A Study to Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Dose in Healthy Volunteers, Repeat Doses in Asthmatic Patients and of Single Dose in COPD Patients of CHF6366

Study Overview
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Brief Summary
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CHF6366 is a novel bifunctional compound displaying both muscarinic receptor antagonist and β2-adrenergic receptor agonist properties (MABA), with the potential to deliver optimal bronchodilation after inhalation dosing via two validated mechanisms in one molecule. The study will consist of three parts: Part 1 will consit of two cohorts of healthy male subjects to assess the safety, tolerability and pharmacokinetics of Single Ascending Dose (SAD) of CHF 6366 Part 2 will consist of four cohorts of asthmatic subjects to assess the saftey, tolerability and pharmacokinetics of Multiple Ascending Dose (MAD) of CHF6366 Part 3 will consist of one cohort of COPD patients to asess safety, tolerability of a single dose of CHF6366 in an active and placebo controlled design

Official Title
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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

Conditions
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Asthma, Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: CHF6366
* Drug: Placebo CHF6366
* Drug: umeclidinium bromide and vilanterol trifenatate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1 male subjects aged 18-55 years inclusive; healthy subjects based on medical evaluation including medical history,physical examination, laboratory tests and cardiac testing Body Mass Index (BMI) between 18.5 and 32.0 kg/m2 extremes inclusive Non- or ex-smokers who smoked < 5 pack years (pack-years = the number of cigarette packs per day times the number of years) and stopped smoking > 1 year; Good physical and mental status, determined on the basis of the medical history and a general clinical examination; Lung function equal to or more than 80% of predicted normal value and FEV1/FVC ratio > 0.70; Part 2 Adult male and female subjects aged 18 to 75 years Clinical diagnosis of mild persistent asthma FEV1 reversibility of ≥ 12% or 200 ml over the baseline value starting within 30 mins after inhalation of 400 micrograms of salbutamol Patients who are otherwise healthy as determined by medical history, physical examination, 12-lead ECG findings Part 3 Male aged between 40 and 75 years Stable patients with a post-bronchodilator 40% ≤ FEV1 < 80% of the predicted normal value, post-bronchodilator FEV1/FVC < 0.7 with salbutamol Current smokers and ex-smokers Response to ipratropium bromide defined as an increase in FEV1 of > 7 % starting 30 minutes after inhalation of 80 micrograms ipratropium bromide Response to salbutamol defined an increase in FEV1 of > 7 % starting 15 minutes to 30 min following inhalation of 400 micrograms salbutamol MDI Exclusion Criteria: Part1 Any clinically relevant abnormabilites and/or uncontrolled diseases Abnormal laboratory values Recent respiratory tract infection Hypersensitivity to the drug excipients Positive serology results Positive cotinine, alcohol, drug of abuse tests Part 2 Pregnant and/or breast-feeding women Subjects with a medical history or current diagnosis of COPD or any other pulmonary disease other than asthma Subjects who have cardiovascular condition Clinically significant laboratory abnormalities Subject with serum potassium level below the lower limit of the laboratory reference range History of alcohol, substance or drug abuse Hypersensitivity to the drug excipients Part 3 Female patients Current diagnosis of asthma or allergic rhinitis or other atopic disease Recent COPD exacerbations or a lower respiratory tract infection Hypersensitivity to drug excipients; Abuse of substance or drug t or with a positive urine drug screen Unstable concurrent disease Subjects who have cardiovascular condition Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease Patients with serum potassium levels below the lower limit of the laboratory normal range

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1 alternating cross-over design Part 2 parallel group design Part 3 3-way cross-over design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CHF6366 active<br> | Drug: CHF6366<br>* Drug: CHF6366 (Part 1 - SAD) Single doses of CHF6366 at each period (for up to 3 periods per subject) Drug: CHF6366 (Part 2 - MAD) Once daily doses of CHF6366 for 7 days Drug: CHF6366 (Part 3) Single dose of CHF6366<br>|
| Placebo Comparator: CHF6366<br> | Drug: Placebo CHF6366<br>* Drug: Placebo (Part 1 - SAD) Single doses of placebo matching CHF6366 at each period (for up to 3 periods per subjects) Drug: Placebo (Part 2 - MAD) Once daily dose of placebo matching CHF6366 for 7 days Drug: Placebo (Part 3) Single dose of placebo matching CHF6366<br>|
| Active Comparator: Comparator<br> | Drug: umeclidinium bromide and vilanterol trifenatate<br>* Part 3 Single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events |  | Part 1 from Day 1 until day 3, Part 2 from Day 1 until day 8, Part 3 from Day 1 until Day 3 (per each period) | 
| Vital signs | Systolic, diastolic Blood Pressure | Part 1 from Day 1 until Day 3, Part 2 from Day 1 until day 8, Part 3 from Day 1 until Day 3 (per each period) | 
| Change in Holter ECG parameters | HR, PR, QRS, QTcF, QT | Part 1 from Day 1 until Day 3, Part 2 from Day 1 until day 8, Part 3 from Day 1 until Day 3 (per each period) | 
| Change in Holter parameters |  | Part 1 from Day 1 until Day 3, Part 2 from Day 1, until Day 8, Part 3 from Day 1 until Day 3(per each period) | 
| Change in FEV1 | Forced expiratory capacity in the first second | Part 1 drom Day 1 until Day 3, Part 2 from Day 1 until Day 8 | 
| Change in Laboratiry parameters | clinical chemistry, haematology and urinanalysis | Part 1 Day -1 and Day 3, Part 2 Day -2 and Day 8, Part 3 Day -1 and Day 2 | 
| Change in serum potassium level |  | Part 1 Day 1, Part 2 Day 1 and Day 7, Part 3 Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration vs time curve |  | Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period) | 
| Peak plasma concentration (Cmax) | maximum plasma concentration of CHF6366 | Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period) | 
| Time to reach the maximum plasma concentration (tmax) |  | Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period) | 
| Elimination half-life (t1/2) |  | Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period) | 
| Clearance (CL/F) |  | Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period) | 
| Volume of distribution (Vz/F) |  | Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period) | 
| Area under the plasma concentration vs time curve during selected dosing interval |  | Part 2 Day 7 | 
| Peak plasma concentration during selected dosing (Cmaxss) |  | Part 2 Day 7 | 
| Value of minimum plasma concentration post dosing at selected dosing interval (Cminss) |  | Part 2 Day 7 | 
| Time of minimum plasma concentration post dosing at selected dosing interval (Tminss) |  | Part 2 Day 7 | 
| Time to reach the maximum plasma concentration at selected dosing interval(tmaxss) |  | Part 2 Day 7 | 
| Clearance at selected dosing interval (CL/Fss) |  | Part 2 Day 7 | 
| Volume of distribution at selected dosing interval (Vz/Fss) |  | Part 2 Day 7 | 
| Accumulation ratio (Rac) |  | Part 2 Day 7 | 
| Steady state concentration (Css) |  | Part 2 Day 7 | 
| Urinary excretion (Ae) |  | Part 1 from Day 1 until Day 3, Part 2 Day 1 and Day 7, Part 3 from Day 1 until Day 3 (per each period) | 
| fraction excreted (fe) |  | Part 1 from Day 1 until Day 3, Part 2 Day 1 and Day 7, Part 3 from Day 1 until Day 3 (per each period) | 
| Clearance (CLr) |  | Part 1 from Day 1 until Day 3, Part 2 Day 1 and Day 7, Part 3 from Day 1 until Day 3 (per each period) |