Design and rationale of a randomized clinical trial assessing the effect of inclisiran on atherosclerotic plaque in individuals without previous cardiovascular event and without flow- limiting lesions identified in an in-hospital screening: The VICTORION-PLAQUE primary prevention trial

BACKGROUND: The impact of low-density lipoprotein cholesterol (LDL-C) on atherosclerotic cardiovascular disease (ASCVD) risk is influenced by both the magnitude and duration of exposure. Patients with nonobstructive coronary artery disease (NOCAD) and a CT-adapted Leaman score (CT-LeSc) >5 have a higher risk of cardiac events. The CT-LeSc semi-quantitatively assesses total coronary atherosclerotic burden via coronary computed tomography angiography (CCTA). Treatment with an antiproprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody (mAb) leads to significant reductions in LDL-C levels. The addition of an anti-PCSK9 mAb to statin therapy produced greater LDL-C lowering and significant reduction in percent atheroma volume (PAV) and total atheroma volume (TAV) in patients with CAD. Inclisiran, a small-interfering ribonucleic acid (siRNA) therapy, targets PCSK9 messenger ribonucleic acid (mRNA) to reduce LDL-C levels by approximately 50% providing sustained and effective long-term LDL-C reduction after an initial and 90-day dose and a favorable safety profile alongside maximally tolerated statins. A similar treatment impact on total atheroma volume reduction is therefore hypothetically expected with inclisiran, given its exceptional dosing interval. METHODS: VICTORION-PLAQUE is a multicenter, international, randomized, double-blind, placebo-controlled trial assessing inclisiran's efficacy in reducing total coronary atheroma volume in patients with NOCAD without prior cardiovascular (CV) events. Patients receive inclisiran or placebo in addition to maximally tolerated high-intensity statin therapy. The primary objective is to demonstrate inclisiran's superiority compared to placebo in reducing total coronary atheroma volume, measured by CCTA, from baseline to Month 24. The primary endpoint is percentage change from baseline to Month 24 in total coronary atheroma volume. Secondary endpoints include percentage change in LDL-C from baseline to Month 24, percentage change in low attenuation plaque volume evaluated by CCTA, percentage of participants with progression, regression, or no change in total plaque atheroma volume, and incidence and severity of treatment-emergent adverse event (TEAEs) and serious adverse event (SAEs) and their relationship with the study drug. In total, 608 patients have been randomized at 96 sites across 18 countries worldwide and enrolment was closed on October 25, 2024. SUMMARY: The VICTORION-PLAQUE study evaluates the efficacy of inclisiran, compared with placebo, on top of maximally tolerated statin therapy, in reducing total coronary atheroma volume in NOCAD patients, as assessed by CCTA. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT05360446.