Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I)

A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction

C. Michael Gibson, Serge Korjian, Pierluigi Tricoci, Yazan Daaboul, John H. Alexander, Philippe G. Steg, A. Michael Lincoff, John J P Kastelein, Roxana Mehran, Denise D'Andrea, B. Merkely, Maciej Zarebinski, Ton Oude Ophius, Robert A. Harrington

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Despite aggressive pharmacotherapy and stenting, there is a residual risk of major adverse cardiovascular events among patients with acute coronary syndrome. High-density lipoprotein (HDL) has been a major target for secondary acute coronary syndrome prevention; however, a better understanding of the physiologic function of HDL has demonstrated that a high cholesterol efflux capacity, rather than high HDL concentrations alone, may be critical to improving outcomes. CSL112, a reconstituted, infusible human apolipoprotein A-I, has been demonstrated to increase cholesterol efflux capacity and to have a protective effect in experimental models of atherosclerotic cardiovascular disease. Design The AEGIS-I trial (ClinicalTrials.gov NCT02108262) is a phase 2b, multicenter, randomized, placebo-controlled, dose-ranging clinical trial to evaluate the hepatic and renal safety of multiple administrations of 2 doses of CSL112 among subjects with acute myocardial infarction (AMI). Approximately 1,200 subjects (400 per treatment group) with either normal renal function or mild renal impairment will be enrolled up to 7 days after an AMI and will be stratified by renal function and randomized in a 1:1:1 ratio to either 1 of 2 doses of CSL112 (either 2 g or 6 g) or placebo as a weekly 2-hour infusion over the course of 4 consecutive weeks. The coprimary safety endpoints will be the incidence of hepatic and renal toxicity, defined as either confirmed ALT >3 × ULN, total bilirubin >2 × ULN, serum creatinine ≥1.5×baseline value, or a new requirement for renal replacement therapy through the end of the active treatment period. Summary The AEGIS-I trial will characterize the safety profile of CSL112, a reconstituted formulation of apolipoprotein A-I, and will assess if administration to patients with a recent AMI is associated with a clinically significant alteration in either liver or kidney function when compared with placebo.

Original languageEnglish
Pages (from-to)22-28
Number of pages7
JournalAmerican Heart Journal
Volume180
DOIs
Publication statusPublished - Oct 1 2016

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Apolipoprotein A-I
Myocardial Infarction
Placebos
Kidney
Safety
HDL Lipoproteins
Acute Coronary Syndrome
Liver
Cholesterol
Renal Replacement Therapy
Bilirubin
CSL112
Creatinine
Theoretical Models
Cardiovascular Diseases
Clinical Trials
Drug Therapy
Incidence
Therapeutics
Serum

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I) : A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction. / Gibson, C. Michael; Korjian, Serge; Tricoci, Pierluigi; Daaboul, Yazan; Alexander, John H.; Steg, Philippe G.; Lincoff, A. Michael; Kastelein, John J P; Mehran, Roxana; D'Andrea, Denise; Merkely, B.; Zarebinski, Maciej; Ophius, Ton Oude; Harrington, Robert A.

In: American Heart Journal, Vol. 180, 01.10.2016, p. 22-28.

Research output: Contribution to journalArticle

Gibson, C. Michael ; Korjian, Serge ; Tricoci, Pierluigi ; Daaboul, Yazan ; Alexander, John H. ; Steg, Philippe G. ; Lincoff, A. Michael ; Kastelein, John J P ; Mehran, Roxana ; D'Andrea, Denise ; Merkely, B. ; Zarebinski, Maciej ; Ophius, Ton Oude ; Harrington, Robert A. / Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I) : A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction. In: American Heart Journal. 2016 ; Vol. 180. pp. 22-28.
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abstract = "Despite aggressive pharmacotherapy and stenting, there is a residual risk of major adverse cardiovascular events among patients with acute coronary syndrome. High-density lipoprotein (HDL) has been a major target for secondary acute coronary syndrome prevention; however, a better understanding of the physiologic function of HDL has demonstrated that a high cholesterol efflux capacity, rather than high HDL concentrations alone, may be critical to improving outcomes. CSL112, a reconstituted, infusible human apolipoprotein A-I, has been demonstrated to increase cholesterol efflux capacity and to have a protective effect in experimental models of atherosclerotic cardiovascular disease. Design The AEGIS-I trial (ClinicalTrials.gov NCT02108262) is a phase 2b, multicenter, randomized, placebo-controlled, dose-ranging clinical trial to evaluate the hepatic and renal safety of multiple administrations of 2 doses of CSL112 among subjects with acute myocardial infarction (AMI). Approximately 1,200 subjects (400 per treatment group) with either normal renal function or mild renal impairment will be enrolled up to 7 days after an AMI and will be stratified by renal function and randomized in a 1:1:1 ratio to either 1 of 2 doses of CSL112 (either 2 g or 6 g) or placebo as a weekly 2-hour infusion over the course of 4 consecutive weeks. The coprimary safety endpoints will be the incidence of hepatic and renal toxicity, defined as either confirmed ALT >3 × ULN, total bilirubin >2 × ULN, serum creatinine ≥1.5×baseline value, or a new requirement for renal replacement therapy through the end of the active treatment period. Summary The AEGIS-I trial will characterize the safety profile of CSL112, a reconstituted formulation of apolipoprotein A-I, and will assess if administration to patients with a recent AMI is associated with a clinically significant alteration in either liver or kidney function when compared with placebo.",
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AU - Gibson, C. Michael

AU - Korjian, Serge

AU - Tricoci, Pierluigi

AU - Daaboul, Yazan

AU - Alexander, John H.

AU - Steg, Philippe G.

AU - Lincoff, A. Michael

AU - Kastelein, John J P

AU - Mehran, Roxana

AU - D'Andrea, Denise

AU - Merkely, B.

AU - Zarebinski, Maciej

AU - Ophius, Ton Oude

AU - Harrington, Robert A.

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