A Study of CSL112 in Adults With Moderate Renal Impairment and Acute Myocardial Infarction

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

Official Title
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A Phase 2, Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group, Study to Investigate the Safety and Tolerability of Multiple Dose Administration of CSL112 in Subjects With Moderate Renal Impairment and Acute Myocardial Infarction

Conditions
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Acute Myocardial Infarction, Moderate Renal Impairment

Intervention / Treatment
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* Biological: CSL_112
* Other: 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 moderate renal impairment (an eGFR ≥ 30 and <60 mL/min/1.73 m2) and myocardial necrosis in a clinical setting consistent with a type I (spontaneous) acute myocardial infarction (AMI). Exclusion Criteria: Symptoms, biomarker elevation or electrocardiogram (ECG) changes other than those of the index event that are consistent with a diagnosis of AMI but are likely not due to primary myocardial ischemia Ongoing hemodynamic instability Planned coronary artery bypass surgery Evidence of hepatobiliary disease History of acute kidney injury (AKI) after previous exposure to an intravenous contrast agent. History of nephrotic range proteinuria. Known history of allergy to soy beans or peanuts, immunoglobulin A (IgA) deficiency, antibodies to IgA , or hypersensitivity 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSL_112<br>CSL112 will be administered intravenously, once weekly for 4 consecutive weeks (4 infusions in total). | Biological: CSL_112<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 will be administered at the same frequency, volume and duration as the CSL112 infusion. | 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 |
| --- | --- | --- |
| Percent of Participants With at Least One Occurrence of Treatment-emergent Renal Serious Adverse Events (SAEs) (SAF) | A renal SAE is defined as any SAE with a MedDRA preferred term included in the Acute Renal Failure narrow Standard MedDRA Query or a preferred term of renal tubular necrosis, renal cortical necrosis, renal necrosis, or renal papillary necrosis. | Up to 9 weeks | 
| Percent of Participants With Treatment-emergent Acute Kidney Injury (AKI ) | Acute kidney injury is defined as an absolute increase in serum creatinine from baseline ≥ 0.3 mg/dL during the Active Treatment Period that is sustained upon repeat measurement by the central laboratory no earlier than 24 hours after the elevated value. If no repeat value is obtained, a single serum creatinine value that is increased from baseline ≥ 0.3 mg/dL (26.5 μmol/L) during the Active Treatment Period would also fulfil the definition of AKI. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) |  | Up to 9 weeks | 
| Percentage of Participants With TEAEs |  | Up to 9 weeks | 
| Total Number of TEAEs |  | Up to 9 weeks | 
| Number of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR | Adverse drug reactions or suspected adverse drug reactions are defined as: All TEAEs, including local tolerability events, that begin during or within 1 hour after the end of an infusion; or Those TEAEs that the investigator or sponsor indicate may be causally related to product administration; or All TEAEs for which the Investigator's causality assessment is missing or indeterminate; or All TEAEs 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 9 weeks | 
| Percentage of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR | Adverse drug reactions or suspected adverse drug reactions are defined as: All TEAEs, including local tolerability events, that begin during or within 1 hour after the end of an infusion; or Those TEAEs that the investigator or sponsor indicate may be causally related to product administration; or All TEAEs for which the Investigator's causality assessment is missing or indeterminate; or All TEAEs 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 9 weeks | 
| Number of Participants With Change in Renal Status | Number of participants with changes in renal status defined as: Absolute increases from baseline in serum creatinine as follows: i. ≤ baseline value ii. > 0 to < 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. > 0.5 mg/dL Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL Initiation of renal replacement therapy Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit | Baseline and up to 4 weeks | 
| Percentage of Participants With Change in Renal Status | Percentage of participants with changes in renal status defined as: Absolute increases from baseline in serum creatinine as follows: i. ≤ baseline value ii. > 0 to < 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. > 0.5 mg/dL Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL Initiation of renal replacement therapy Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit | Baseline and up to 4 weeks | 
| Number of Participants With Change in Hepatic Status | Number of participants with a change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement, defined as: Alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) ALT > 5 x ULN ALT > 10 x ULN Serum total bilirubin > 1.5 x ULN Serum total bilirubin > 2 x ULN Possible Hy's law cases, as defined in the FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009). | Baseline and up to 4 weeks | 
| Percentage of Participants With Change in Hepatic Status | Percentage of participants with a change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement, defined as: Alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) ALT > 5 x ULN ALT > 10 x ULN Serum total bilirubin > 1.5 x ULN Serum total bilirubin > 2 x ULN Possible Hy's law cases, as defined in the FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009). | Baseline and up to 4 weeks | 
| Number of Participants With Treatment-emergent Bleeding Events | Bleeding events are as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al., 2011). | Up to 9 weeks | 
| Percentage of Participants With Treatment-emergent Bleeding Events | Bleeding events are as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al., 2011). | Up to 9 weeks | 
| Percentage of Participants With Binding Antibodies Specific to Apolipoprotein A-I (Apo-A1) and CSL112 |  | Up to 9 weeks | 
| Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 1 for apoA-I and PC |  | Immediately after end of infusion | 
| Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 4 for apoA-I and PC |  | Immediately after end of infusion | 
| Plasma apoA-I and Phosphatidylcholine (PC) Accumulation Ratio After Infusion 4 | The plasma apoA-I and PC accumulation ratio will be determined for CSL112-treated subjects. | Immediately after end of infusion |