A Phase 2b Study of CSL112 in Subjects With Acute Myocardial Infarction.

Study Overview
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Brief Summary
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This is a multicenter randomized, double-blind, placebo-controlled, parallel-group, dose-ranging phase 2b study to investigate the hepatic and renal safety and tolerability of multiple dose administration of two dose levels of CSL112 compared with placebo in subjects with acute myocardial infarction (AMI).

Official Title
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A Phase 2b, Multi-center, Randomized, Placebo-controlled, Dose-ranging Study to Investigate the Safety and Tolerability of Multiple Dose Administration of CSL112 in Subjects With Acute Myocardial Infarction.

Conditions
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Acute Myocardial Infarction

Intervention / Treatment
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* Biological: CSL112
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women, at least 18 years of age, with evidence of myocardial necrosis in a clinical setting consistent with a type I (spontaneous) acute myocardial infarction (AMI), in the last week. Exclusion Criteria: Ongoing hemodynamic instability Evidence of hepatobiliary disease Evidence of chronic kidney disease (CKD) (Stage III, IV, or V), defined as moderate or severe renal impairment or if subject is receiving dialysis Evidence of unstable renal function History of acute kidney injury after previous exposure to an intravenous contrast agent. 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

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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No

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: CSL112 - low dose<br>CSL112 (low dose) is to be administered as an intravenous (IV) infusion once weekly for 4 consecutive weeks. | 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>|
| Experimental: CSL112 - high dose<br>CSL112 (high dose) is to be administered as an IV infusion once weekly for 4 consecutive weeks. | 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>|
| Placebo Comparator: Placebo<br>Placebo is to be administered as an IV infusion at the same frequency, volume and duration as either the low dose or high dose CSL112 infusion. | Biological: 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 |
| --- | --- | --- |
| Percent of Participants With 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 first infusion) to Day 29. | 
| Percent of Participants With 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. | From baseline (before first infusion) to Day 29. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With a Time-to-first Major Adverse Cardiovascular Event (MACE) | The MACE is a 4-component composite comprised of the time to the first of the following events: CV death, nonfatal myocardial infarction, ischemic stroke (non-hemorrhagic), and hospitalization for unstable angina. | From the start of the first infusion up to approximately 382 days | 
| Change From Baseline in Concentrations of Apolipoprotein A-I (apoA-I) and Phosphatidylcholine (PC) at End of First Infusion for All Participants | Apolipoprotein A-I (apoA-I) and Phosphatidylcholine (PC) are analytes of CSL112 | Before first infusion and end of first infusion | 
| Change From Baseline in Plasma Concentrations of apoA-I and PC at End of Fourth Infusion for All Participants |  | Before first infusion and end of fourth infusion | 
| Change From Baseline in Plasma Concentrations of apoA-I and PC at End of First Infusion for Participants With Normal Renal Function | apoA-I and PC are analytes of CSL112 | Before first infusion and end of first infusion | 
| Change From Baseline in Plasma Concentrations of apoA-I and PC at End of Fourth Infusion for Participants With Normal Renal Function | apoA-I and PC are analytes of CSL112 | Before first infusion and end of fourth infusion | 
| Change From Baseline in Plasma Concentrations of apoA-I and PC at End of First Infusion for Participants With Mild Renal Impairment | apoA-I and PC are analytes of CSL112 | Before first infusion and end of first infusion | 
| Change From Baseline in Plasma Concentrations of apoA-I and PC at End of Fourth Infusion for Participants With Mild Renal Impairment | apoA-I and PC are analytes of CSL112 | Before first infusion and end of fourth infusion | 
| Change From Baseline in Plasma Cmax for apoA-I and PC After First Infusion for All Participants | Cmax is the maximal plasma concentration. | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Cmax for apoA-I and PC After Fourth Infusion for All Participants | Cmax is the maximal plasma concentration. | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Cmax for apoA-I and PC After First Infusion for Participants With Normal Renal Function | Cmax is the maximal plasma concentration. | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Cmax for apoA-I and PC After Fourth Infusion for Participants With Normal Renal Function | Cmax is the maximal plasma concentration. | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Cmax for apoA-I and PC After First Infusion for Participants With Mild Renal Impairment | Cmax is the maximal plasma concentration. | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Cmax for apoA-I and PC After Fourth Infusion for Participants With Mild Renal Impairment | Cmax is the maximal plasma concentration. | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Tmax for apoA-I and PC After First Infusion for All Participants | Tmax is time to maximal plasma concentration | Before and for 7 days after the first infusion | 
| Change From Baseline in Plasma Tmax for apoA-I and PC After Fourth Infusion for All Participants | Tmax is time to maximal plasma concentration | Before and for 7 days after the fourth infusion | 
| Change From Baseline in Plasma Tmax for apoA-I and PC After First Infusion for Participants With Normal Renal Function | Tmax is time to maximal plasma concentration | Before and for 7 days after the first infusion | 
| Change From Baseline in Plasma Tmax for apoA-I and PC After Fourth Infusion for Participants With Normal Renal Function | Tmax is time to maximal plasma concentration | Before and for 7 days after the fourth infusion | 
| Change From Baseline in Plasma Tmax for apoA-I and PC After First Infusion for Participants With Mild Renal Impairment | Tmax is time to maximal plasma concentration | Before and for 7 days after the first infusion | 
| Change From Baseline in Plasma Tmax for apoA-I and PC After Fourth Infusion for Participants With Mild Renal Impairment | Tmax is time to maximal plasma concentration | Before and for 7 days after the fourth infusion | 
| Change From Baseline in Plasma Area Under the Curve (AUC) AUC0 - Last for apoA-I and PC After First Infusion for All Participants | Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last] | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma AUC0 - Last for apoA-I and PC After Fourth Infusion for All Participants | Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last] | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma AUC0 - Last for apoA-I and PC After First Infusion for Participants With Normal Renal Function | Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last] | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma AUC0 - Last for apoA-I and PC After Fourth Infusion for Participants With Normal Renal Function | Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last] | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma AUC0 - Last for apoA-I and PC After First Infusion for Subjects With Mild Renal Impairment | Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last] | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma AUC0 - Last for apoA-I and PC After Fourth Infusion for Participants With Mild Renal Impairment | Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last] | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma AUC0-t for apoA-I and PC After First Infusion for All Participants | AUC from baseline to time point t (AUC0-t) | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma AUC0-t for apoA-I and PC After Fourth Infusion for All Participants | AUC from baseline to time point t (AUC0-t) | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma AUC0-t for apoA-I and PC After First Infusion for Participants With Normal Renal Function | AUC from baseline to time point t (AUC0-t) | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma AUC0-t for apoA-I and PC After Fourth Infusion for Participants With Normal Renal Function | AUC from baseline to time point t (AUC0-t) | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma AUC0-t for apoA-I and PC After First Infusion for Participants With Mild Renal Impairment | AUC from baseline to time point t (AUC0-t) | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma AUC0-t for apoA-I and PC After Fourth Infusion for Participants With Mild Renal Impairment | AUC from baseline to time point t (AUC0-t) | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma AUC0-∞ for apoA-I and PC After First Infusion for All Participants | AUC0-∞ is plasma area under the curve (AUC0-infinity) | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma AUC0-∞ for apoA-I and PC After Fourth Infusion for All Participants | AUC0-∞ is plasma area under the curve (AUC0-infinity) | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma AUC0-∞ for apoA-I and PC After First Infusion for Participants With Normal Renal Function | AUC0-∞ is plasma area under the curve (AUC0-infinity) | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma AUC0-∞ for apoA-I and PC After Fourth Infusion for Participants With Normal Renal Function | AUC0-∞ is plasma area under the curve (AUC0-infinity) | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma AUC0-∞ for apoA-I and PC After First Infusion for Participants With Mild Renal Impairment | AUC0-∞ is plasma area under the curve (AUC0-infinity) | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma AUC0-∞ for apoA-I and PC After Fourth Infusion for Participants With Mild Renal Impairment | AUC0-∞ is plasma area under the curve (AUC0-infinity) | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Terminal Half-life (t1/2) for apoA-I and PC After First Infusion for All Participants |  | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Terminal Half-life (t1/2) for apoA-I and PC After Fourth Infusion for All Participants |  | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Terminal Half-life (t1/2) for apoA-I and PC After First Infusion for Participants With Normal Renal Function |  | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Terminal Half-life (t1/2) for apoA-I and PC After Fourth Infusion for Participants With Normal Renal Function |  | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Terminal Half-life (t1/2) for apoA-I and PC After First Infusion for Participants With Mild Renal Impairment |  | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Terminal Half-life (t1/2) for apoA-I and PC After Fourth Infusion for Participants With Mild Renal Impairment |  | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Clearance (CL) for apoA-I and PC After First Infusion for All Participants |  | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Clearance (CL) for apoA-I and PC After Fourth Infusion for All Participants |  | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Clearance (CL) for apoA-I and PC After First Infusion for Participants With Normal Renal Function |  | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Clearance (CL) for apoA-I and PC After Fourth Infusion for Participants With Normal Renal Function |  | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Clearance (CL) for apoA-I and PC After First Infusion for Participants With Mild Renal Impairment |  | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Clearance (CL) for apoA-I and PC After Fourth Infusion for Participants With Mild Renal Impairment |  | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Volume of Distribution at Steady State (Vss) for apoA-I and PC After First Infusion for All Participants |  | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Vss for apoA-I and PC After Fourth Infusion for All Participants |  | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Vss for apoA-I and PC After First Infusion for Participants With Normal Renal Function |  | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Vss for apoA-I and PC After Fourth Infusion for Participants With Normal Renal Function |  | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Change From Baseline in Plasma Vss for apoA-I and PC After First Infusion for Participants With Mild Renal Impairment |  | Before first infusion (baseline) and for up to approximately 7 days after first infusion | 
| Change From Baseline in Plasma Vss for apoA-I and PC After Fourth Infusion for Participants With Mild Renal Impairment |  | Before first infusion (baseline) and for up to approximately 7 days after fourth infusion | 
| Percent of Participants With the Occurrence of Suspected Adverse Drug Reactions | The overall percentage of subjects: with adverse events (AEs), including local tolerability events, that begin during or within 1 hour of an infusion; or with AEs considered to be causally related to the test product; or who experience an AE for which the incidence rate 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. | From the start of first infusion, up to approximately Day 382 | 
| Percent of Participants With Any Adverse Event (AE) |  | From the start of first infusion, up to approximately Day 382 | 
| Percent of Participants Who Experience Bleeding Events | The number of subjects who experience bleeding events as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al, 2011) | From the start of first infusion, up to approximately Day 112 | 
| Change From Baseline in Serum Antibodies to CSL112 and apoA-I |  | Before first infusion, up to approximately Day 112 | 
| Number of Participants With Positive Serology Results for IgG and IgM Antibodies to Parvovirus B19 |  | Study Day 112 | 
| Number of Participants With Parvovirus B19 DNA in Serum |  | Study Day 112 |