Clinical trial NCT03378648: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Asthma
Chronic Obstructive Pulmonary Disease
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
First posted: 2017-12-20
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part 1 alternating cross-over design

Part 2 parallel group design

Part 3 3-way cross-over design
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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

Primary outcomes:
measure: Adverse Events
timeFrame: 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)
measure: Vital signs
timeFrame: 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)
measure: Change in Holter ECG parameters
timeFrame: 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)
measure: Change in Holter parameters
timeFrame: 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)
measure: Change in FEV1
timeFrame: Part 1 drom Day 1 until Day 3, Part 2 from Day 1 until Day 8
measure: Change in Laboratiry parameters
timeFrame: Part 1 Day -1 and Day 3, Part 2 Day -2 and Day 8, Part 3 Day -1 and Day 2
measure: Change in serum potassium level
timeFrame: Part 1 Day 1, Part 2 Day 1 and Day 7, Part 3 Day 1
Secondary outcomes:
measure: Area under the plasma concentration vs time curve
timeFrame: Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period)
measure: Peak plasma concentration (Cmax)
timeFrame: Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period)
measure: Time to reach the maximum plasma concentration (tmax)
timeFrame: Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period)
measure: Elimination half-life (t1/2)
timeFrame: Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period)
measure: Clearance (CL/F)
timeFrame: Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period)
measure: Volume of distribution (Vz/F)
timeFrame: Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period)
measure: Area under the plasma concentration vs time curve during selected dosing interval
timeFrame: Part 2 Day 7
measure: Peak plasma concentration during selected dosing (Cmaxss)
timeFrame: Part 2 Day 7
measure: Value of minimum plasma concentration post dosing at selected dosing interval (Cminss)
timeFrame: Part 2 Day 7
measure: Time of minimum plasma concentration post dosing at selected dosing interval (Tminss)
timeFrame: Part 2 Day 7
measure: Time to reach the maximum plasma concentration at selected dosing interval(tmaxss)
timeFrame: Part 2 Day 7
measure: Clearance at selected dosing interval (CL/Fss)
timeFrame: Part 2 Day 7
measure: Volume of distribution at selected dosing interval (Vz/Fss)
timeFrame: Part 2 Day 7
measure: Accumulation ratio (Rac)
timeFrame: Part 2 Day 7
measure: Steady state concentration (Css)
timeFrame: Part 2 Day 7
measure: Urinary excretion (Ae)
timeFrame: 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)
measure: fraction excreted (fe)
timeFrame: 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)
measure: Clearance (CLr)
timeFrame: 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)
Other outcomes:
Locations:
city: Manchester
country: United Kingdom
facility: Medicines Evaluation Unit
Study officials:
affiliation: Medicines Evaluation Unit
name: Dave Singh, MD
role: PRINCIPAL_INVESTIGATOR
References: