

End point description

Part 1 - Cmax - Single ascending dose - Healthy subjects. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

On Day 1, at pre-dose, 5, 10, 15, 30 and 45 mi, at 1, 1.5, 2, 4, 6, 8, 12, and 18 h post-dose. On Day 2, at 24 h post-dose. On Day 3, at 48 h post-dose.

End point values	Part 1 - Healthy subjects - CHF 6366, 10 µg	Part 1 - Healthy subjects - CHF 6366, 20 µg	Part 1 - Healthy subjects - CHF 6366, 40 µg	Part 1 - Healthy subjects - CHF 6366, 80 µg	Part 1 - Healthy subjects - CHF 6366, 160 µg	Part 1 - Healthy subjects - CHF 6366, 360 µg
Number of subjects analysed	3 ^[54]	6	8	7	8 ^[55]	8 ^[56]
Units: pg/mL
geometric mean (geometric coefficient of variation)
CHF 6361	10.30 ( 26.73 )	7.821 ( 31.12 )	18.43 ( 23.70 )	32.30 ( 49.51 )	67.57 ( 40.21 )	167.3 ( 38.42 )

Notes
[54] - Pharmacokinetic population was used for the analysis of each group.
[55] - Results for Cmax: CHF 6366: ND CHF 6387: N=5; 29.95 (7.380) pg/mL
[56] - Results for Cmax: CHF 6366: N=3; 6.995 (10.38) pg/mL CHF 6387: N=8; 61.08 (48.58) pg/mL

No statistical analyses for this end point

Secondary: 22_Part 1 - AUC(0-last) - Single ascending dose - Healthy subjects

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End point title

22_Part 1 - AUC(0-last) - Single ascending dose - Healthy subjects

End point description

Part 1 - AUC(0-last) - Single ascending dose - Healthy subjects. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

On Day 1, at pre-dose, 5, 10, 15, 30 and 45 mi, at 1, 1.5, 2, 4, 6, 8, 12, and 18 h post-dose. On Day 2, at 24 h post-dose. On Day 3, at 48 h post-dose.

End point values	Part 1 - Healthy subjects - CHF 6366, 10 µg	Part 1 - Healthy subjects - CHF 6366, 20 µg	Part 1 - Healthy subjects - CHF 6366, 40 µg	Part 1 - Healthy subjects - CHF 6366, 80 µg	Part 1 - Healthy subjects - CHF 6366, 160 µg	Part 1 - Healthy subjects - CHF 6366, 360 µg
Number of subjects analysed	3 ^[57]	5	8	7	8 ^[58]	8 ^[59]
Units: pg·h/mL
geometric mean (geometric coefficient of variation)
CHF 6361	12.31 ( 55.32 )	8.678 ( 38.03 )	38.17 ( 64.95 )	108.7 ( 62.67 )	270.8 ( 56.56 )	1023 ( 27.99 )

Notes
[57] - Pharmacokinetic population was used for the analysis of each group.
[58] - For AUC(0-last) pg·h/mL CHF 6366: ND CHF 6387: N=2; 24.08 (53.36)
[59] - For AUC(0-last) pg·h/mL CHF 6366: ND CHF 6387: N=8; 141.2 (95.35)

No statistical analyses for this end point

Secondary: 23_Part 2 - Tmax - Multiple ascending dose - Subjects with asthma - Day 1

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End point title

23_Part 2 - Tmax - Multiple ascending dose - Subjects with asthma - Day 1

End point description

Part 2 - Tmax - Multiple ascending dose - Subjects with asthma. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

Day 1, pre-dose and 5, 10, 15, 30 and 45 min, 1, 1.5, 2, 4, 6, 8, 12 h post-dose. Day 2, 18 h post-Day 1 dose. Day 2 to Day 6 pre-dose. Day 7, pre-dose and 5, 10, 15, 30 and 45 min, 1, 1.5, 2, 4, 6, 8, 12, 18 h post-dose. Day 8 at 24 h post-dose.

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg
Number of subjects analysed	8 ^[60]	9	9 ^[61]	9
Units: hour
median (full range (min-max))
CHF 6361	0.7500 (0.500 to 1.067)	1.0000 (0.500 to 1.500)	1.0000 (0.733 to 1.500)	1.0000 (0.750 to 1.500)

Notes
[60] - Pharmacokinetic population was used for the analysis of each group.
[61] - For Tmax hour CHF 6366: ND CHF 6387: N=3; 1.0000 (0.500 - 1.500)

No statistical analyses for this end point

Secondary: 24_Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma - Day 1

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End point title

24_Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma - Day 1

End point description

Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg
Number of subjects analysed	5 ^[62]	5	5	5
Units: hour
geometric mean (geometric coefficient of variation)
CHF 6361	1.685 ( 23.87 )	2.648 ( 53.19 )	6.886 ( 96.15 )	11.04 ( 65.67 )

Notes
[62] - Pharmacokinetic population was used for the analysis of each group.

No statistical analyses for this end point

Secondary: 25_Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 1

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End point title

25_Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 1

End point description

Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 1. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg
Number of subjects analysed	8 ^[63]	9	9 ^[64]	9
Units: pg/mL
geometric mean (geometric coefficient of variation)
CHF 6361	14.08 ( 39.98 )	26.24 ( 74.53 )	54.79 ( 77.85 )	43.60 ( 52.97 )

Notes
[63] - Pharmacokinetic population was used for the analysis of each group.
[64] - For Cmax pg/mL CHF 6366: ND CHF 6387: N=3; 31.34 (16.86)

No statistical analyses for this end point

Secondary: 26_Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma - Day 1

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End point title

26_Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma - Day 1

End point description

Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg
Number of subjects analysed	8 ^[65]	9	9 ^[66]	9
Units: pg·h/mL
geometric mean (geometric coefficient of variation)
CHF 6361	23.03 ( 71.85 )	60.92 ( 141.8 )	241.4 ( 121.2 )	208.2 ( 80.49 )

Notes
[65] - Pharmacokinetic population was used for the analysis of each group.
[66] - For AUC(0-last) pg·h/mL CHF 6366: ND CHF 6387: N=3; 14.80 (189.8)

No statistical analyses for this end point

Secondary: 27_Part 2 - Tmax - Multiple ascending dose - Subjects with asthma - Day 7

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End point title

27_Part 2 - Tmax - Multiple ascending dose - Subjects with asthma - Day 7

End point description

Part 2 - Tmax - Multiple ascending dose - Subjects with asthma - Day 7. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg
Number of subjects analysed	6 ^[67]	8	9 ^[68]	8 ^[69]
Units: hour
median (full range (min-max))
CHF 6361	0.8750 (0.750 to 1.517)	0.8750 (0.517 to 1.000)	1.0000 (0.500 to 1.533)	1.0165 (0.750 to 2.000)

Notes
[67] - Pharmacokinetic population was used for the analysis of each group.
[68] - For Tmax hour CHF 6366: ND CHF 6387: N=5; 0.7500 (0.500 - 1.000)
[69] - For Tmax hour CHF 6366: ND CHF 6387: N=5; 1.0000 (0.750 - 2.000)

No statistical analyses for this end point

Secondary: 28_Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma - Day 7

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End point title

28_Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma - Day 7

End point description

Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma - Day 7. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg
Number of subjects analysed	5 ^[70]	5	3	8
Units: hour
geometric mean (geometric coefficient of variation)
CHF 6361	3.130 ( 56.85 )	7.964 ( 91.13 )	16.63 ( 37.01 )	24.05 ( 71.54 )

Notes
[70] - Pharmacokinetic population was used for the analysis of each group.

No statistical analyses for this end point

Secondary: 29_Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 7

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End point title

29_Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 7

End point description

Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 7. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg
Number of subjects analysed	6 ^[71]	8	9 ^[72]	8 ^[73]
Units: pg/mL
geometric mean (geometric coefficient of variation)
CHF 6361	12.93 ( 21.22 )	27.13 ( 87.00 )	65.48 ( 52.35 )	78.98 ( 49.70 )

Notes
[71] - Pharmacokinetic population was used for the analysis of each group.
[72] - For Cmax pg/mL CHF 6366: ND CHF 6387: N=5; 32.59 (22.77)
[73] - For Cmax pg/mL CHF 6366: ND CHF 6387: N=5; 38.44 (24.56)

No statistical analyses for this end point

Secondary: 30_Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma - Day 7

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End point title

30_Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma - Day 7

End point description

Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma - Day 7. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

End point values	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg
Number of subjects analysed	7 ^[74]	8	9 ^[75]	9 ^[76]
Units: pg·h/mL
geometric mean (geometric coefficient of variation)
CHF 6361	30.55 ( 70.10 )	147.0 ( 146.4 )	463.2 ( 57.7 )	618.5 ( 50.05 )

Notes
[74] - Pharmacokinetic population was used for the analysis of each group.
[75] - For AUC(0-last) pg·h/mL CHF 6366: ND CHF 6387: N=5; 17.75 (167.9)
[76] - For AUC(0-last) pg·h/mL CHF 6366: ND CHF 6387: N=6; 36.85 (228.4)

No statistical analyses for this end point

Secondary: 31_Part 3 - Tmax - Single dose - Subjects with COPD

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End point title

31_Part 3 - Tmax - Single dose - Subjects with COPD

End point description

Part 3 - Tmax - Single dose - Subjects with COPD. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

Day 1, at pre-dose and 5, 10, 15, 30 and 45 min, at 1, 1.5, 2, 4, 6, 8, 12, and 18 h. Day 2, at 24 h post-dose. Day 3, at 48 h post-dose.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg
Number of subjects analysed	3 ^[77]
Units: hour
median (full range (min-max))
CHF 6366	0.1830 (0.167 to 0.250)
CHF 6387	1.0330 (0.750 to 2.033)
CHF 6361	1.0000 (0.500 to 2.000)

Notes
[77] - Pharmacokinetic population was used for the analysis of each group. N=3 N=5 N=20

No statistical analyses for this end point

Secondary: 32_Part 3 - T1/2 - Single dose - Subjects with COPD

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End point title

32_Part 3 - T1/2 - Single dose - Subjects with COPD

End point description

Part 3 - T1/2 - Single dose - Subjects with COPD. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

Day 1, at pre-dose and 5, 10, 15, 30 and 45 min, at 1, 1.5, 2, 4, 6, 8, 12, and 18 h. Day 2, at 24 h post-dose. Day 3, at 48 h post-dose.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg
Number of subjects analysed	17 ^[78]
Units: hour
geometric mean (geometric coefficient of variation)
CHF 6361	4.608 ( 94.25 )

Notes
[78] - Pharmacokinetic population was used for the analysis.

No statistical analyses for this end point

Secondary: 33_Part 3 - Cmax - Single dose - Subjects with COPD

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End point title

33_Part 3 - Cmax - Single dose - Subjects with COPD

End point description

Part 3 - Cmax - Single dose - Subjects with COPD. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

Day 1, at pre-dose and 5, 10, 15, 30 and 45 min, at 1, 1.5, 2, 4, 6, 8, 12, and 18 h. Day 2, at 24 h post-dose. Day 3, at 48 h post-dose.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg
Number of subjects analysed	3 ^[79]
Units: pg/mL
geometric mean (geometric coefficient of variation)
CHF 6366	7.167 ( 18.55 )
CHF 6387	31.89 ( 23.88 )
CHF 6361	48.86 ( 47.26 )

Notes
[79] - Pharmacokinetic population was used for the analysis of each group. N=3 N=5 N=20

No statistical analyses for this end point

Secondary: 34_Part 3 - AUC(0-last) - Single dose - Subjects with COPD

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End point title

34_Part 3 - AUC(0-last) - Single dose - Subjects with COPD

End point description

Part 3 - AUC(0-last) - Single dose - Subjects with COPD. Citrated blood was collected for PK assessment (in plasma) occurred at the specified time points. Results show data for PK parameters of CHF 6366 (parent compound) and its metabolites CHF 6387 and CHF 6361. For some of the PK parameters (when low concentration of CHF 6366 was administered), the plasma concentration of the parent compound CHF 6366 and of the metabolite CHF 6387 was not determined. This was because the plasma concentration was 'Below the limit of quantification' (BLQ). Available data for the parent compound and metabolites CHF 6387, are shown in the footnotes of the results table. The number of subjects contributing to the data is indicated.

End point type

Secondary

End point timeframe

Day 1, at pre-dose and 5, 10, 15, 30 and 45 min, at 1, 1.5, 2, 4, 6, 8, 12, and 18 h. Day 2, at 24 h post-dose. Day 3, at 48 h post-dose.

End point values	Part 3 - Subjects with COPD - CHF 6366, 240 µg
Number of subjects analysed	2 ^[80]
Units: pg·h/mL
geometric mean (geometric coefficient of variation)
CHF 6387	35.87 ( 78.31 )
CHF 6361	198.2 ( 73.67 )

Notes
[80] - Pharmacokinetic population was used for the analysis of each group. N=2 N=21

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events (AEs) were reported from the time of the patient informed consent signature up to the study completion or discontinuation. For all study parts, a follow-up visit was between 7 to 14 days after the last dose administration.

Adverse event reporting additional description

Safety population was used for the evaluation of AE (shown as TEAEs). Safety population: all randomised subjects who received at least one dose of study treatment. TEAEs: AEs starting on or after the first dose of study drug administration, but on or before date of last dose of study drug +7 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Part 1 - Healthy subjects - CHF 6366, 5 µg

Reporting group description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 5 µg.

Reporting group title

Part 1 - Healthy subjects - CHF 6366, 10 µg

Reporting group description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 10 µg.

Reporting group title

Part 1 - Healthy subjects - CHF 6366, 20 µg

Reporting group description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 20 µg.

Reporting group title

Part 1 - Healthy subjects - CHF 6366, 40 µg

Reporting group description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 40 µg.

Reporting group title

Part 1 - Healthy subjects - CHF 6366, 80 µg

Reporting group description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 80 µg.

Reporting group title

Part 1 - Healthy subjects - CHF 6366, 160 µg

Reporting group description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 160 µg.

Reporting group title

Part 1 - Healthy subjects - CHF 6366, 360 µg

Reporting group description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, 360 µg.

Reporting group title

Part 1 - Healthy subjects - Placebo

Reporting group description

Part 1 of the study. Healthy subjects who received placebo.

Reporting group title

Part 1 - Healthy subjects - CHF 6366, any dose

Reporting group description

Part 1 of the study. Healthy subjects who received a single ascending dose of CHF 6366, any dose.

Reporting group title

Part 2 - Subjects with asthma - CHF 6366, 40 µg

Reporting group description

Part 2 of the study. Subjects with asthma who received multiple ascending dose of CHF 6366, 40 µg for 7 days, according to the escalation scheme.

Reporting group title

Part 2 - Subjects with asthma - CHF 6366, 80 µg

Reporting group description

Part 2 of the study. Subjects with asthma who received multiple ascending dose of CHF 6366, 80 µg for 7 days, according to the escalation scheme.

Reporting group title

Part 2 - Subjects with asthma - CHF 6366, 160 µg

Reporting group description

Part 2 of the study. Subjects with asthma who received multiple ascending dose of CHF 6366, 160 µg for 7 days, according to the escalation scheme.

Reporting group title

Part 2 - Subjects with asthma - CHF 6366, 240 µg

Reporting group description

Part 2 of the study. Subjects with asthma who received multiple ascending dose of CHF 6366, 240 µg for 7 days, according to the escalation scheme.

Reporting group title

Part 2 - Subjects with asthma - Placebo

Reporting group description

Part 2 of the study. Subjects with asthma who received placebo for 7 days.

Reporting group title

Part 3 - Subjects with COPD - CHF 6366, 240 µg

Reporting group description

Part 3 of the study. Subjects with COPD, who received a single-dose of CHF 6366, 240 µg, according to a randomised, placebo-controlled, active-controlled*, 3-way cross-over design. *The active control was Anoro [Anoro Ellipta (umeclidinium and vilanterol dry powder inhaler, 55/22 μg)].

Reporting group title

Part 3 - Subjects with COPD - Anoro, 55/22 µg

Reporting group description

Part 3 of the study. Subjects with COPD, who received a single-dose of Anoro*, according to a randomised, placebo-controlled, active-controlled*, 3-way cross-over design. *The active control was Anoro [Anoro Ellipta (umeclidinium and vilanterol dry powder inhaler, 55/22 μg)].

Reporting group title

Part 3 - Subjects with COPD - Placebo

Reporting group description

Part 3 of the study. Subjects with COPD, who received a single-dose of placebo, according to a randomised, placebo-controlled, active-controlled*, 3-way cross-over design. *The active control was Anoro [Anoro Ellipta (umeclidinium and vilanterol dry powder inhaler, 55/22 μg)].

Reporting group title

Part 3 - Subjects with COPD - Overall

Reporting group description

Part 3 of the study. Subjects with COPD - overall summary. Subjects received a single-dose of the 3 treatments CHF 6366 (240 µg), Anoro*, according to a randomised, and placebo-controlled, active-controlled*, 3-way cross-over design. *The active control was Anoro [Anoro Ellipta (umeclidinium and vilanterol dry powder inhaler, 55/22 μg)].

Part 1 - Healthy subjects - CHF 6366, 5 µg

Part 1 - Healthy subjects - CHF 6366, 10 µg

Part 1 - Healthy subjects - CHF 6366, 20 µg

Part 1 - Healthy subjects - CHF 6366, 40 µg

Part 1 - Healthy subjects - CHF 6366, 80 µg

Part 1 - Healthy subjects - CHF 6366, 160 µg

Part 1 - Healthy subjects - CHF 6366, 360 µg

Part 1 - Healthy subjects - Placebo

Part 1 - Healthy subjects - CHF 6366, any dose

Part 2 - Subjects with asthma - CHF 6366, 40 µg

Part 2 - Subjects with asthma - CHF 6366, 80 µg

Part 2 - Subjects with asthma - CHF 6366, 160 µg

Part 2 - Subjects with asthma - CHF 6366, 240 µg

Part 2 - Subjects with asthma - Placebo

Part 3 - Subjects with COPD - CHF 6366, 240 µg

Part 3 - Subjects with COPD - Anoro, 55/22 µg

Part 3 - Subjects with COPD - Placebo

Part 3 - Subjects with COPD - Overall

Total subjects affected by serious adverse events

subjects affected / exposed

0 / 8 (0.00%)

0 / 24 (0.00%)

0 / 30 (0.00%)

0 / 9 (0.00%)

0 / 12 (0.00%)

0 / 21 (0.00%)

0 / 23 (0.00%)

0 / 24 (0.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Part 1 - Healthy subjects - CHF 6366, 5 µg	Part 1 - Healthy subjects - CHF 6366, 10 µg	Part 1 - Healthy subjects - CHF 6366, 20 µg	Part 1 - Healthy subjects - CHF 6366, 40 µg	Part 1 - Healthy subjects - CHF 6366, 80 µg	Part 1 - Healthy subjects - CHF 6366, 160 µg	Part 1 - Healthy subjects - CHF 6366, 360 µg	Part 1 - Healthy subjects - Placebo	Part 1 - Healthy subjects - CHF 6366, any dose	Part 2 - Subjects with asthma - CHF 6366, 40 µg	Part 2 - Subjects with asthma - CHF 6366, 80 µg	Part 2 - Subjects with asthma - CHF 6366, 160 µg	Part 2 - Subjects with asthma - CHF 6366, 240 µg	Part 2 - Subjects with asthma - Placebo	Part 3 - Subjects with COPD - CHF 6366, 240 µg	Part 3 - Subjects with COPD - Anoro, 55/22 µg	Part 3 - Subjects with COPD - Placebo	Part 3 - Subjects with COPD - Overall
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 8 (25.00%)	1 / 8 (12.50%)	2 / 8 (25.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	2 / 8 (25.00%)	2 / 8 (25.00%)	9 / 24 (37.50%)	9 / 30 (30.00%)	5 / 9 (55.56%)	7 / 9 (77.78%)	5 / 9 (55.56%)	5 / 9 (55.56%)	6 / 12 (50.00%)	9 / 21 (42.86%)	9 / 23 (39.13%)	12 / 24 (50.00%)	19 / 24 (79.17%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 24 (4.17%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1
General disorders and administration site conditions
Infusion site bruising
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)	2 / 24 (8.33%)	3 / 24 (12.50%)
occurrences all number	0	0	1	0	0	0	0	0	1	0	0	0	0	0	1	0	2	3
Medical device site reaction
Additional description: AE was due to the Holter device electrode patch.
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 8 (12.50%)	2 / 24 (8.33%)	4 / 30 (13.33%)	0 / 9 (0.00%)	6 / 9 (66.67%)	4 / 9 (44.44%)	1 / 9 (11.11%)	4 / 12 (33.33%)	1 / 21 (4.76%)	2 / 23 (8.70%)	2 / 24 (8.33%)	4 / 24 (16.67%)
occurrences all number	0	1	0	0	1	1	1	2	4	0	6	4	1	4	1	2	2	5
Application site dermatitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Chest discomfort
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Puncture site pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Feeling hot
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 24 (4.17%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Immune system disorders
Food allergy
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Reproductive system and breast disorders
Breast tenderness
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Dysmenorrhoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Nipple pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	1 / 23 (4.35%)	2 / 24 (8.33%)	4 / 24 (16.67%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1	2	2	5
Nasal congestion
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 24 (12.50%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0	0	0	0	0	1	0	0	0	0
Cough
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	1 / 21 (4.76%)	1 / 23 (4.35%)	3 / 24 (12.50%)	4 / 24 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1	1	3	5
Epistaxis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Throat irritation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	1 / 23 (4.35%)	1 / 24 (4.17%)	3 / 24 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1	1	3
Rhinorrhoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	2 / 24 (8.33%)	2 / 24 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	2
Investigations
Chlamydia test positive
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Blood urine present
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	1
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Contusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Ear injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Skin abrasion
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	1
Nervous system disorders
Headache
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 24 (8.33%)	4 / 30 (13.33%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	2 / 9 (22.22%)	1 / 12 (8.33%)	1 / 21 (4.76%)	3 / 23 (13.04%)	2 / 24 (8.33%)	5 / 24 (20.83%)
occurrences all number	2	0	1	0	1	1	0	2	5	0	1	2	2	1	1	4	2	7
Dizziness
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	1	0	1	0	0	1
Dizziness postural
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Lethargy
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Presyncope
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Eye disorders
Photopsia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Haematochezia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Aphthous ulcer
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Gingival pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Nausea
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Oral pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Toothache
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 24 (4.17%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Papule
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	1	0	0	0	0	0	0	0	0	0
Urticaria
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 24 (0.00%)	1 / 30 (3.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0	0	0	0	0	0	0
Pain in extremity
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Arthralgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	3 / 24 (12.50%)	3 / 24 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	3	3
Musculoskeletal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Musculoskeletal stiffness
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Infections and infestations
Rhinitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Vulvovaginal candidiasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 24 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Diverticulitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Oral candidiasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)	0 / 30 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 24 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

13 Jul 2018

1) New proposed maximum dose (360 μg/day) to be tested during the first part of the phI clinical trial is still supported by the preclinical data (Rat 4-week inhalation, Dog 4-week inhalation). 2) An additional Cohort (Cohort H) has been included for testing the highest dosage planned in Part 1 (320 µg). As for Cohort A and B, 12 subjects will be randomized in a 2:1 ratio to active CHF 6366 SD7 (8 subjects) and placebo (4 subjects). Subjects can be recruited from the two previous Cohorts (A and B) or be new individuals, respecting the study inclusion and exclusion criteria.

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.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1_Part 1 - SBP and DBP - Single ascending dose - Healthy subjects - Any post-dose timepoint

Primary: 1_Part 1 - SBP and DBP - Single ascending dose - Healthy subjects - Any post-dose timepoint

Primary: 2_Part 1 - Heart rate (0-24h) - Single ascending dose - Healthy subjects - Change from baseline

Primary: 2_Part 1 - Heart rate (0-24h) - Single ascending dose - Healthy subjects - Change from baseline

Primary: 3_Part 1 - QTcF - Single ascending dose - Healthy subjects - Any post-dose timepoint

Primary: 3_Part 1 - QTcF - Single ascending dose - Healthy subjects - Any post-dose timepoint

Primary: 4_Part 1 - FEV1 - Single ascending dose - Healthy subjects - Decrease from baseline

Primary: 4_Part 1 - FEV1 - Single ascending dose - Healthy subjects - Decrease from baseline

Primary: 5_Part 2 - SBP and DBP - Multiple ascending dose - Subjects with Asthma - Any post-dose timepoint

Primary: 5_Part 2 - SBP and DBP - Multiple ascending dose - Subjects with Asthma - Any post-dose timepoint

Primary: 6_Part 2 - Heart rate (0-24h) - Multiple ascending dose - Subjects with asthma - Change from baseline

Primary: 6_Part 2 - Heart rate (0-24h) - Multiple ascending dose - Subjects with asthma - Change from baseline

Primary: 7_Part 2 - QTcF - Multiple ascending dose - Subjects with asthma - Any post-dose timepoint

Primary: 7_Part 2 - QTcF - Multiple ascending dose - Subjects with asthma - Any post-dose timepoint

Primary: 8_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Change from baseline - Day 1

Primary: 8_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Change from baseline - Day 1

Primary: 9_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Change from pre-dose - Day 7

Primary: 9_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Change from pre-dose - Day 7

Primary: 10_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from pre-dose ≥ 20% - Day 7

Primary: 10_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from pre-dose ≥ 20% - Day 7

Primary: 11_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from baseline ≥ 20% - Any post-dose timepoint

Primary: 11_Part 2 - FEV1 - Multiple ascending dose - Subjects with asthma - Decrease from baseline ≥ 20% - Any post-dose timepoint

Primary: 12_Part 3 - SBP and DBP - Single dose - Subjects with COPD - Any post-dose timepoint

Primary: 12_Part 3 - SBP and DBP - Single dose - Subjects with COPD - Any post-dose timepoint

Primary: 13_Part 3 - Heart rate (0-24h) - Single dose - Subjects with COPD - Change from baseline

Primary: 13_Part 3 - Heart rate (0-24h) - Single dose - Subjects with COPD - Change from baseline

Primary: 14_Part 3 - QTcF - Single dose - Subjects with COPD - Any post-dose timepoint

Primary: 14_Part 3 - QTcF - Single dose - Subjects with COPD - Any post-dose timepoint

Primary: 15_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1(0-24h)/24 h

Primary: 15_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1(0-24h)/24 h

Primary: 16_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Through

Primary: 16_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Through

Primary: 17_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Peak

Primary: 17_Part 3 - FEV1 - Single dose - Subjects with COPD - FEV1 Peak

Primary: 18_Part 3 - FEV1 - Single dose - Subjects with COPD - Decrease from baseline ≥ 20%

Primary: 18_Part 3 - FEV1 - Single dose - Subjects with COPD - Decrease from baseline ≥ 20%

Secondary: 19_Part 1 - Tmax - Single ascending dose - Healthy subjects

Secondary: 19_Part 1 - Tmax - Single ascending dose - Healthy subjects

Secondary: 20_Part 1 - T1/2 - Single ascending dose - Healthy subjects

Secondary: 20_Part 1 - T1/2 - Single ascending dose - Healthy subjects

Secondary: 21_Part 1 - Cmax - Single ascending dose - Healthy subjects

Secondary: 21_Part 1 - Cmax - Single ascending dose - Healthy subjects

Secondary: 22_Part 1 - AUC(0-last) - Single ascending dose - Healthy subjects

Secondary: 22_Part 1 - AUC(0-last) - Single ascending dose - Healthy subjects

Secondary: 23_Part 2 - Tmax - Multiple ascending dose - Subjects with asthma - Day 1

Secondary: 23_Part 2 - Tmax - Multiple ascending dose - Subjects with asthma - Day 1

Secondary: 24_Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma - Day 1

Secondary: 24_Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma - Day 1

Secondary: 25_Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 1

Secondary: 25_Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 1

Secondary: 26_Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma - Day 1

Secondary: 26_Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma - Day 1

Secondary: 27_Part 2 - Tmax - Multiple ascending dose - Subjects with asthma - Day 7

Secondary: 27_Part 2 - Tmax - Multiple ascending dose - Subjects with asthma - Day 7

Secondary: 28_Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma - Day 7

Secondary: 28_Part 2 - T1/2 - Multiple ascending dose - Subjects with asthma - Day 7

Secondary: 29_Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 7

Secondary: 29_Part 2 - Cmax - Multiple ascending dose - Subjects with asthma - Day 7

Secondary: 30_Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma - Day 7

Secondary: 30_Part 2 - AUC(0-last) - Multiple ascending dose - Subjects with asthma - Day 7

Secondary: 31_Part 3 - Tmax - Single dose - Subjects with COPD

Secondary: 31_Part 3 - Tmax - Single dose - Subjects with COPD

Secondary: 32_Part 3 - T1/2 - Single dose - Subjects with COPD

Secondary: 32_Part 3 - T1/2 - Single dose - Subjects with COPD

Secondary: 33_Part 3 - Cmax - Single dose - Subjects with COPD

Secondary: 33_Part 3 - Cmax - Single dose - Subjects with COPD

Secondary: 34_Part 3 - AUC(0-last) - Single dose - Subjects with COPD

Secondary: 34_Part 3 - AUC(0-last) - Single dose - Subjects with COPD

Adverse events

Adverse events

More information