| Title: |
Safety and tolerability of CSL112, a reconstituted, infusible, plasma-derived apolipoprotein A-I, after acute myocardial infarction |
| Authors: |
Gibson, CM; Korjian, S; Tricoci, P; Daaboul, Y; Yee, M; Jain, P; Alexander, JH; Steg, PG; Lincoff, AM; Kastelein, JJP; Mehran, R; D'Andrea, DM; Deckelbaum, LI; Merkely, B; Zarebinski, M; Ophuis, TO; Harrington, RA |
| Source: |
1930 ; 1918 |
| Publisher Information: |
Wolters Kluwer Health |
| Publication Year: |
2016 |
| Collection: |
Imperial College London: Spiral |
| Subject Terms: |
Science & Technology; Life Sciences & Biomedicine; Cardiac & Cardiovascular Systems; Peripheral Vascular Disease; Cardiovascular System & Cardiology; alipoprotein A-I; myocardial infarction; HIGH-DENSITY-LIPOPROTEIN; CHOLESTEROL EFFLUX CAPACITY; ACUTE CORONARY SYNDROME; EXTENDED-RELEASE NIACIN/LAROPIPRANT; ESTER TRANSFER PROTEIN; CARDIOVASCULAR-DISEASE; HDL-CHOLESTEROL; HEART-DISEASE; FOLLOW-UP; HIGH-RISK; Acute Disease; Adult; Aged; Alanine Transaminase; Bilirubin; Biomarkers; Creatinine; Dose-Response Relationship; Drug; Double-Blind Method; Drug Administration Schedule; Female; Half-Life |
| Description: |
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: ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
Circulation; http://hdl.handle.net/10044/1/49582; https://dx.doi.org/10.1161/CIRCULATIONAHA.116.025687 |
| DOI: |
10.1161/CIRCULATIONAHA.116.025687 |
| Availability: |
http://hdl.handle.net/10044/1/49582; https://doi.org/10.1161/CIRCULATIONAHA.116.025687 |
| Rights: |
© 2016 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. |
| Accession Number: |
edsbas.B10486F3 |
| Database: |
BASE |