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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).
- Source :
-
Circulation [Circulation] 2016 Dec 13; Vol. 134 (24), pp. 1918-1930. Date of Electronic Publication: 2016 Nov 15. - Publication Year :
- 2016
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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.<br />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).<br />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.<br />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.<br />Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.<br /> (© 2016 The Authors.)
- Subjects :
- Acute Disease
Adult
Aged
Alanine Transaminase blood
Bilirubin blood
Biomarkers blood
Creatinine blood
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Female
Half-Life
Hemorrhage etiology
Humans
Lipoproteins, HDL adverse effects
Lipoproteins, HDL pharmacokinetics
Male
Middle Aged
Myocardial Infarction pathology
Placebo Effect
Proportional Hazards Models
Treatment Outcome
Lipoproteins, HDL therapeutic use
Myocardial Infarction drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 134
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 27881559
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.116.025687