A Clinical Study to Test the Safety, Exposure, and Pharmacodynamic Markers of CSL311 in Patients With Mild-to-moderate Asthma and in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
This is a phase 1, first-in-human (FIH), multi-center, randomized, double-blind, placebo-controlled study of CSL311 in patients with mild-to-moderate asthma. The primary objective of this study is to assess the safety and tolerability of single ascending doses (SAD) and multiple ascending doses (MAD) of CSL311.

Official Title
-----------------
A Clinical Study to Test the Safety, Exposure, and Pharmacodynamic Markers of CSL311 in Subjects With Mild-to-moderate Asthma and in Healthy Volunteers

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Biological: Human beta common receptor antagonist monoclonal antibody
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects 18 to 65 years of age with diagnosis of mild-to-moderate asthma for Parts A and B. For part C healthy, male or female subjects 18 to 50 years Exclusion Criteria: Oral/parenteral corticosteroids or anti-interleukin-6 therapy within 6 months prior to screening, or any prohibited therapies prior to screening. History or presence of clinically significant hypertension or other significant cardiovascular abnormality. Any clinically significant abnormality on electrocardiogram at screening. Parasitic infestation within 6 months before screening, or travel or intention to travel to a country with a high prevalence of such infections within 1 year before screening or within 85 days after the last dose of CSL311. Occurrence of asthma exacerbation and/or upper/lower respiratory tract infection, or any acute infection or disease within the last 6 weeks before screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSL311 Cohort A1 (SAD Dose 1)<br>Human beta common receptor antagonist monoclonal antibody administered intravenously at a Single Ascending Dose (SAD) | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort A2 (SAD Dose 2)<br>Human beta common receptor antagonist monoclonal antibody administered intravenously at a SAD | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort A3 (SAD Dose 3)<br>Human beta common receptor antagonist monoclonal antibody administered intravenously at a SAD | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort A4 (SAD Dose 4)<br>Human beta common receptor antagonist monoclonal antibody administered intravenously at a SAD | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort A5 (SAD Dose 5)<br>Human beta common receptor antagonist monoclonal antibody administered intravenously at a SAD | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort A6 (SAD Dose 6)<br>Human beta common receptor antagonist monoclonal antibody administered intravenously at a SAD | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort A7 (SAD Dose 7)<br>Human beta common receptor antagonist monoclonal antibody administered intravenously at a SAD | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort A8 (SAD Dose 8)<br>Human beta common receptor antagonist monoclonal antibody administered intravenously at a SAD | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort B1 (MAD Dose 1)<br>Human beta common receptor antagonist monoclonal antibody administered intravenously at a MAD | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Placebo Comparator: Placebo<br>0.9% sodium chloride solution administered intravenously | Drug: Placebo<br>* 0.9% sodium chloride, same volume and same duration as CSL311<br>|
| Placebo Comparator: Placebo (2)<br>0.9% sodium chloride solution administered subcutaneously | Drug: Placebo<br>* 0.9% sodium chloride, same volume and same duration as CSL311<br>|
| Experimental: CSL311 Cohort C1 (MAD Dose 1)<br>Human beta common receptor antagonist monoclonal antibody administered subcutaneously (SC) | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort C2 (MAD Dose 2)<br>Human beta common receptor antagonist monoclonal antibody administered subcutaneously | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|
| Experimental: CSL311 Cohort C3 (MAD Dose 3)<br>Human beta common receptor antagonist monoclonal antibody administered subcutaneously | Biological: Human beta common receptor antagonist monoclonal antibody<br>* Human beta common receptor antagonist monoclonal antibody<br>* Other names: CSL311;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects with treatment-emergent adverse events (TEAEs) in SC single dose, single ascending doses (SAD) and multiple ascending doses (MAD - SC and IV) |  | After infusion or injection, up to Day 85 for Cohorts A1 to A7, Day 57 for Cohort A8, Day 114 for Cohort B1 and Day 85 for Cohorts C1 to C3 | 
| Percentage of subjects with related TEAEs in SC single dose, SAD and MAD (SC and IV) |  | After infusion or injection, up to Day 85 for Cohorts A1 to A7, Day 57 for Cohort A8, Day 114 for Cohort B1 and Day 85 for Cohorts C1 to C3 | 
| Percentage of subjects with TEAEs by severity in SC single dose, SAD and MAD (SC and IV) | Severity of TEAEs defined as mild, moderate, or severe | After infusion or injection, up to Day 85 for Cohorts A1 to A7, Day 57 for Cohort A8, Day 114 for Cohort B1 and Day 85 for Cohorts C1 to C3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of CSL311 in SAD |  | Up to 85 days after infusion | 
| Time to reach Cmax (tmax) of CSL311 in SAD |  | Up to 85 days after infusion | 
| Area under the concentration-time curve from time 0 to the last measurable concentration (AUC0-last) of CSL311 in SAD |  | Up to 85 days after infusion | 
| Area under the concentration-time curve from time 0 extrapolated to infinite time (AUC0-inf) of CSL311 in SAD |  | Up to 85 days after infusion | 
| Half-life (t½) of CSL311 in SAD |  | Up to 85 days after infusion | 
| Clearance (CL) of CSL311 in SAD |  | Up to 85 days after infusion | 
| Volume of distribution (Vd) of CSL311 in SAD |  | Up to 85 days after infusion | 
| Area under the concentration-time curve from time 0 to the last measurable concentration per dose of CSL311 (AUC0-last/dose) in SAD |  | Up to 85 days after infusion | 
| Cmax/dose of CSL311 in SAD |  | Up to 85 days after infusion | 
| AUCtau for CSL311 in MAD (SC and IV) after first dose |  | Up to 15 days after infusion or injection | 
| AUCtau/dose for CSL311 in MAD (SC and IV) after first dose |  | Up to 15 days after infusion or injection | 
| Cmax of CSL311 in MAD (SC and IV) after first dose |  | Up to 15 days after infusion or injection | 
| Cmax/dose of CSL311 in MAD (SC and IV) after first dose | Dose-normalized maximum plasma concentration | Up to 15 days after infusion or injection | 
| tmax of CSL311 in MAD (SC and IV) after first dose |  | Up to 15 days after infusion or injection | 
| Cmax of CSL311 in MAD (SC and IV) after last dose |  | Up to 85 days (SC) and 114 days (IV) after infusion or injection | 
| AUCtau for CSL311 in MAD (SC and IV) after last dose |  | Up to 85 days (SC) and 114 days (IV) after infusion or injection | 
| Cmax/dose of CSL311 in MAD (SC and IV) after last dose |  | Up to 85 days (SC) and 114 days (IV) after infusion or injection | 
| tmax of CSL311 in MAD (SC and IV) after last dose |  | Up to 85 days (SC) and 114 days (IV) after infusion or injection | 
| AUCtau/dose for CSL311 in MAD (SC and IV) after last dose | Dose-normalized area under the concentration-time curve over a dosing interval | Up to 85 days (SC) and 114 days (IV) after infusion or injection | 
| Half-life (t½) of CSL311 in MAD (SC and IV) after last dose |  | Up to 85 days (SC) and 114 days (IV) after infusion or injection | 
| Clearance (CL) of CSL311 in MAD (IV) after last dose |  | Up to 114 days after infusion | 
| Apparent Clearance (CL/F) of CSL311 in MAD (SC) after last dose |  | Up to 85 days after injection | 
| Volume of distribution (Vd) of CSL311 in MAD (IV) after last dose |  | Up to 114 days after infusion | 
| Apparent volume of distribution during terminal phase (Vz/F) of CSL311 in MAD (SC) after last dose |  | Up to 85 days after injection | 
| Number of subjects with detectable anti-CSL311 antibodies in SAD and MAD (SC and IV) |  | After infusion or injection, up to 85 days for SAD, and up to 85 days for MAD (SC) and 114 days for MAD (IV) | 
| Percentage of subjects with TEAEs of Infections and Infestations in SAD and MAD (SC and IV) by treatment (CSL311 or placebo), by causality, and by CSL311 dose level |  | After infusion or injection, up to 85 days for SAD, and up to 85 days for MAD (SC) and 114 days for MAD (IV) | 
| Percentage of subjects with severe or life-threatening Neutropenia in SAD and MAD (SC and IV) by treatment (CSL311 or placebo), by causality, and by CSL311 dose level |  | After infusion or injection, up to 85 days for SAD, and up to 85 days for MAD (SC) and 114 days for MAD (IV) | 
| Percentage of subjects with TEAEs of Worsening Asthma in SAD and MAD (SC and IV) by treatment (CSL311 or placebo), by causality, and by CSL311 dose level |  | After infusion or injection, up to 85 days for SAD, and up to 85 days for MAD (SC) and 114 days for MAD (IV) |