Effect of bempedoic acid/ezetimibe plus high‑intensity statin therapy on plaque regression in coronary atherosclerosis patients without prior CV events

Trial ID: 2025-524625-41-00
Protocol: DSE-BMP-0005-CIS-MA
Sponsor: Daiichi Sankyo Europe GmbH

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Diseases & Conditions

Arteriosclerosis coronary artery

Objectives

Primary objective: to assess the efficacy of the triple regimen (bempedoic acid, ezetimibe, and a high‑intensity statin) in reducing plaque burden in individuals with coronary atherosclerosis who have not experienced cardiovascular events, addressing the core therapeutic goal of disease modification. Secondary objectives include:

Evaluation of changes in plaque composition and plaque morphology.
Assessment of regression in total plaque volume, non‑calcified plaque volume, and low‑attenuation plaque volume.
Investigation of the effect on coronary calcification.
Correlation of LDL‑C levels with plaque burden and non‑calcified plaque burden.
Determination of the proportion of participants achieving total plaque volume regression.
Measurement of changes in non‑invasive coronary flow reserve.
Analysis of biochemical impact on key atherosclerotic biomarkers.
Evaluation of liver health parameters.
Monitoring of adverse events and treatment discontinuation rates.

Participants

The sponsor did not provide the total number of participants. The trial enrolled adult subjects aged 22 years and older, inclusive of both male and female individuals. Participants were required to have extensive coronary atherosclerosis, defined by unequivocal disease in at least five American Heart Association coronary segments and a CAD‑RADS category of 1, 2, or 3, without an indication for revascularisation during the study period. Eligible individuals were lipid‑lowering treatment‑naïve with untreated LDL‑C levels between 2.6 mmol/L and 4.5 mmol/L, and they provided informed consent. The population comprised patients considered vulnerable, reflecting the inclusion of a broad clinical spectrum. Selection was based on the specified inclusion criteria, and no additional lifestyle restrictions such as diet or physical activity were stipulated in the provided information.

Plans and Procedures

The study is a randomized, double-blind, controlled trial evaluating the effect of a triple therapy consisting of bempedoic acid/ezetimibe, atorvastatin 40 mg, and rosuvastatin 20 mg on plaque regression and stabilization in patients with coronary atherosclerosis who have not experienced cardiovascular events. After obtaining informed consent, participants undergo a screening visit to confirm eligibility, including assessment of extensive coronary atherosclerosis (≥5 AHA segments, CAD‑RADS 1–3) and untreated LDL‑C levels between 2.6 and 4.5 mmol/L. Eligible subjects are then randomized to receive the triple regimen or control therapy and commence baseline assessments. Follow‑up visits are scheduled at 3 months, 6 months, and at the end‑of‑treatment (approximately 12 months after baseline) to collect imaging, laboratory, and safety data; an end‑of‑study visit concludes the trial. The primary efficacy measure is the annualised change in percentage plaque burden (Δ%PB) at the end of treatment, with multiple secondary endpoints assessing plaque composition, calcium score, fractional flow reserve, lipid parameters, inflammatory markers, and adverse event incidence. Participant involvement therefore spans roughly one year, with the possibility of early termination if serious adverse events occur, if revascularisation becomes indicated, or if the participant withdraws consent. The recruitment period is planned from June 2026 to July 2028.

Treatment

The study evaluates a triple‑therapy regimen comprising a high‑intensity statin, a fixed‑dose combination of bempedoic acid with ezetimibe, and an additional statin, to assess plaque regression and stabilization in patients without prior cardiovascular events.

One investigational arm includes atorvastatin administered orally at a dose of 40 mg once daily. The pharmaceutical form is not specified in the source data.

Another investigational arm utilizes rosuvastatin given orally at a dose of 20 mg once daily. The pharmaceutical form is not specified in the source data.

The fixed‑dose combination product containing bempedoic acid and ezetimibe is provided in the oral formulation identified as PHF00082MIG, delivering a total of 180.10 mg of active substances daily.

All study medications are taken once daily, preferably at the same time each day, with or without food. Participant adherence is monitored through pill counts at each study visit and review of electronic or paper medication diaries. No additional comparator or placebo treatments are described in the source information.

Efficacy

The primary efficacy parameter is the annualised change in percentage plaque burden (Δ%PB) measured at the end of treatment. Plaque burden will be quantified using coronary computed tomography angiography, with analysis of plaque volume metrics.

Secondary efficacy assessments include the annualised change in normalised non‑calcified plaque volume, the proportion of participants with regression in normalised total plaque volume, normalised non‑calcified plaque volume, and normalised low‑attenuation plaque volume at end of treatment, the change in absolute Agatston coronary artery calcium score, and the relationship between the annualised change in LDL‑C and plaque metrics. Additional secondary measures comprise the annualised change in total plaque volume, the proportion of participants with regression in total plaque volume, absolute annualised changes in fractional flow reserve derived from computed tomography for the vessel with the lowest baseline FFR and for the average of the three main epicardial coronary arteries, and mean absolute changes in atherosclerosis‑related biomarkers (total cholesterol, LDL‑C, HDL‑C, non‑HDL‑C, triglycerides, lipoprotein(a), apolipoprotein B, and high‑sensitivity C‑reactive protein) assessed at 3 months, 6 months, and at end of treatment. Annualised changes in the Framingham steatosis index and fibrosis‑4 score, cumulative incidence of adverse events, and treatment discontinuation rates are also recorded.

Imaging assessments will be performed at baseline, at predefined intervals (e.g., 3 months, 6 months), and at the end of treatment. Computed tomography data will be processed to derive plaque volume and FFRCT values. Laboratory analyses for lipid and inflammatory biomarkers will be conducted using validated assays at the same time points. All efficacy data will be analysed to calculate annualised changes and regression rates using appropriate statistical methods.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥22 years
Having provided informed consent for participation in this trial
Lipid-lowering treatment-naïve
Presence of extensive coronary atherosclerosis meeting all of the criteria below: - Unequivocal atherosclerosis in ≥5 American Heart Association (AHA) coronary segments18 (corresponding to a risk equivalent of obstructive coronary artery disease) and coronary artery disease – reporting and data system (CAD-RADS)19 category 1, 2, or 3 - Not expected to be a candidate for revascularisation during the duration of the trial Note: Suspected obstructive coronary artery disease on PCD-CTA that was deemed non-obstructive during subsequent invasive coronary angiography (preferably assessed with invasive coronary physiology testing, e.g., fractional flow reserve), does not exclude patients from participating in the trial. - Untreated LDL-C ≥2.6 mmol/L and ≤4.5 mmol/L (where a diet without pharmacological treatment is considered ‘untreated')
Able to provide informed consent

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Exclusion Criteria

Known or suspected heterozygous or homozygous familial hypercholesterolaemia or familial combined hyperlipidaemia
Myopathy or other known contraindication for BA, EZE, atorvastatin, and/or rosuvastatin. A participant with a contraindication for atorvastatin, can be assigned to triple therapy with rosuvastatin, and vice versa.
Not expected to remain on a stable dose of high intensity triple therapy for the duration of the trial.
History of myocardial infarction, stroke, or peripheral artery disease (PAD), and/or coronary revascularisation (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG])
Significant stenosis in the left main artery (≥50%) or proximal LAD artery (≥70%), or 3-vessel coronary artery disease (≥70% stenosis in major branches), clinically indicated for revascularisation
Known significant liver disease (e.g., positive hepatitis B or hepatitis C serology) or significant hepatic dysfunction (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >3 x upper limit of normal [ULN])
Known history of gout and/or uric acid levels at Screening ≥6.8 mg/dL
Known estimated glomerular filtration rate (eGFR) <40 mL/min/1.73m² and/or receiving dialysis
Active malignancy (not including non-melanoma skin cancer)
Pregnant or breastfeeding
Body mass index (BMI) >35 kg/m2
Anticipated life expectancy <52 weeks at the discretion of the local investigator
Requiring emergent procedures or having any evidence of ongoing or active clinical instability, including acute chest pain (sudden onset), cardiogenic shock, unstable blood pressure with systolic blood pressure <90 mmHg, severe congestive heart failure (New York Heart Association [NYHA] III or IV), or acute pulmonary oedema
Suspicion of acute coronary syndrome (where acute myocardial infarction and unstable angina have not been ruled out)
Complex congenital heart disease
Known or suspected severe valvular heart disease or valvular heart disease anticipated to require intervention within 52 weeks at the discretion of the local investigator
Cardiac arrythmia or tachycardia with significant likelihood of resulting in poor PCD-CTA image quality (especially atrial fibrillation or frequent premature beats)
Intracoronary stents
Prior pacemaker, internal defibrillator, or abandoned lead implantation
Prosthetic heart valves
Contraindications to contrast media or other medications needed for proper imaging (e.g., beta blockers and nitroglycerin)
Use of any experimental or investigational drug within 40 days or 5 half-lives prior to Screening (whichever is longer), or parallel participation in another interventional study