Asthma, Chronic Obstructive Pulmonary Disease
Conditions
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
Interventions
DRUGCHF6366
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
DRUGPlacebo 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
DRUGumeclidinium bromide and vilanterol trifenatate
Part 3 Single dose
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Part 1 double-blind Part 2 double-blind Part 3 placebo-controlled (double-blind), active-controlled (open labelled)
Intervention model description
Part 1 alternating cross-over design Part 2 parallel group design Part 3 3-way cross-over design
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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) | Systolic, diastolic Blood Pressure |
| Change in Holter ECG 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) | HR, PR, QRS, QTcF, QT |
| 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 | Part 1 drom Day 1 until Day 3, Part 2 from Day 1 until Day 8 | Forced expiratory capacity in the first second |
| Change in Laboratiry parameters | Part 1 Day -1 and Day 3, Part 2 Day -2 and Day 8, Part 3 Day -1 and Day 2 | clinical chemistry, haematology and urinanalysis |
| Change in serum potassium level | Part 1 Day 1, Part 2 Day 1 and Day 7, Part 3 Day 1 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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) | — |
| 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) | — |
| Volume of distribution at selected dosing interval (Vz/Fss) | Part 2 Day 7 | — |
| Peak plasma concentration (Cmax) | Part 1 Day 1 until Day 3, Part 2 Day 1 , Part 3 Day 1 until Day 3 (per each period) | maximum plasma concentration of CHF6366 |
| 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 | — |
Countries
United Kingdom
Outcome results
None listed