Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial

A Randomized Clinical Trial

Stephen J. Nicholls, Jordan Andrews, John J.P. Kastelein, B. Merkely, Steven E. Nissen, Kausik K. Ray, Gregory G. Schwartz, Stephen G. Worthley, Connie Keyserling, Jean Louis Dasseux, Liddy Griffith, Susan W. Kim, Alex Janssan, Giuseppe Di Giovanni, Anthony D. Pisaniello, Daniel J. Scherer, Peter J. Psaltis, Julie Butters

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Importance: CER-001 is a negatively charged, engineered pre-β high-density lipoprotein (HDL) mimetic containing apolipoprotein A-I and sphingomyelin. Preliminary studies demonstrated favorable effects of CER-001 on cholesterol efflux and vascular inflammation. A post hoc reanalysis of a previously completed study of intravenous infusion of CER-001, 3 mg/k, showed that the intravenous infusion in patients with a high coronary plaque burden promoted regression as assessed by intravascular ultrasonography. Objective: To determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients. Design, Setting, and Participants: A double-blind, randomized, multicenter trial evaluating the effect of 10 weekly intravenous infusions of CER-001, 3 mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than 30% in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patients were enrolled from August 15, 2015, to November 19, 2016. Interventions: Participants were randomized to receive weekly CER-001, 3 mg/kg, or placebo for 10 weeks in addition to statins. Main Outcomes and Measures: The primary efficacy measure was the nominal change in PAV from baseline to day 78 measured by serial intravascular ultrasonography imaging. The secondary efficacy measures were nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results: Among 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men [79.8%] and 261 white race/ethnicity [96.0%]), 86 (29%) had statin prior use prior to the index ACS and 272 (92.8%) had evaluable imaging at follow-up. The placebo and CER-001 groups had similar posttreatment median levels of low-density lipoprotein cholesterol (74 mg/dL vs 79 mg/dL; P =.15) and high-density lipoprotein cholesterol (43 mg/dL vs 44 mg/dL; P =.66). The primary efficacy measure, PAV, decreased 0.41% with placebo (P =.005 compared with baseline), but not with CER-001 (-0.09%; P =.67 compared with baseline; between group differences, 0.32%; P =.15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV (57.7% vs 53.3%; P =.49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups. Conclusions and Relevance: Infusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden. Trial Registration: ClinicalTrials.gov Identifier: NCT2484378.

Original languageEnglish
JournalJAMA Cardiology
DOIs
Publication statusAccepted/In press - Jan 1 2018

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HDL Lipoproteins
Acute Coronary Syndrome
Coronary Artery Disease
Atherosclerosis
Randomized Controlled Trials
Atherosclerotic Plaques
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Interventional Ultrasonography
Placebos
Intravenous Infusions
CER-001
Sphingomyelins
Hungary
Apolipoprotein A-I
Community Hospital
Coronary Angiography
Netherlands
LDL Cholesterol
HDL Cholesterol
Multicenter Studies

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial : A Randomized Clinical Trial. / Nicholls, Stephen J.; Andrews, Jordan; Kastelein, John J.P.; Merkely, B.; Nissen, Steven E.; Ray, Kausik K.; Schwartz, Gregory G.; Worthley, Stephen G.; Keyserling, Connie; Dasseux, Jean Louis; Griffith, Liddy; Kim, Susan W.; Janssan, Alex; Di Giovanni, Giuseppe; Pisaniello, Anthony D.; Scherer, Daniel J.; Psaltis, Peter J.; Butters, Julie.

In: JAMA Cardiology, 01.01.2018.

Research output: Contribution to journalArticle

Nicholls, SJ, Andrews, J, Kastelein, JJP, Merkely, B, Nissen, SE, Ray, KK, Schwartz, GG, Worthley, SG, Keyserling, C, Dasseux, JL, Griffith, L, Kim, SW, Janssan, A, Di Giovanni, G, Pisaniello, AD, Scherer, DJ, Psaltis, PJ & Butters, J 2018, 'Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial: A Randomized Clinical Trial', JAMA Cardiology. https://doi.org/10.1001/jamacardio.2018.2121
Nicholls, Stephen J. ; Andrews, Jordan ; Kastelein, John J.P. ; Merkely, B. ; Nissen, Steven E. ; Ray, Kausik K. ; Schwartz, Gregory G. ; Worthley, Stephen G. ; Keyserling, Connie ; Dasseux, Jean Louis ; Griffith, Liddy ; Kim, Susan W. ; Janssan, Alex ; Di Giovanni, Giuseppe ; Pisaniello, Anthony D. ; Scherer, Daniel J. ; Psaltis, Peter J. ; Butters, Julie. / Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial : A Randomized Clinical Trial. In: JAMA Cardiology. 2018.
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title = "Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial: A Randomized Clinical Trial",
abstract = "Importance: CER-001 is a negatively charged, engineered pre-β high-density lipoprotein (HDL) mimetic containing apolipoprotein A-I and sphingomyelin. Preliminary studies demonstrated favorable effects of CER-001 on cholesterol efflux and vascular inflammation. A post hoc reanalysis of a previously completed study of intravenous infusion of CER-001, 3 mg/k, showed that the intravenous infusion in patients with a high coronary plaque burden promoted regression as assessed by intravascular ultrasonography. Objective: To determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients. Design, Setting, and Participants: A double-blind, randomized, multicenter trial evaluating the effect of 10 weekly intravenous infusions of CER-001, 3 mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than 30{\%} in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patients were enrolled from August 15, 2015, to November 19, 2016. Interventions: Participants were randomized to receive weekly CER-001, 3 mg/kg, or placebo for 10 weeks in addition to statins. Main Outcomes and Measures: The primary efficacy measure was the nominal change in PAV from baseline to day 78 measured by serial intravascular ultrasonography imaging. The secondary efficacy measures were nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results: Among 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men [79.8{\%}] and 261 white race/ethnicity [96.0{\%}]), 86 (29{\%}) had statin prior use prior to the index ACS and 272 (92.8{\%}) had evaluable imaging at follow-up. The placebo and CER-001 groups had similar posttreatment median levels of low-density lipoprotein cholesterol (74 mg/dL vs 79 mg/dL; P =.15) and high-density lipoprotein cholesterol (43 mg/dL vs 44 mg/dL; P =.66). The primary efficacy measure, PAV, decreased 0.41{\%} with placebo (P =.005 compared with baseline), but not with CER-001 (-0.09{\%}; P =.67 compared with baseline; between group differences, 0.32{\%}; P =.15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV (57.7{\%} vs 53.3{\%}; P =.49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups. Conclusions and Relevance: Infusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden. Trial Registration: ClinicalTrials.gov Identifier: NCT2484378.",
author = "Nicholls, {Stephen J.} and Jordan Andrews and Kastelein, {John J.P.} and B. Merkely and Nissen, {Steven E.} and Ray, {Kausik K.} and Schwartz, {Gregory G.} and Worthley, {Stephen G.} and Connie Keyserling and Dasseux, {Jean Louis} and Liddy Griffith and Kim, {Susan W.} and Alex Janssan and {Di Giovanni}, Giuseppe and Pisaniello, {Anthony D.} and Scherer, {Daniel J.} and Psaltis, {Peter J.} and Julie Butters",
year = "2018",
month = "1",
day = "1",
doi = "10.1001/jamacardio.2018.2121",
language = "English",
journal = "JAMA Cardiology",
issn = "2380-6583",
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TY - JOUR

T1 - Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial

T2 - A Randomized Clinical Trial

AU - Nicholls, Stephen J.

AU - Andrews, Jordan

AU - Kastelein, John J.P.

AU - Merkely, B.

AU - Nissen, Steven E.

AU - Ray, Kausik K.

AU - Schwartz, Gregory G.

AU - Worthley, Stephen G.

AU - Keyserling, Connie

AU - Dasseux, Jean Louis

AU - Griffith, Liddy

AU - Kim, Susan W.

AU - Janssan, Alex

AU - Di Giovanni, Giuseppe

AU - Pisaniello, Anthony D.

AU - Scherer, Daniel J.

AU - Psaltis, Peter J.

AU - Butters, Julie

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Importance: CER-001 is a negatively charged, engineered pre-β high-density lipoprotein (HDL) mimetic containing apolipoprotein A-I and sphingomyelin. Preliminary studies demonstrated favorable effects of CER-001 on cholesterol efflux and vascular inflammation. A post hoc reanalysis of a previously completed study of intravenous infusion of CER-001, 3 mg/k, showed that the intravenous infusion in patients with a high coronary plaque burden promoted regression as assessed by intravascular ultrasonography. Objective: To determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients. Design, Setting, and Participants: A double-blind, randomized, multicenter trial evaluating the effect of 10 weekly intravenous infusions of CER-001, 3 mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than 30% in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patients were enrolled from August 15, 2015, to November 19, 2016. Interventions: Participants were randomized to receive weekly CER-001, 3 mg/kg, or placebo for 10 weeks in addition to statins. Main Outcomes and Measures: The primary efficacy measure was the nominal change in PAV from baseline to day 78 measured by serial intravascular ultrasonography imaging. The secondary efficacy measures were nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results: Among 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men [79.8%] and 261 white race/ethnicity [96.0%]), 86 (29%) had statin prior use prior to the index ACS and 272 (92.8%) had evaluable imaging at follow-up. The placebo and CER-001 groups had similar posttreatment median levels of low-density lipoprotein cholesterol (74 mg/dL vs 79 mg/dL; P =.15) and high-density lipoprotein cholesterol (43 mg/dL vs 44 mg/dL; P =.66). The primary efficacy measure, PAV, decreased 0.41% with placebo (P =.005 compared with baseline), but not with CER-001 (-0.09%; P =.67 compared with baseline; between group differences, 0.32%; P =.15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV (57.7% vs 53.3%; P =.49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups. Conclusions and Relevance: Infusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden. Trial Registration: ClinicalTrials.gov Identifier: NCT2484378.

AB - Importance: CER-001 is a negatively charged, engineered pre-β high-density lipoprotein (HDL) mimetic containing apolipoprotein A-I and sphingomyelin. Preliminary studies demonstrated favorable effects of CER-001 on cholesterol efflux and vascular inflammation. A post hoc reanalysis of a previously completed study of intravenous infusion of CER-001, 3 mg/k, showed that the intravenous infusion in patients with a high coronary plaque burden promoted regression as assessed by intravascular ultrasonography. Objective: To determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients. Design, Setting, and Participants: A double-blind, randomized, multicenter trial evaluating the effect of 10 weekly intravenous infusions of CER-001, 3 mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than 30% in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patients were enrolled from August 15, 2015, to November 19, 2016. Interventions: Participants were randomized to receive weekly CER-001, 3 mg/kg, or placebo for 10 weeks in addition to statins. Main Outcomes and Measures: The primary efficacy measure was the nominal change in PAV from baseline to day 78 measured by serial intravascular ultrasonography imaging. The secondary efficacy measures were nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results: Among 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men [79.8%] and 261 white race/ethnicity [96.0%]), 86 (29%) had statin prior use prior to the index ACS and 272 (92.8%) had evaluable imaging at follow-up. The placebo and CER-001 groups had similar posttreatment median levels of low-density lipoprotein cholesterol (74 mg/dL vs 79 mg/dL; P =.15) and high-density lipoprotein cholesterol (43 mg/dL vs 44 mg/dL; P =.66). The primary efficacy measure, PAV, decreased 0.41% with placebo (P =.005 compared with baseline), but not with CER-001 (-0.09%; P =.67 compared with baseline; between group differences, 0.32%; P =.15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV (57.7% vs 53.3%; P =.49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups. Conclusions and Relevance: Infusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden. Trial Registration: ClinicalTrials.gov Identifier: NCT2484378.

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