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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)

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 s...

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Autores principales: Michael Gibson, C., Korjian, Serge, Tricoci, Pierluigi, Daaboul, Yazan, Yee, Megan, Jain, Purva, Alexander, John H., Steg, P. Gabriel, Lincoff, A. Michael, Kastelein, John J.P., Mehran, Roxana, D’Andrea, Denise M., Deckelbaum, Lawrence I., Merkely, Bela, Zarebinski, Maciej, Ophuis, Ton Oude, Harrington, Robert A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147036/
https://www.ncbi.nlm.nih.gov/pubmed/27881559
http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025687
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author Michael Gibson, C.
Korjian, Serge
Tricoci, Pierluigi
Daaboul, Yazan
Yee, Megan
Jain, Purva
Alexander, John H.
Steg, P. Gabriel
Lincoff, A. Michael
Kastelein, John J.P.
Mehran, Roxana
D’Andrea, Denise M.
Deckelbaum, Lawrence I.
Merkely, Bela
Zarebinski, Maciej
Ophuis, Ton Oude
Harrington, Robert A.
author_facet Michael Gibson, C.
Korjian, Serge
Tricoci, Pierluigi
Daaboul, Yazan
Yee, Megan
Jain, Purva
Alexander, John H.
Steg, P. Gabriel
Lincoff, A. Michael
Kastelein, John J.P.
Mehran, Roxana
D’Andrea, Denise M.
Deckelbaum, Lawrence I.
Merkely, Bela
Zarebinski, Maciej
Ophuis, Ton Oude
Harrington, Robert A.
author_sort Michael Gibson, C.
collection PubMed
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: 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.
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spelling pubmed-51470362016-12-22 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) Michael Gibson, C. Korjian, Serge Tricoci, Pierluigi Daaboul, Yazan Yee, Megan Jain, Purva Alexander, John H. Steg, P. Gabriel Lincoff, A. Michael Kastelein, John J.P. Mehran, Roxana D’Andrea, Denise M. Deckelbaum, Lawrence I. Merkely, Bela Zarebinski, Maciej Ophuis, Ton Oude Harrington, Robert A. Circulation Original Research Articles 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. Lippincott Williams & Wilkins 2016-12-13 2016-12-12 /pmc/articles/PMC5147036/ /pubmed/27881559 http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025687 Text en © 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 (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
spellingShingle Original Research Articles
Michael Gibson, C.
Korjian, Serge
Tricoci, Pierluigi
Daaboul, Yazan
Yee, Megan
Jain, Purva
Alexander, John H.
Steg, P. Gabriel
Lincoff, A. Michael
Kastelein, John J.P.
Mehran, Roxana
D’Andrea, Denise M.
Deckelbaum, Lawrence I.
Merkely, Bela
Zarebinski, Maciej
Ophuis, Ton Oude
Harrington, Robert A.
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)
title 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)
title_full 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)
title_fullStr 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)
title_full_unstemmed 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)
title_short 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)
title_sort 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)
topic Original Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147036/
https://www.ncbi.nlm.nih.gov/pubmed/27881559
http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025687
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