A Study to Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Repeat Doses of CHF6297 in Healthy Subjects and Patients With COPD

Study Overview
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Brief Summary
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CHF6297 is a potent and selective inhibitor of human MAP kinase p38 being developed as an anti-inflammatory agent for the treatment of inflammatory airways diseases. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat doses of CHF6297 as dry powder formulation in healthy subjects and in COPD patients. This study is the first administration in humans. The study will comprise four parts: Part 1 will consist of two cohorts of healthy male subjects to assess the safety, tolerability and pharmacokinetics of Single Ascending Dose (SAD) of CHF6297. Part 2 will consist of four cohorts of healthy male subjects to assess the safety, tolerability and pharmacokinetics of Multiple Ascending Dose (MAD) of CHF6297. Part 3 will consist of one cohort of COPD patients to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a repeat dose of CHF6297 Part 4 will consist of one cohort of healthy subjects to assess the anti-inflammatory effect of a repeat dose of CHF6297 after LPS challenge.

Official Title
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A Randomised, Double-blind, Placebo-controlled Study to Investigate the Safety, Tolerability and Pharmacokinetics of CHF 6297 After Single and Repeated Ascending Doses in Healthy Male Subjects Followed by a Repeated Dose in COPD Patients and a 2-way, Crossover, Double-blind, Placebo-controlled, Repeated Dose Part to Investigate the Anti-inflammatory Effect of CHF 6297 After Lipopolysaccaride (LPS) Challenge in Healthy Male Subjects

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: CHF6297 (Part 1 - SAD)
* Drug: Placebo (Part 1 - SAD)
* Drug: CHF6297 (Part 2 - MAD)
* Drug: Placebo (Part 2 - MAD)
* Drug: CHF6297 (Part 3)
* Drug: Placebo (Part 3)
* Drug: CHF6297 (Part 4)
* Drug: Placebo (Part 4)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Part 1, Part 2, Part 4 (Healthy subjects): Male subjects aged 18-55 years; Non smokers Lung function above 80% of predicted normal value Healthy subjects based on medical evaluation including medical history, physical examination, laboratory tests and cardiac testing ability to produce an adequate induced sputum sample (study part 4 only) Part 3 (COPD patients): Males and females aged 40-75 years Current or past smokers stable patients with a post-bronchodilator FEV1 between 40 and 80% of predicted normal value and FEV1/FVC ratio <0.7 Ability to produce a spontaneous and an adequate induced sputum sample Exclusion Criteria: Parts 1,2, 4 (Healthy subjects): Any clinically relevant abnormalities and/or uncontrolled diseases Abnormal laboratory values Recent respiratory tract infection Hypersensitivity to the drug or excipients Positive serology results Positive cotinine, alcohol, drug of abuse tests Part 3 (COPD patients): Females of childbearing potential History of asthma Unstable concomitant diseases Abnormal relevant Holter ECG parameters Recent acute exacerbations of COPD or respiratory tract infection Hypersensitivity to the drug or excipients Positive serology results

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CHF6297 Active<br> | Drug: CHF6297 (Part 1 - SAD)<br>* Single doses of CHF6297 at each period (for up to 3 periods per subject)<br>Drug: CHF6297 (Part 2 - MAD)<br>* Twice daily doses of CHF6297 for 7 days<br>Drug: CHF6297 (Part 3)<br>* Twice daily doses of CHF6297 for 14 days<br>Drug: CHF6297 (Part 4)<br>* Twice daily doses of CHF6297 for 7 days<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo (Part 1 - SAD)<br>* Single doses of placebo matching CHF6297 at each period (for up to 3 periods per subject)<br>Drug: Placebo (Part 2 - MAD)<br>* Twice daily doses of placebo matching CHF6297 for 7 days<br>Drug: Placebo (Part 3)<br>* Twice daily doses of placebo matching CHF6297 for 14 days<br>Drug: Placebo (Part 4)<br>* Twice daily doses of placebo matching CHF6297 for 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Treatment-related Adverse events | Part 1 from Day 1 until Day 4, Part 2 from Day 1 until Day 8, Part 3 from Day 1 until Day 17, Part 4 from Day 1 until Day 8 | 
| Change in Vital signs | Blood pressure | Part 1 from Day 1 until Day 4, Part 2 from Day 1 until Day 8, Part 3 from Day 1 until Day 17 | 
| Change in Holter ECG parameters | HR, QTcF, PR, QRS + holter recording abnormalities | Part 1 Day 1-2, Part 2 Day 1-2 and Day 7-8, Part 3 Day 1-2 and Day 14-15 | 
| Change in FEV1 | Forced exhalation volume in the first second | Part 1 Day 1-2, Part 2 Day 1 and Day 7-8, Part 3 Day 1, Day 10 and Day 14 | 
| Change in Laboratory parameters | Clinical chemistry and haematology + urinalysis | Part 1 Day 1 and Day 4, Part 2 Day 1 and Day 8, Part 3 Day 1 and Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration vs time curve |  | Part 1 Day 1 until Day 4, Part 2 Day 1 and Day 7, Part 3 Day 1 and Day 14 | 
| Peak plasma concentration (Cmax) | maximum plasma concentration of CHF6297 | Part 1 Day 1 until Day 4, Part 2 Day 1 and Day 7, Part 3 Day 1 and Day 14 | 
| Time to reach the maximum plasma concentration (tmax) |  | Part 1 Day 1 until Day 4, Part 2 Day 1 and Day 7, Part 3 Day 1 and Day 14 | 
| Elimination half-life (t1/2) |  | Part 1 Day 1 until Day 4, Part 2 Day 1 and Day 7, Part 3 Day 1 and Day 14 | 
| Clearance (CL/F) | Absolute plasma clearance | Part 1 Day 1 until Day 4, Part 2 Day 1 and Day 7, Part 3 Day 1 and Day 14 | 
| Volume of distribution (Vz/F) | plasma volume of distribution | Part 1 Day 1 until Day 4, Part 2 Day 1 and Day 7, Part 3 Day 1 and Day 14 | 
| Urinary excretion (Ae) | Amount of CHF6297 excreted in urine | Part 1 from Day 1 to Day 4, Part 2 Day 1 and Day 7 | 
| fraction excreted (fe) | Percentage of drug excreted in urine | Part 1 from Day 1 to Day 4, Part 2 Day 1 and Day 7 | 
| Renal clearance (CLr) |  | Part 1 from Day 1 to Day 4, Part 2 Day 1 and Day 7 |