Coronary Atherosclerosis, Hypercholesterolemia, Mixed Dyslipidemia
Conditions
Keywords
Coronary atherosclerosis, Primary non-familial hypercholesterolaemia, Mixed dyslipidaemia, Bempedoic acid, Ezetimibe, Atorvastatin, Rosuvastatin
Brief summary
The overall objective of the trial is to evaluate the effect of the triple therapy consisting of bempedoic acid (BA), ezetimibe (EZE), and high-intensity atorvastatin or rosuvastatin on changes in coronary plaque burden and plaque morphology in patients with coronary atherosclerosis without significant obstructive coronary artery disease and without prior history of an ischemic vascular event.
Detailed description
The primary objective is to evaluate the effectiveness of the triple therapy in reducing plaque burden. The key secondary objective is to assess the efficacy of the triple therapy by evaluating changes in plaque composition and morphology.
Interventions
DRUGBempedoic acid
FDC: 180 mg
DRUGEzetimibe
FDC: 10 mg
DRUGRosuvastatin
20 mg dose
DRUGAtorvastatin
40 mg dose
Sponsors
Daiichi Sankyo
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
In order to be eligible to participate in this trial, a potential participant must meet all of the following criteria: 1. Age ≥18 years 2. Having provided informed consent for participation in this trial 3. Lipid-lowering treatment-naïve 4. Presence of extensive coronary atherosclerosis meeting all of the criteria below: * Unequivocal atherosclerosis in ≥5 American Heart Association (AHA) coronary segments (corresponding to a risk equivalent of obstructive coronary artery disease) and coronary artery disease - reporting and data system (CAD-RADS) category 1, 2, or 3 * Not expected to be a candidate for revascularisation during the duration of the trial * Untreated LDL-C ≥2.6 mmol/L and ≤4.5 mmol/L (where a diet without pharmacological treatment is considered 'untreated') 5. Able to provide informed consent
Exclusion criteria
A potential participant who meets any of the following criteria will be excluded from participation in this trial: 1. Known or suspected heterozygous or homozygous familial hypercholesterolaemia or familial combined hyperlipidaemia 2. 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. 3. Not expected to remain on a stable dose of high intensity triple therapy for the duration of the trial. 4. History of myocardial infarction, stroke, or peripheral artery disease (PAD), and/or coronary revascularisation (percutaneous coronary intervention \[PCI\] or coronary artery bypass grafting \[CABG\]) 5. 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 6. 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 \[ULN\]) 7. Known history of gout and/or uric acid levels at Screening ≥6.8 mg/dL 8. Known estimated glomerular filtration rate (eGFR) \<40 mL/min/1.73m² and/or receiving dialysis 9. Active malignancy (not including non-melanoma skin cancer) 10. Pregnant or breastfeeding 11. Body mass index (BMI) \>35 kg/m² 12. Anticipated life expectancy \<52 weeks at the discretion of the local investigator 13. 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 14. Suspicion of acute coronary syndrome (where acute myocardial infarction and unstable angina have not been ruled out) 15. Complex congenital heart disease 16. 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 17. Cardiac arrythmia or tachycardia with significant likelihood of resulting in poor PCD-CTA image quality (especially atrial fibrillation or frequent premature beats) 18. Intracoronary stents 19. Prior pacemaker, internal defibrillator, or abandoned lead implantation 20. Prosthetic heart valves 21. Contraindications to contrast media or other medications needed for proper imaging (e.g., beta blockers and nitroglycerin) 22. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualised change in percentage plaque burden (Δ%PB) | Baseline up to 12 months | This endpoint will evaluate the effectiveness of the triple therapy in reducing plaque burden (PB). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key Secondary: Annualised change in normalised non-calcified plaque volume (PV) | Baseline up to 12 months | This endpoint will assess the efficacy of the triple therapy by evaluating changes in plaque composition and morphology. |
| Percentage of participants with regression in normalised total plaque volume (TPV), normalised non-calcified PV, and normalised low attenuation PV at EoT (i.e., ΔPV and Δnon-calcified PV, and Δlow-attenuation PV) | Baseline up to 12 months | This endpoint will evaluate the potential impact of the triple therapy on total plaque volume (TPV) regression, non-calcified PV regression, and low attenuation PV regression. |
| Change in the absolute Agatston coronary artery calcium (CAC) score | Baseline up to 12 months | This endpoint will evaluate the potential impact of the triple therapy on coronary calcification. CAC measures the total area and density of calcified plaque in the heart's arteries, ranging from 0 to over 400. A score of 0 indicates no plaque, while higher scores indicate increased risk of cardiovascular events, with \>400 indicating extensive disease. |
| Annualised ΔTotal Plaque Volume (TPV) | Baseline up to 12 months | This endpoint will evaluate the effectiveness of the triple therapy in reducing TPV. |
| Percentage of participants with regression in TPV (i.e., negative ΔTPV) | Baseline up to 12 months | This endpoint will assess the proportion of participants exhibiting regression in TPV with triple therapy. |
| Absolute annualised change in fractional flow reserve derived from computed tomography (FFRCT) of the vessel with the lowest FFR at Baseline | Baseline up to 12 months | This endpoint will assess changes in non-invasive coronary flow reserve. |
| Absolute annualised change in FFRCT of the average of 3 main epicardial coronary arteries (left anterior descending artery [LAD], circumflex artery [Cx], right coronary artery [RCA]) | Baseline up to 12 months | This endpoint will assess changes in non-invasive coronary flow reserve. |
| Mean absolute changes in atherosclerosis-related biomarker total cholesterol | Baseline up to 12 months | This endpoint will evaluate the biochemical impact of triple therapy on critical biomarkers associated with atherosclerosis. |
| Mean absolute changes in atherosclerosis-related biomarker low-density lipoprotein cholesterol (LDL-C) | Baseline up to 12 months | This endpoint will evaluate the biochemical impact of triple therapy on critical biomarkers associated with atherosclerosis. |
| Mean absolute changes in atherosclerosis-related biomarker high-density lipoprotein cholesterol (HDL-C) | Baseline up to 12 months | This endpoint will evaluate the biochemical impact of triple therapy on critical biomarkers associated with atherosclerosis. |
| Mean absolute changes in atherosclerosis-related biomarker non-high-density lipoprotein cholesterol (non-HDL-C) | Baseline up to 12 months | This endpoint will evaluate the biochemical impact of triple therapy on critical biomarkers associated with atherosclerosis. |
| Mean absolute changes in atherosclerosis-related biomarkers lipoprotein a (Lp(a)) and apolipoprotein B (apoB) | Baseline up to 12 months | This endpoint will evaluate the biochemical impact of triple therapy on critical biomarkers associated with atherosclerosis. |
| Mean absolute changes in atherosclerosis-related biomarker high-sensitive C reactive protein (hs-CRP) | Baseline up to 12 months | This endpoint will evaluate the biochemical impact of triple therapy on critical biomarkers associated with atherosclerosis. |
| Annualised changes in Framingham steatosis index (FSI) and fibrosis-4 (Fib-4) | Baseline up to 12 months | This endpoint will assess the potential impact of the triple therapy on measures of liver health. |
| Cumulative incidence of adverse events (AEs) under triple therapy during the trial | Baseline up to 12 months | This endpoint will monitor and assess adverse events (AEs) under triple treatment. |
| Rate of treatment discontinuation during the trial | Baseline up to 12 months | This endpoint will to determine the rate and reasons for treatment discontinuation among trial participants receiving triple therapy. |
Countries
Germany, Italy, Spain
Contacts
CONTACTDaiichi Sankyo Contact for Clinical Trial Information
Outcome results
None listed