First-In-Human Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Escalating Single And Multiple Doses Of CSL040 In Healthy Subjects

Study Overview
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Brief Summary
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First-In-Human Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Escalating Single And Multiple Doses Of CSL040 In Healthy Subjects

Official Title
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A Phase 1, Double-Blind (Sponsor-Unblinded), Placebo-Controlled, Dose Escalation Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Single And Multiple Doses Of CSL040 In Healthy Adult Subjects

Conditions
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Complement Deficiencies

Intervention / Treatment
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* Drug: CSL040
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female 18 to 64 years of age, inclusive, at Screening Body weight in the range of ≥ 50 kg and ≤ 100 kg, with a body mass index of ≥ 18 kg/m2 and ≤ 30 kg/m2, at Screening Judged as healthy by an Investigator after completion of a comprehensive clinical assessment Capable of providing written informed consent and willing and able to adhere to all protocol requirements Can understand the nature, scope, and possible consequences of the study and able to comply with study procedures, restrictions, and requirements Able to provide proof of vaccination against meningococcal disease according to local requirements or willing to receive meningococcal vaccination aligned with local guidelines (vaccination with recombinant meningococcal B vaccine against B serogroup [Men B] and quadrivalent meningococcal conjugate vaccine against A, C, W, and Y serogroups [Men ACWY]), at least 14 days before the first dose of CSL040 Exclusion Criteria: Any individual at high risk of exposure to Neisseria meningitidis, including, but not limited to, health care workers, doctors, nurses, students working a clinical setting, laboratory workers with exposure to N. meningitidis, individuals residing in a dormitory setting (eg, military workers), and childcare workers Other than the required meningococcal vaccines, any live vaccinations within the last 90 days before and during the study and / or up to 90 days after the last administration of the investigational product A positive test result for QuantiFERON Gold, hepatitis B surface antigen (HBsAg), hepatitis C antibody, or human immunodeficiency virus-1/2 antibody. History concerning for a N. meningitidis infection History of allergy or intolerance to Penicillin V History of unexplained, recurrent infection, life-threatening infection, or history that suggests any immunodeficiency (functional immunodeficiency), including asplenia / functional asplenia Infection requiring treatment with systemic antibiotics (IV and / or oral administration for more than 3 days) within the last 90 days prior to dosing Clinical evidence of current active serious infection, including any localized infections, or any infection which makes the participation in this study of healthy subjects unacceptably high risk Blood pressure or pulse rate measurements outside the normal range for the subject's age Known history of severe hypersensitivity reactions or suspected hypersensitivity to the CSL040 or any of the excipients or other monoclonal antibodies Subject has any condition that may compromise their safety or compliance, impede successful conduct of the study, interfere with interpretation of the results or would otherwise render the subject unsuitable for participation in the study A positive test result for drugs of abuse (including alcohol) at Screening and / or Day -1. Weekly alcohol intake of > 10 units for females and > 14 units for males during the 3 months before Day -1. Any values above the upper limit of normal (ULN) for alanine aminotransaminase (ALT) or aspartate aminotransaminase (AST), or bilirubin test result Use of prescription or over-the-counter medication, anticoagulant therapy, or drugs with antiplatelet action (including aspirin and nonsteroidal anti-inflammatory drugs [NSAIDS]), within 14 days before administration of investigational product Female subject of childbearing potential or fertile male subject who are neither using nor willing to use a highly effective method of contraception Pregnant, lactating, or breastfeeding Donation or loss of more than 500 mL of blood within 3 months, or donated plasma within 7 days, before admission to the unit Any planned surgical procedures during the study period Participation in any other investigational product study in which receipt of an investigational product occurred within 5 half-lives or 28 days (whichever is longer) before dosing of study drug, or participation in more than 4 clinical studies involving administration of an investigational product within the last 12 months before Screening Subject who met all eligibility criteria but was not needed (ie, alternate subjects). Alternate subjects are eligible to participate in subsequent cohorts.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A (SAD): CSL040 (minimum dose)<br>Intravenous (IV) administration | Drug: CSL040<br>* IV Administration<br>|
| Experimental: Part A (SAD): CSL040 (lower dose)<br>IV Administration | Drug: CSL040<br>* IV Administration<br>|
| Experimental: Part A (SAD): CSL040 (low dose)<br>IV Administration | Drug: CSL040<br>* IV Administration<br>|
| Experimental: Part A (SAD): CSL040 (medium dose)<br>IV Administration | Drug: CSL040<br>* IV Administration<br>|
| Experimental: Part A (SAD): CSL040 (medium-high dose)<br>IV Administration | Drug: CSL040<br>* IV Administration<br>|
| Experimental: Part A (SAD): CSL040 (maximum dose)<br>IV Administration | Drug: CSL040<br>* IV Administration<br>|
| Placebo Comparator: Part A (SAD): Placebo<br>IV Administration | Drug: Placebo<br>* 0.9% w/v NaCI<br>|
| Experimental: Part B (MAD): CSL040 (minimum dose)<br>IV Administration not to exceed 5 doses over 14 days) | Drug: CSL040<br>* IV Administration<br>|
| Experimental: Part B (MAD): CSL040 (medium dose)<br>IV Administration not to exceed 5 doses over 14 days | Drug: CSL040<br>* IV Administration<br>|
| Experimental: Part B (MAD): CSL040 (high dose)<br>IV Administration not to exceed 5 doses over 14 days | Drug: CSL040<br>* IV Administration<br>|
| Experimental: Part B (MAD): Placebo<br>IV Administration not go exceed 5 doses over 14 days | Drug: Placebo<br>* 0.9% w/v NaCI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency counts for subjects with treatment emergent TEAEs leading to withdrawal or discontinuation of investigational product |  | Up to 12 weeks | 
| Percentages for subjects with treatment emergent TEAEs leading to withdrawal or discontinuation of investigational product |  | Up to 12 weeks | 
| Change from Baseline in tympanic temperature |  | Up to 12 weeks | 
| Change from Baseline in pulse rate |  | Up to 12 weeks | 
| Change from Baseline in blood pressure |  | Up to 12 weeks | 
| Change from Baseline in leukocytes (white blood cell count) |  | Up to 12 weeks | 
| Change from Baseline of hemoglobin values |  | Up to 12 weeks | 
| Change from Baseline of C-reactive protein (CRP) |  | Up to 12 weeks | 
| Change from Baseline in Creatinine levels |  | Up to 12 weeks | 
| Change from Baseline above the upper limit of normal (ULN) for alanine aminotransaminase (ALT) |  | Up to 12 weeks | 
| Change from Baseline above the upper limit of normal (ULN) for aspartate aminotransaminase (AST) |  | Up to 12 weeks | 
| Change from Baseline in corrected QT interval using Fridericia's formula (QTcF) values of triplicate electrocardiograms |  | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A (Single Ascending Dose [SAD]): Time to Maximum concentration (Cmax) |  | Up to 56 Days | 
| Part A (SAD): Time to reach maximum concentration (Tmax) |  | Up to 56 Days | 
| Part A (SAD): Time to Area under the concentration-time curve from time 0 to the last measurable concentration (AUC0-last) |  | Up to 56 Days | 
| Part A (SAD): Area under the concentration-time curve from time 0 to infinity (AUC0-infinity) |  | Up to 56 Days | 
| Part A (SAD): Total systemic clearance (CL) |  | Up to 56 Days | 
| Part A (SAD): Volume of distribution (V) |  | Up to 56 Days | 
| Part A (SAD): Terminal elimination half-life (T1/2) |  | Up to 56 Days | 
| Part B (Multiple Ascending Dose [MAD]): Maximum concentration (Cmax) |  | Up to 56 Days | 
| Part B (MAD): Time to reach maximum concentration (Tmax) |  | Up to 56 Days | 
| Part B (MAD): Time to Area under the concentration-time curve in 1 dosing interval (AUCtau) |  | Up to 56 Days | 
| Part B (MAD): Accumulation index (accumulation ratio determined by the ratio of steady state AUCtau to single dose AUCtau |  | Up to 56 Days | 
| Part B (MAD): Lowest concentration prior to dosing (Ctrough) |  | Up to 56 Days | 
| Part B (MAD): Total systemic clearance (CL) |  | Up to 56 Days | 
| Part B (MAD): Volume of distribution at steady state (Vss) |  | Up to 56 Days | 
| Part A (SAD) and Part B (MAD): Maximum percent change from Baseline (Emax | Using Percent change from Baseline versus time course profiles of complement activation components | Up to 56 Days | 
| Part A (SAD) and Part B (MAD): Time to maximum percent change from Baseline (TEmax) | Using Percent change from Baseline versus time course profiles of complement activation components | Up to 56 Days | 
| Part A (SAD) and Part B (MAD): Time to return to baseline | Using Percent change from Baseline versus time course profiles of complement activation components | Up to 56 Days | 
| Part A (SAD) and Part B (MAD): Presence of antidrug antibodies after administration of CSL040 |  | Up to 56 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complement