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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 Cardiol. 2018 09 01; 3(9):815-822.JC

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.

Authors+Show Affiliations

South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.Heart and Vascular Center, Semmelweis University, Budapest, Hungary.Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.School of Public Health, Imperial College London, London, England.University of Colorado School of Medicine, Aurora.Genesis Healthcare, Sydney, Alexandria, Australia.Cerenis Pharmaceuticals, Toulouse, France.Cerenis Pharmaceuticals, Toulouse, France.South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30046828

Citation

Nicholls, Stephen J., et al. "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, vol. 3, no. 9, 2018, pp. 815-822.
Nicholls SJ, Andrews J, Kastelein JJP, et al. 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 Cardiol. 2018;3(9):815-822.
Nicholls, S. J., Andrews, J., Kastelein, J. J. P., Merkely, B., Nissen, S. E., Ray, K. K., Schwartz, G. G., Worthley, S. G., Keyserling, C., Dasseux, J. L., Griffith, L., Kim, S. W., Janssan, A., Di Giovanni, G., Pisaniello, A. D., Scherer, D. J., Psaltis, P. J., & 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, 3(9), 815-822. https://doi.org/10.1001/jamacardio.2018.2121
Nicholls SJ, et al. 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 Cardiol. 2018 09 1;3(9):815-822. PubMed PMID: 30046828.
* Article titles in AMA citation format should be in sentence-case
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: A Randomized Clinical Trial. AU - Nicholls,Stephen J, AU - Andrews,Jordan, AU - Kastelein,John J P, AU - Merkely,Bela, 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 - 2018/7/27/pubmed PY - 2019/10/8/medline PY - 2018/7/27/entrez SP - 815 EP - 822 JF - JAMA cardiology JO - JAMA Cardiol VL - 3 IS - 9 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. SN - 2380-6591 UR - https://www.unboundmedicine.com/medline/citation/30046828/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_ L2 - https://jamanetwork.com/journals/jamacardiology/fullarticle/10.1001/jamacardio.2018.2121 DB - PRIME DP - Unbound Medicine ER -