Study to Assess CSL787 in Non-cystic Fibrosis Bronchiectasis (NCFB)

Study Overview
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Brief Summary
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This study is a prospective, multicenter, randomized, double-blind, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and exploratory efficacy of nebulized CSL787 after administrations of single (SAD) ascending doses in healthy subjects and multiple (MAD) ascending doses in subjects with NCFB.

Official Title
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A Phase 1, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Exploratory Efficacy of Nebulized CSL787 in Healthy Subjects and Subjects With Non-Cystic Fibrosis Bronchiectasis (NCFB)

Conditions
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Noncystic Fibrosis Bronchiectasis (NCFB)

Intervention / Treatment
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* Biological: CSL787
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged ≥ 18 years at the time of providing written informed consent For Part A (SAD) Only: Healthy and free of medical conditions that could in the opinion of the investigator affect's the subject's participation in the study or the interpretation of results. For Part B (MAD) Only: Diagnosis of NCFB made by a respiratory physician, confirmed per CT showing bronchial wall dilatation with or without bronchial wall thickening, with a FEV1 ≥ 40% of the predicted value regarding age, height, gender, ethnicity, and FEV1 ≥ 1 L (pre-bronchodilator values) at the Screening Visit. No antibiotic use within 1 month before the Screening Visit. Presence of one or more of the following bacteria (H. influenzae, P. aeruginosa, M. catarrhalis, S. pneumoniae, members of Enterobacterales family or S. aureus) in the sputum culture at the Screening Visit. Has been fully vaccinated against COVID-19 (as per country recommendations) at least 7 days prior to Day 1 Exclusion Criteria: Evidence of a clinically significant medical condition, disorder, or disease, including but not limited to any of the following: hepatic (hepatitis, cirrhosis); biliary; renal; cardiac; bronchopulmonary; vascular; hematologic; gastrointestinal; allergy; endocrine / metabolic (diabetes, thyroid disorders, adrenal disease); neurologic; psychiatric; immunodeficiency; cancer. History of chronic respiratory disease (eg, COPD or bronchiectasis) or current asthma with regular treatment including occasional use of an inhaler for exercise induced asthma. Current moderate-severe allergic disease (eg, allergic rhinitis) with regular treatment. Diagnosis of cystic fibrosis, mycobacterial disease, connective tissue disease, or alpha-1 antitrypsin deficiency as underlying disease for bronchiectasis. Oral/parenteral corticosteroid 28 days before the Screening Visit until EOS Visit. Use of long acting bronchodilators (long acting muscarinic antagonists (LAMA) and / or long acting beta2 agonists (LABA) and/or inhaled corticosteroids that have been at a stable dose for at least 3 months before the Screening Visit is permitted; inhalation with hypertonic saline solution is permitted up to and including Day -1. Any systemic or inhaled antibiotic for acute pulmonary exacerbation within 1 month before the Screening Visit until EOS Visit.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSL787 (SAD dose 1)<br>Inhalation by mouth of a nebulized aerosol in healthy subjects | Biological: CSL787<br>* Human plasma-derived polyvalent immunoglobulin G (IgG) administered via inhalation of an aerosol produced using a nebulizer<br>|
| Experimental: CSL787 (SAD dose 2)<br>Inhalation by mouth of a nebulized aerosol in healthy subjects | Biological: CSL787<br>* Human plasma-derived polyvalent immunoglobulin G (IgG) administered via inhalation of an aerosol produced using a nebulizer<br>|
| Experimental: CSL787 (SAD dose 3)<br>Inhalation by mouth of a nebulized aerosol in healthy subjects | Biological: CSL787<br>* Human plasma-derived polyvalent immunoglobulin G (IgG) administered via inhalation of an aerosol produced using a nebulizer<br>|
| Experimental: CSL787 (SAD dose 4)<br>Inhalation by mouth of a nebulized aerosol in healthy subjects | Biological: CSL787<br>* Human plasma-derived polyvalent immunoglobulin G (IgG) administered via inhalation of an aerosol produced using a nebulizer<br>|
| Experimental: CSL787 (MAD dose 1)<br>Inhalation by mouth of a nebulized aerosol in NCFB subjects | Biological: CSL787<br>* Human plasma-derived polyvalent immunoglobulin G (IgG) administered via inhalation of an aerosol produced using a nebulizer<br>|
| Experimental: CSL787 (MAD dose 2)<br>Inhalation by mouth of a nebulized aerosol in NCFB subjects | Biological: CSL787<br>* Human plasma-derived polyvalent immunoglobulin G (IgG) administered via inhalation of an aerosol produced using a nebulizer<br>|
| Experimental: CSL787 (MAD dose 3)<br>Inhalation by mouth of a nebulized aerosol in NCFB subjects | Biological: CSL787<br>* Human plasma-derived polyvalent immunoglobulin G (IgG) administered via inhalation of an aerosol produced using a nebulizer<br>|
| Placebo Comparator: Placebo<br>Inhalation by mouth of a nebulized aerosol | Drug: Placebo<br>* Normal saline (0.9% NaCl)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with treatment emergent adverse events (TEAEs) - overall, severity and causality |  | Up to 8 days (healthy volunteers); Up to 21 days (NCFB patients) | 
| Percent of subjects with TEAEs - overall, severity and causality |  | Up to 8 days (healthy volunteers); Up to 21 days (NCFB patients) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration (Cmax) of CSL787 in sputum and serum in healthy subjects |  | Up to 8 days from inhalation | 
| Time of maximum concentration (Tmax) of CSL787 in sputum and serum in healthy subjects |  | Up to 8 days from inhalation | 
| Area under the concentration-time curve from time 0 to 24 hours (AUC0-24h) of CSL787 in sputum and serum in healthy subjects |  | Up to 8 days from inhalation | 
| Area under the concentration-time curve from time 0 to last quantifiable time point (AUC0-last) of CSL787 in sputum and serum in healthy subjects |  | Up to 8 days from inhalation | 
| Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) of CSL787 in sputum and serum in healthy subjects |  | Up to 8 days from inhalation | 
| Apparent total clearance of the drug (CL/F) of CSL787 in sputum and serum in healthy subjects |  | Up to 8 days from inhalation | 
| Apparent volume of distribution during the elimination phase (V/F) of CSL787 in sputum and serum in healthy subjects |  | Up to 8 days from inhalation | 
| Terminal elimination half-life (T1/2) of CSL787 in sputum and serum in healthy subjects |  | Up to 8 days from inhalation | 
| Cmax of CSL787 in sputum and serum of NCFB subjects |  | On Day 1, after dosing | 
| Tmax of CSL787 in sputum and serum of NCFB subjects |  | On Day 1, after dosing | 
| Ctrough of CSL787 in sputum and serum of NCFB subjects |  | On Day 1, after dosing | 
| AUCtau of CSL787 in sputum and serum of NCFB subjects |  | On Day 1, after dosing | 
| Cmax of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose | 
| Tmax of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose | 
| Ctrough of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose | 
| AUCtau of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose | 
| T1/2 of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose | 
| CL/F of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose | 
| V/F of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose | 
| Accumulation Ratio (AR) for Cmax of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose | 
| AR for Ctrough of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose | 
| AR for AUCtau of CSL787 in sputum and serum of NCFB subjects |  | On Day 14, after last dose |