A Study to Investigate Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of CHF6333 in Healthy Subjects

Study Overview
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Brief Summary
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Human Neutrophil Elastase (HNE) plays a pivotal role in innate immunity and in neutrophilic lung inflammation that characterized many diseases. CHF 6333 is a potent and 24h-durable inhibitor of HNE, developed as Dry Powder Inhaler (DPI) formulation. This study is designed to investigate the tolerability, safety and pharmacokinetics of inhaled CHF6333 DPI in healthy male subjects. The study will comprise two parts: Part 1 will consist of two alternated cohorts of healthy male subjects to assess the safety, tolerability and pharmacokinetics of Single Ascending Dose (SAD) of CHF6333. Part 2 will consist of four sequential cohorts of healthy male subjects to assess the safety, tolerability and pharmacokinetics of Multiple Ascending Dose (MAD) of CHF6333

Official Title
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A Phase I, Randomised, Double-blind, Placebo-controlled Study to Investigate the Safety, Tolerability and Pharmacokinetics of Inhaled CHF 6333 After Single and Repeated Ascending Doses in Healthy Male Subjects

Conditions
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Non-Cystic Fibrosis Bronchiectasis, Cystic Fibrosis

Intervention / Treatment
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* Drug: CHF6333 (Part 1 - SAD)
* Drug: Placebo (Part 1 - SAD)
* Drug: CHF6333 (Part 2 - MAD)
* Drug: Placebo (Part 2 - MAD)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects aged 18-55 years BMI between 18-30 kg/m2 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 Exclusion Criteria: 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 Unsuitable veins for repeated venepuncture

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

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
Interventional Model Description: Part 1: alternating cross-over design Part 2: parallel design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CHF6333 Active<br> | Drug: CHF6333 (Part 1 - SAD)<br>* Single doses of CHF6333 at each period<br>Drug: CHF6333 (Part 2 - MAD)<br>* once daily multiple doses of CHF6333 for 14 days<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo (Part 1 - SAD)<br>* Single doses of placebo matching CHF6333 at each period<br>Drug: Placebo (Part 2 - MAD)<br>* once daily multiple doses of placebo matching CHF6333 for 14 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 to 5, Part 2 from Day 1 to 15 | 
| Change in Vital signs | Blood pressure | Part 1 from Day 1 to 5, Part 2 from Day 1 to 15 | 
| Heart Rate | Change in Heart Rate (from ECG) | Part 1 Day 1-2, Part 2 Day 1-2 and Day 14-15 | 
| QTcF interval | Change in QTcF interval (from ECG) | Part 1 Day 1-2, Part 2 Day 1-2 and Day 14-15 | 
| PR interval | Change in PR interval (from ECG) | Part 1 Day 1-2, Part 2 Day 1-2 and Day 14-15 | 
| QRS interval | Change in QRS interval (from ECG) | Part 1 Day 1-2, Part 2 Day 1-2 and Day 14-15 | 
| Holter recording abnormalities | 24h-holter ECG recording | Part 1 Day 1-2, Part 2 Day 1-2 and Day 14-15 | 
| FEV1 | Change in FEV1 (Forced exhalation volume in the first second) | Part 1 Day 1-2, Part 2 Day 1-14-15 | 
| Clinical chemistry and haematology | change in Clinical chemistry and haematology parameters | Part 1 Day 1-5, Part 2 Day 1-15 | 
| Urinalysis | Change in urinalysis parameters | Part 1 Day 1-5, Part 2 Day 1-15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration |  | Part 1 from Day 1 to 5, Part 2 from Day 1-2 and Day 14-15 | 
| Peak plasma concentration (Cmax) | maximum plasma concentration of CHF6333 | Part 1 from Day 1 to 5, Part 2 from Day 1-2 and Day 14-15 | 
| Time to reach the maximum plasma concentration (tmax) |  | Part 1 from Day 1 to 5, Part 2 from Day 1-2 and Day 14-15 | 
| Elimination half-life (t1/2) |  | Part 1 from Day 1 to 5, Part 2 from Day 1-2 and Day 14-15 | 
| Clearance (CL/F) | Absolute plasma clearance | Part 1 from Day 1 to 5, Part 2 from Day 1-2 and Day 14-15 | 
| Volume of distribution (Vz/F) | plasma volume of distribution | Part 1 from Day 1 to 5, Part 2 from Day 1-2 and Day 14-15 | 
| Urinary excretion (Ae) | Amount of CHF6333 excreted in urine | Part 1 from Day 1 to 5, Part 2 from Day 1-2 and Day 14-15 | 
| fraction excreted (fe) | Percentage of drug excreted in urine | Part 1 from Day 1 to 5, Part 2 from Day 1-2 and Day 14-15 | 
| Renal clearance (CLr) |  | Part 1 from Day 1 to 5, Part 2 from Day 1-2 and Day 14-15 |