Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I).
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2016-12
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Abstract
Background
Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction.Methods
The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy).Results
A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar.Conclusions
Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial.Clinical trial registration
URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.Type
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Michael Gibson, C, Serge Korjian, Pierluigi Tricoci, Yazan Daaboul, Megan Yee, Purva Jain, John H Alexander, P Gabriel Steg, et al. (2016). Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I). Circulation, 134(24). pp. 1918–1930. 10.1161/circulationaha.116.025687 Retrieved from https://hdl.handle.net/10161/22871.
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John Hunter Peel Alexander
John H. Alexander, MD, MHS is a cardiologist and Professor of Medicine in the Department of Medicine, Division of Cardiology at Duke University School of Medicine, as well as the Vice Chief, Clinical Research in the Division of Cardiology. He is the Director of Cardiovascular Research at the Duke Clinical Research Institute where he oversees a large group of clinical research faculty and a broad portfolio of cardiovascular clinical trials and observational clinical research programs. He is a member of the American Society of Clinical Investigation.
Dr. Alexander’s clinical interests are in acute and general cardiovascular disease, valvular heart disease, and echocardiology. His research is focused on the translation of novel therapeutic concepts into clinical data through clinical trials, specifically on the therapeutics of acute coronary syndromes, chronic coronary artery disease, and cardiac surgery and on novel methodological approaches to clinical trials. He was on the Executive Committee of the ARISTOTLE trial of apixaban in patients with atrial fibrillation and was the Principal Investigator of the APPRAISE-2 trial of apixaban in patients with acute coronary syndromes.
Dr. Alexander has published extensively and has served as the principal investigator of numerous multicenter clinical trials. He currently serves as the co-chair of the Clinical Trial Transformation Initiative (CTTI).
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