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

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

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

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease; Asthma
• Intervention / Treatment: Drug: CHF6366; Drug: Placebo CHF6366; Drug: umeclidinium bromide and vilanterol trifenatate

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Manchester, United Kingdom
    • Medicines Evaluation Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Comparator	Drug: umeclidinium bromide and vilanterol trifenatate; Part 3 Single dose
Experimental: CHF6366 active	Drug: CHF6366; 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
Placebo Comparator: CHF6366	Drug: Placebo CHF6366; 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.

Publications and helpful links

Helpful Links

• Study Record on EU Clinical Trials Register including results

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2017
• Primary Completion (Actual): April 16, 2019
• Study Completion (Actual): April 16, 2019

Study Registration Dates

• First Submitted: December 14, 2017
• First Submitted That Met QC Criteria: December 14, 2017
• First Posted (Actual): December 20, 2017

Study Record Updates

• Last Update Posted (Actual): May 7, 2020
• Last Update Submitted That Met QC Criteria: May 5, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Anticonvulsants; Bromides
• Other Study ID Numbers: CCD-06366AA1-01; 2015-005551-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No