A Study of CSL112 in Healthy Adults and in Adults With Moderate Renal Impairment

Study Overview
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Brief Summary
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This is a phase 1 multicenter, randomized, double-blind, placebo-controlled, ascending dose study to investigate the pharmacokinetics (PK), safety, and tolerability of CSL112 in adult subjects with moderate renal impairment and in healthy adult subjects with normal renal function.

Official Title
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A Double-blind, Randomized, Placebo-controlled, Pharmacokinetic, Safety and Tolerability Study of CSL112 in Adult Subjects With Moderate Renal Impairment and in Healthy Adult Subjects With Normal Renal Function

Conditions
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Acute Myocardial Infarction

Intervention / Treatment
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* Biological: CSL112
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women aged 18 to 85 years (inclusive) of age, with body weight 50 kg or more. Subjects with renal impairment (RI) must have stable chronic moderate RI (estimated glomerular filtration rate [eGFR] ≥ 30 and < 60 mL/min/1.73 m2) Healthy subjects must have normal renal function (eGFR ≥ 90 mL/min/1.73 m2) Exclusion Criteria: Evidence of a clinically significant medical condition, disorder or disease Evidence of hepatobiliary disease Any clinically relevant abnormal laboratory test result Known history of allergies, hypersensitivity or deficiencies to CSL112 or any of its components Other severe comorbid condition, concurrent medication, or other issue that renders the subject unsuitable for participation in the study, including: history of cancer, low platelet count, bleeding disorder or coagulopathy, significantly altered electrocardiogram waveform, unstable glycemia control in subjects with diabetes, acute renal failure, recent donation or loss of blood Evidence or history of alcohol or substance abuse

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low<br>A low dose of either CSL112 or placebo is to be administered as a single intravenous (IV) infusion. The placebo will be administered at the same frequency, volume and duration as the CSL112 infusion. | Biological: CSL112<br>* CSL112 is a novel formulation of apolipoprotein A-I (apoA-I) purified from human plasma and reconstituted to form high-density lipoprotein (HDL) particles.<br>Other: Placebo<br>* 0.9% weight/volume sodium chloride solution (ie, normal saline)<br>|
| Experimental: High<br>A high dose of either CSL112 or placebo is to be administered as a single intravenous (IV) infusion. The placebo will be administered at the same frequency, volume and duration as the CSL112 infusion. | Biological: CSL112<br>* CSL112 is a novel formulation of apolipoprotein A-I (apoA-I) purified from human plasma and reconstituted to form high-density lipoprotein (HDL) particles.<br>Other: Placebo<br>* 0.9% weight/volume sodium chloride solution (ie, normal saline)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma apolipoprotein A-I (apoA-I) and phosphatidylcholine (PC) area under the curve (AUC) | Baseline corrected plasma apoA-I and PC AUC0-infinity | Before and at up to 10 time points (during up to 7 days) after infusion | 
| Plasma apoA-I and PC AUC0-last and AUC 0-t | AUC from time point zero to the last quantifiable time point before the analyte first returns to baseline (AUC0-last) and/or a partial AUC from baseline to time point t (AUC0-t) with and without baseline correction | Before and at up to 10 time points (during up to 7 days) after infusion | 
| Plasma apoA-I and PC Cmax |  | Before and at up to 10 time points (during up to 7 days) after infusion | 
| Plasma apoA-I and PC Tmax |  | Before and at up to 10 time points (during up to 7 days) after infusion | 
| Plasma apoA-I and PC Volume of distribution during terminal phase |  | Before and at up to 10 time points (during up to 7 days) after infusion | 
| Plasma apoA-I and PC clearance |  | Before and at up to 10 time points (during up to 7 days) after infusion | 
| Plasma apoA-I and PC t1/2 |  | Before and at up to 10 time points (during up to 7 days) after infusion | 
| Urinary excretion of apoA-I (Ae0-t) | Amount excreted (Ae) of apoA-I over a collection interval 0-t. | Before and up to 48 hours after infusion | 
| Urinary excretion of apoA-I (%fe0-t) | Percent fraction excreted (%fe) of apoA-I in urine over time interval 0-t, calculated as Ae0-t/Dose x 100. | Before and up to 48 hours after infusion | 
| Renal clearance of apoA-I | Renal clearance of apoA-I, calculated as Ae0-48/AUC0-48 | Before and up to 48 hours after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary excretion of sucrose(Ae0-t) | Amount of sucrose excreted over a collection interval 0-t. | Before and up to 48 hours after infusion | 
| Urinary excretion of sucrose (%fe0-t) | Percent fraction excreted sucrose in urine over time interval 0-t, calculated as Ae0-t/Dose x 100. | Before and up to 48 hours after infusion | 
| Urinary excretion of sucrose (clearance) | Renal clearance of sucrose, calculated as Ae0-48/AUC0-48 | Before and up to 48 hours after infusion | 
| Adverse drug reaction (ADR) or suspected ADR frequency (%) | The overall percentage of participants with adverse reactions or suspected adverse reactions: That begin during or within 1 hour of an infusion; or That may be causally related to the administration of the investigational product; or For which the Investigator's causality assessment is missing or indeterminate; or For which the incidence in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more. | Up to approximately 127 days | 
| Clinically significant changes in routine safety assessments | The number of participants with clinically significant changes in any of the following assessments: clinical laboratory tests, physical examinations, body weight, electrocardiograms, vital signs, immunogenicity testing, serology, nucleic acid testing or proteinuria findings. | Up to approximately 97 days | 
| Clinically important change in drug-induced liver injury | A clinically important change in drug-induced liver injury is defined as a change (from baseline) in alanine aminotransferase (ALT) greater than 3 times the upper limit of normal (ULN) or a change in total bilirubin greater than 2 times ULN, that is confirmed upon repeat measurement. | From baseline (before infusion) up to Day 16. | 
| Clinically important change in renal status | A clinically important change in renal status is defined as a serum creatinine (Cr) increase to ≥ 1.5 x the baseline value that is confirmed upon repeat measurement, or the need for renal replacement therapy. | From baseline (before infusion) up to Day 16. | 
| Plasma sucrose AUC | Baseline corrected plasma sucrose AUC0-infinity | Before and at up to 7 time points (during up to 2 days) after infusion | 
| Plasma sucrose AUC0-last and AUC 0-t | AUC from time point zero to the last quantifiable time point before the analyte first returns to baseline (AUC0-last) and/or a partial AUC from baseline to time point y (AUC0-t) with and without baseline correction | Before and at up to 7 time points (during up to 2 days) after infusion | 
| Plasma sucrose Cmax |  | Before and at up to 7 time points (during up to 2 days) after infusion | 
| Plasma sucrose Tmax |  | Before and at up to 7 time points (during up to 2 days) after infusion | 
| Plasma sucrose Volume of distribution during terminal phase |  | Before and at up to 7 time points (during up to 2 days) after infusion | 
| Plasma sucrose Clearance |  | Before and at up to 7 time points (during up to 2 days) after infusion | 
| Plasma sucrose t1/2 |  | Before and at up to 7 time points (during up to 2 days) after infusion | 
| Adverse drug reaction (ADR) or suspected ADR frequency | The overall number of participants with adverse reactions or suspected adverse reactions: That begin during or within 1 hour of an infusion; or That may be causally related to the administration of the investigational product; or For which the Investigator's causality assessment is missing or indeterminate; or For which the incidence in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more. | Up to approximately 127 days | 
| Number of subjects with AEs |  | After the start of infusion up to approximately 127 days |