Rationale and design overview

The path from lipid lowering to event reduction traverses changes in plaque biology that can be quantified by contemporary imaging. For patients at risk of Coronary Artery Disease but without prior events, those mechanistic changes guide whether an intervention warrants broader adoption. Inclisiran lowers LDL Cholesterol through hepatocyte-targeted RNA Interference against PCSK9, enabling sustained potency with infrequent injections. VICTORION-PLAQUE tests whether that mechanism yields measurable regression or stabilization of Atherosclerotic Plaque in a primary prevention population, using prespecified plaque burden and composition metrics rather than solely relying on circulating biomarkers. By fixing the imaging schedule and analytic plan in advance, the protocol aims to minimize bias and improve reproducibility across centers.

Population and eligibility

The target population consists of adults without previous myocardial infarction, stroke, or revascularization who have evidence of subclinical atherosclerosis on institutional screening but no flow-limiting stenosis by noninvasive evaluation. This selection frames the question squarely within Primary Prevention, where absolute risk reduction hinges on both baseline risk and the magnitude of plaque modification achievable on top of standard care. Background therapy includes guideline-directed diet and lipid-lowering medications according to local standards, reflecting contemporary practice while allowing the incremental effect of inclisiran to be measured. Exclusions typically address contraindications to contrast imaging, recent acute illnesses, and unstable comorbidities that could confound longitudinal plaque assessment. By focusing on individuals with nonobstructive disease, the protocol avoids the confounding influence of flow-limiting lesions that may mandate intervention and alter natural plaque evolution.

Randomization, blinding, and interventions

The trial employs centralized randomization with allocation concealment and a double-blind, placebo-controlled design to isolate the treatment effect. Participants receive inclisiran or matching placebo on day 1 and day 90, then at 6-month intervals thereafter, aligning with the pharmacodynamic profile that maintains durable PCSK9 suppression. Such a schedule reduces adherence challenges compared with more frequent dosing regimens and should limit differential dropout based on treatment burden. Blinding extends to participants, treating clinicians, imaging analysts, and investigators responsible for endpoint evaluation to minimize expectation bias. Concomitant medications, including statins and ezetimibe, are allowed and recorded, with emphasis on stability to reduce confounding when attributing imaging changes to the randomized intervention.

Imaging strategy and endpoints

The primary efficacy signal derives from quantitative atherosclerotic burden and vulnerability readouts measured with standardized, multimodality imaging. Depending on site capability and artery beds identified at screening, modalities may include Coronary CT Angiography, carotid ultrasound, or vessel wall MRI, each offering complementary sensitivity to plaque composition and volume. A typical primary endpoint is the change from baseline in total or noncalcified plaque volume within prespecified segments, whereas key secondary endpoints focus on compositional hallmarks of instability such as low-attenuation plaque burden, lipid-rich necrotic core, or positive remodeling indices. Imaging core laboratories apply harmonized acquisition protocols and blinded analyses to mitigate intercenter variability. The protocol defines lesion selection, segment matching, artifact handling, and quality scoring to support interpretable delta measures over time.

Visit schedule and timing of assessments

Participants undergo baseline imaging prior to first dose, early follow-up to capture near-term biologic effects, and later follow-up to assess durability of plaque modification. The timing balances sensitivity to detect change against practical considerations of radiation exposure for computed tomography and participant burden for MRI-based sequences. Intervening visits collect safety data, fasting lipids, and adherence to background therapy, enabling mediation analyses between LDL lowering and plaque change. To maintain internal validity, rescue therapy thresholds and protocol deviations that might influence atherosclerosis trajectories are prespecified and adjudicated. The imaging window accommodates scheduling realities while ensuring sufficient uniformity to support pooled analyses across centers.

Statistical plan and operational considerations

Powering a plaque imaging trial hinges on expected variability in quantitative measurements, plausible effect size from LDL reduction, and correlation between baseline and follow-up values. The protocol builds assumptions from prior intravascular and noninvasive imaging experiences with statins and monoclonal PCSK9 inhibitors, while acknowledging that RNAi kinetics and twice-yearly dosing may influence temporal trajectories. A conservative allowance for attrition and non-evaluable scans is included, recognizing that motion artifacts, calcification blooming, or off-protocol imaging can reduce analyzable segments. Analyses adjust for baseline plaque burden and relevant covariates to increase precision and limit confounding. Sensitivity analyses probe robustness to missing data mechanisms and alternative model specifications.

Sample size and power assumptions

Sample size calculations target the minimal detectable difference in change in plaque burden between inclisiran and placebo groups with a two-sided alpha appropriate for the hierarchy of endpoints. The plan incorporates within-subject correlations for repeated measures and the coefficient of variation typical of each imaging modality. Practical inflation accounts for screen failure due to image quality, contraindications emerging after randomization, or withdrawal. Expected effect sizes are informed by the relationship between absolute LDL change and noncalcified plaque regression observed in prior lipid-lowering programs, translated cautiously to a primary prevention setting. The design favors adequate power for the primary endpoint while devoting exploratory breadth to secondary compositional measures.

Analysis populations and models

The intention-to-treat population forms the primary efficacy analysis set, preserving randomization benefits and reflecting real-world adherence. Per-protocol and on-treatment analyses serve as sensitivity checks to assess the impact of protocol deviations and discontinuation. Continuous endpoints such as change in total plaque volume are modeled with analysis of covariance or linear mixed-effects approaches, adjusting for baseline values and imaging center as needed. Categorical vulnerability features are analyzed using logistic models or ordinal methods when appropriate definitions of worsening or improvement apply. Prespecified subgroup analyses explore consistency across sex, baseline LDL, background statin intensity, and vascular bed, with careful interpretation due to limited power.

Multiplicity, missing data, and sensitivity checks

Multiplicity control follows a hierarchical testing framework that prioritizes the primary plaque burden endpoint, then proceeds to key compositional outcomes if statistical significance is achieved. This approach balances control of type I error with the desire to interrogate multiple, biologically linked aspects of plaque. Missing data are addressed by preplanned mixed-model strategies under missing at random assumptions and via multiple imputation for sensitivity. Additional sensitivity analyses include pattern-mixture or tipping point methods to evaluate departures from assumptions. Imaging adjudication rules for technically inadequate scans and prespecified imputation for segment-level failures help maintain analytic integrity while avoiding biased exclusions.

Safety monitoring and adjudication

Safety assessments include treatment-emergent adverse events, laboratory parameters, and injection-site reactions, a known class effect in PCSK9-targeting medicines administered subcutaneously. An independent data monitoring committee reviews unblinded safety data at defined intervals with stopping rules focused on unexpected harms rather than efficacy signals, reflecting the surrogate endpoint nature of the trial. Clinical cardiovascular events are collected and centrally adjudicated using standardized definitions to contextualize imaging findings, without powering the trial for event differences. Concomitant lipid-lowering changes and intercurrent illnesses are tracked to attribute adverse events appropriately. The safety analysis mirrors the efficacy set while also providing an as-treated lens for events plausibly linked to exposure.

Interpretation, limitations, and expected impact

Imaging surrogates provide a window into vascular biology but require careful interpretation when extrapolating to clinical benefit. Changes in plaque burden and vulnerability correlate with outcomes at the population level, yet validation as a surrogate endpoint depends on consistent treatment effects across programs and concordance with event reductions. The protocol situates inclisiran within the broader landscape of lipid modification by contextualizing plaque changes alongside biochemical LDL reduction and adherence durability from twice-yearly dosing. Generalizability will be influenced by selection criteria that enrich for subclinical disease while excluding obstructive lesions, striking a balance between signal detection and real-world applicability. Ultimately, the value of the findings will rest on the magnitude and consistency of imaging changes and their alignment with established cardiovascular risk pathways.

External validity and generalizability

Primary prevention populations are heterogeneous, spanning varying baseline risk, comorbidities, and background therapy intensity. By requiring subclinical atherosclerosis without flow-limiting lesions, the protocol addresses a common clinical scenario where intensifying lipid-lowering is contemplated but event risk is modest. External validity hinges on whether participating centers represent routine practice and whether imaging protocols can be replicated with community equipment and expertise. The inclusion of multiple vascular beds and modalities improves transportability but adds complexity to standardization. Future health system implementation will require streamlined acquisition workflows and quality assurance to realize the protocolized precision achieved in the trial.

Surrogacy and clinical outcomes

The trial is not event-driven, so its conclusions will focus on biological plausibility and effect sizes in imaging biomarkers rather than hard outcomes. Strong LDL lowering is associated with fewer events, but the connection between a given magnitude of noncalcified plaque regression and risk reduction lacks a fixed conversion in primary prevention. Embedding adjudicated clinical events as secondary or exploratory endpoints allows hypothesis generation for concordance, while avoiding overinterpretation of underpowered comparisons. Longer-term follow-up in separate outcomes trials, or meta-analytic frameworks integrating imaging and events, will be needed to confirm clinical utility. Transparent reporting of absolute and relative changes, variability, and measurement reproducibility will support appropriate synthesis across studies.

Implementation and future directions

If the trial demonstrates favorable shifts in plaque burden and composition, the next translational question is how to target therapy in practice. Risk stratification might combine traditional calculators with imaging markers to prioritize patients with high-risk plaque phenotypes for intensified lipid lowering. Health systems can leverage the twice-yearly administration to address adherence gaps, particularly in settings where daily therapy persistence is suboptimal. Future methodologic work should refine standardized protocols for plaque quantification, harmonize definitions of vulnerability across modalities, and validate thresholds that predict risk change. Integration with cost-effectiveness modeling will inform whether plaque-guided inclisiran use in primary prevention delivers value.

Protocol transparency increases confidence in the downstream readout. Details such as imaging core lab operations, inter-reader reliability thresholds, and predefined remedies for common artifacts are critical for reproducibility. Public registration and accessible protocols also facilitate cross-trial learning and benchmarking. For readers seeking source details, the trial protocol is available via PubMed at https://pubmed.ncbi.nlm.nih.gov/40769373/. As the field advances, harmonized reporting standards for plaque imaging endpoints will accelerate meta-analyses and regulatory dialogue on surrogate acceptance.

In sum, VICTORION-PLAQUE positions inclisiran within a rigorous randomized, double-blind, imaging-based framework tailored to primary prevention. The design aligns pharmacologic durability with pragmatic follow-up, standardizes acquisition and analysis to reduce noise, and prespecifies statistical handling to protect inference. Limitations inherent to surrogate endpoints and potential heterogeneity across imaging modalities are acknowledged and addressed through hierarchy and sensitivity analyses. The results, when available, should clarify the extent to which durable PCSK9 suppression modifies subclinical plaque and inform future outcome-focused strategies.