Rationale and design of the REMBRANDT trial: A phase 3 study to evaluate the effect of obicetrapib/ezetimibe on coronary plaque characteristics
- PMID: 40683616
- DOI: 10.1016/j.ahj.2025.07.012
Rationale and design of the REMBRANDT trial: A phase 3 study to evaluate the effect of obicetrapib/ezetimibe on coronary plaque characteristics
Abstract
Background: Obicetrapib is a potent, selective cholesteryl ester transfer protein (CETP) inhibitor that significantly lowers low-density lipoprotein cholesterol (LDL-C). Additive reductions in LDL-C occur when obicetrapib is combined with ezetimibe. The impact of obicetrapib and ezetimibe fixed-dose combination (FDC) on coronary plaque burden is unknown. Favorable changes in noncalcified coronary atherosclerotic plaque volume (NCPV) may indicate a potential beneficial effect on atherosclerotic cardiovascular disease (ASCVD) events.
Methods: REMBRANDT is a placebo-controlled, double-blind, randomized trial designed to assess the efficacy of obicetrapib and ezetimibe FDC on coronary plaque burden. Individuals aged 45 years or older with ASCVD (imaging evidence of vascular disease or clinically manifested ASCVD) and an LDL-C of ≥70 mg/dL despite maximally tolerated lipid-modifying therapy are eligible to participate. Eligible participants (N = 300) will be randomized in a 1:1 ratio to obicetrapib 10 mg and ezetimibe 10 mg FDC once daily or placebo tablet once daily. The primary efficacy outcome of REMBRANDT is percent change in total NCPV from baseline to 18 months as assessed by coronary computed tomographic angiography (CCTA). Secondary endpoints include absolute change in total NCPV, percent and absolute change in NCPV in the most diseased coronary segment, percent change in LDL-C, and change in perivascular fat attenuation index from baseline to 18 months.
Conclusion: The REMBRANDT trial will determine whether the favorable effects of obicetrapib and ezetimibe FDC on LDL-C translate to a reduction in coronary plaque burden as a potential mechanism for ASCVD risk reduction.
Clinical trial registration: NCT06305559.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Disclosures Dr. McCarthy is supported by a National Heart, Lung, And Blood Institute Career Development Award (K23HL167659) and has received consulting fees/honorarium from Roche Diagnostic, Abbott Laboratories, NewAmsterdam Pharma, and HeartFlow, Inc. Dr. Shirodaria is a co-founder and chief development officer of Caristo Diagnostics Ltd, a CT-image analysis company. Dr. Ditmarsch is Chief Development Officer for NewAmsterdam Pharma. Dr. Kastelein is Chief Scientific Officer for NewAmsterdam Pharma and Emeritus Professor of Medicine at the University of Amsterdam, The Netherlands. Dr. Navar reports honoraria and consulting fees from AstraZeneca, Bayer, Bristol Meyer Squibb, Boehringer Ingelheim, Esperion, Janssen, Eli Lilly, Merck, NewAmsterdam Pharma, Novartis, NovoNordisk, Pfizer, and Silence Therapeutics; and funding for research to her institution from Esperion, Janssen, and Amgen. Dr. Williams is supported by the British Heart Foundation and has given talks for Canon Medical Systems, Siemens Healthineers, and Novartis. Dr. Budoff reports a grant from General Electric outside the submitted work. Dr. Ray reports his institution received unrestricted research grants from Amgen, Sanofi, Regeneron, Daiichi Sankyo, and Ultragenix; consulting fees from Novartis, Daiichi Sankyo, Kowa, Esperion, Novo Nordisk, MSD, Lilly, Silence Therapeutics, AZ, NewAmsterdam Pharma, Bayer, Beren Therapeutics, Cleery, EmendoBio, Scribe, CRISPR, Vaxxinity, Amarin, Regeneron, Ultragenix, Cargene, Resverlogix, for serving as a member of the steering committee or executive committee of clinical trials and roles as PI, NLI; honoraria from Novartis, BI, AZ, Novo Nordisk, Viatris, Amarin, Biologix Pharma, Sanofi, Amgen, Esperion, Daiichi Sankyo, Macleod Pharma for CME and non-CME symposia at international meetings; and he has stock options from NewAmsterdam Pharma, Scribe Therapeutics and PEMI 31. Dr. Ballantyne received grant/research support (all paid to the institution, not individual) from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Eli Lilly, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Roche Diagnostic, NIH, AHA, ADA and reports consulting for 89Bio, Abbott Diagnostics, Amgen, Arrowhead, Astra Zeneca, Denka Seiken, Esperion, Genentech, Ionis, Eli Lilly, Merck, NewAmsterdam Pharma, Novartis, Novo Nordisk, and Roche Diagnostic. Dr. Blankstein has received research support and consulting fees from Amgen Inc and Novartis Inc. Dr. Nicholls received grant/research support from AstraZeneca, New Amsterdam Pharma, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; and was a consultant for AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, and Vaxxinity. Dr. Gibson has received research funding from CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson Corporation, and SCAD Alliance; has received consulting from Angel/Avertix Medical Corporation, AstraZeneca, Bayer Corporation, Beren Therapeutics, Boehringer Ingelheim, Boston Clinical Research Institute, Boston Scientific, Bristol Myers Squibb, Cardiovascular Research Foundation, CeleCor Therapeutics, CSL Behring, DCRI, Esperion, EXCITE International ($0 received), Fortress Biotech, Gilead Sciences, Inc, Janssen, Pharmaceuticals, Johnson & Johnson Corporation, MashUp MD, MD Magazine, Microport, MJHealth, Novartis, NovoNordisk, Pfizer, PHRI, PLxPharma, SCAI, Solstic Health/New Amsterdam Pharma, Somahlution/Marizyme, Vectura, Web MD, and Women as One; has equity in nference, Dyad Medical, Absolutys, Fortress Biotech; and has received royalties as contributor to UpToDate. Dr. Januzzi Jr. is supported in part by the Adolph Hutter professorship and has received research grants from Abbott Diagnostics, Applied Therapeutics, AstraZeneca, HeartFlow, and Novartis; he has received consulting fees/honorarium from Abbott, AstraZeneca, Beckman-Coulter, Boehringer-Ingelheim, Bristol-Myers, Intellia, Jana Care, Novartis, Pfizer, Merck, Roche Diagnostics and Siemens; He participates on data safety monitoring boards or endpoint committees for Abbott, Abbvie, Bayer, CVRx, Pfizer, Roche Diagnostics and Takeda and reports equity holdings in Imbria Pharmaceuticals and Jana Care.
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