Highlights
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This randomized, double-blind, placebo-controlled Phase 3B trial will evaluate the efficacy of inclisiran, in addition to maximally tolerated statins with or without other lipid-lowering therapies (LLT), in reducing total coronary atheroma volume.
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Coronary computed tomography angiography (CCTA) will be employed to assess plaque progression or regression in response to inclisiran.
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The study will enroll patients diagnosed with nonobstructive coronary artery disease (NOCAD) without a history of cardiovascular (CV) events.
ABSTRACT
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
Background and rationale
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality worldwide. The accumulation of LDL and other apolipoprotein B (apoB)-containing lipoproteins within the arterial wall initiates atherosclerosis. Prolonged exposure to elevated low-density lipoprotein cholesterol (LDL-C) levels results in increased LDL accumulation within the arterial wall over time, leading to a progressive increase in atherosclerotic plaque burden and a heightened risk of acute cardiovascular events. Consequently, the biological impact of LDL on the risk of ASCVD is determined by both the magnitude and duration of exposure. Studies of populations with genetically low LDL-C levels have shown that long-term exposure to lower LDL-C levels beginning early in life reduces long-term cardiovascular (CV) risk. ,,,, Maintaining low levels of LDL-C over time with lipid-lowering therapy (LLT) reduces the number of LDL particles accumulated within the arterial wall, slows the progression of atherosclerosis, and delays the formation of mature atherosclerotic plaques which significantly lowers the lifetime risk of ASCVD events. ,
Numerous intravascular ultrasonography studies have demonstrated that therapies lowering LDL-C by upregulating the LDL receptor consistently slow atherosclerosis progression or achieve regression. ,, The degree of plaque progression reduction is directly proportional to the absolute reduction in LDL-C levels, with evidence suggesting that lowering LDL-C below a certain threshold may arrest plaque progression. Additionally, Mendelian randomization studies, often called “nature’s randomization trials,” have shown that maintaining lower LDL-C levels over time significantly reduces the lifetime risk of cardiovascular events. , Previous statin trials have shown that LDL-C lowering reduces ASCVD events. ,,, Based on this evidence, current guidelines recommend drug therapy to lower LDL-C for patients with elevated LDL-C levels who are at high-risk of cardiovascular events. ,,,
Nonobstructive coronary artery disease (NOCAD) is defined as a diameter stenosis of <50% in a major epicardial artery. Despite an elevated risk of ASCVD events in patients with NOCAD, they were not included in the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) Guidelines for the management of dyslipidaemias, nor in the 2018 American Heart Association (AHA)/American College of Cardiology (ACC) Guidelines for the management of blood cholesterol. This exclusion is primarily due to the lack of randomized clinical trial evidence specifically targeting this patient population.
According to the 2019 ESC/EAS Guidelines for Management of Dyslipidemias, patients with documented ASCVD, either clinical or unequivocally documented by imaging, are deemed as very high-risk patients. Unequivocally, documented ASCVD on imaging includes those findings that are known to be predictive of clinical events, such as significant plaque on coronary angiography or CCTA (multivessel CAD with two major epicardial arteries having >50% stenosis), or on carotid ultrasound. The LDL-C goal for these patients is <55 mg/dL (<1.4 mmol/L). The 2019 ESC/EAS Dyslipidaemia Guideline does not mention patients with NOCAD and a CT-adapted Leaman score (CT-LeSc) >5, although these patients are at risk of ASCVD events comparable to those with obstructive coronary artery disease. , In a study which investigated an AI-enabled quantitative coronary plaque and hemodynamic analysis (AI-QCPHA) to predict lesion-level risk in patients with acute coronary syndrome , fractional flow reserve across the lesion, plaque burden, total plaque volume, low-attenuation plaque volume, and averaged percent total myocardial blood flow were found to be the best predictive features.
During the last decade, an extensive amount of literature has confirmed a high sensitivity, specificity, and diagnostic accuracy of coronary CT angiography (CCTA) for anatomical and functional assessment of coronary atherosclerosis. ,, Additionally, AI-based coronary computed tomography angiography (CCTA) quantification and characterization of atherosclerosis have demonstrated strong agreement with IVUS reference standard measurements. Unlike IVUS, CCTA carries no additional risks such as dissection, perforation, arrhythmia, thrombosis, or vasospasm. Therefore, in the context of primary prevention for patients at high risk of cardiovascular events, invasive imaging techniques might not be feasible, and the use of CCTA-derived quantification of atherosclerosis is a clinically appropriate and reliable diagnostic approach.”
In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), a prospective study in the general population, CCTA detected atherosclerosis in 42.1% of a population comprising more than 25,000 individuals without heart disease. In particular, the results of the CONFIRM registry, a large, international multicenter study, confirmed that CCTA has a leading role in mid-term prediction of all-cause mortality among >23,000 individuals without known coronary artery disease (CAD). Nonobstructive and obstructive CAD diagnosed by CCTA were associated with higher rates of myocardial infarction (MI) and mortality. ,,
The CT-LeSc was developed to semi-quantitatively assess total coronary atherosclerotic burden on CCTA. The CT-LeSc is based on three sets of weighting factors: localization of plaque accounting for dominance, type of plaque based on calcification presence, and degree of stenosis (<50% or >50%). CT-LeSc > 5 has been reported as an independent predictor of cardiac events (i.e., cardiac death, acute coronary syndrome, and all-cause mortality) over long-term follow-up. Patients with NOCAD exhibiting CT-LeSc scores >5 present a CV risk analogous to those with obstructive CAD. When coronary obstruction is <50% or ≥50% but not physiologically significant (CCTA derived fractional flow reserve [FFR CT ] ≥0.76), percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) is not recommended.
Current guidelines endorse CCTA for risk assessment and patient monitoring at high risk. ,, Integrating CCTA outcomes in LDL-C reduction trials provides a powerful visual tool, potentially enhancing long-term adherence among patients with NOCAD.
Despite guideline defined and recommended LDL-C goals per CV risk and a scientific consensus around LDL-C reduction “earlier and lower is better,” a majority of patients does not reach their LDL-C goal with insufficient reduction of their cumulative LDL-C exposure for adequate ASCVD prevention. However, recent scientific advances over the past five years have enabled the development of practical strategies for reducing cumulative LDL-C exposure to prevent ASCVD. The approval of novel therapies that achieve substantial and sustained LDL-C reductions has paved the way to a potential strategy to prevent ASCVD events by maintaining low LDL-C levels and slow atherosclerosis progression and benefitting from improved dosing options of these escalation therapy options. , Inclisiran, a first-in-class small-interfering ribonucleic acid (siRNA) therapy that targets hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA) to reduce LDL-C levels, offers an alternative approach with twice-yearly dosing (after an initial and 3 month dose) for effective, sustained and long-term LDL-C reduction alongside demonstrating a well-tolerated safety and tolerability profile when used as an adjunct to maximally tolerated statins. ,, Inclisiran efficiently reduces LDL-C levels by an estimated approximately 50%. ,,
In this manuscript, we describe the study design of VICTORION-PLAQUE. This study aims to evaluate the efficacy of inclisiran, when compared with placebo, on top of maximally tolerated statin therapy with or without other lipid-lowering therapy in reducing total coronary atheroma volume (TAV) and atheroma compositional changes assessed by CCTA in patients diagnosed with NOCAD.
Methods
Study population
Patients presenting to the outpatient clinic with chest pain and suspected coronary artery disease (CAD), as well as those with established risk factors for CAD—including first-degree relatives of individuals with CAD, current smokers, and individuals with a history of diabetes mellitus, hypertension, or dyslipidaemia—underwent coronary computed tomography angiography (CCTA) for CAD screening. Patients meeting predefined inclusion criteria were subsequently enrolled in the study. Eligible participants included male and female patients aged ≥18 to ≤80 years with a diagnosis of NOCAD without previous CV events, uncontrolled LDL-C (≥55 mg/dL [1.4 mmol/L]), no ischemia as documented by FFR CT (FFR CT ≥ 0.76) and a CT-LeSc of >5 despite receiving maximally tolerated statin therapy with or without other lipid-lowering therapy (aligned with the indication as mentioned in the contemporary label of inclisiran at the time of designing the study). If applicable, patients were also receiving an additional LLT (except anti-PCSK9 monoclonal antibody) in combination with a stable dose of statin for at least 30 days prior to screening. The complete list of inclusion criteria is provided in Tables 1 , and 2 .
Table 1
List of inclusion criteria.
| Inclusion criteria |
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Table 2
Study objectives and related endpoints.
| Objective(s) | Endpoint(s) |
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| Primary objective(s) | Endpoint(s) for primary objective(s) |
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| Secondary objective(s) | Endpoint(s) for secondary objective(s) |
| Efficacy secondary objectives | |
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| Safety secondary objective | |
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CCTA, coronary computed tomography angiography; CV, cardiovascular; FFR ct , fractional flow reserve– computed tomography; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); SAE, serious adverse event; SAP, statistical analysis plan; TEAE, treatment-emergent adverse event;
Briefly, patients diagnosed with NOCAD without previous CV events are included. Conversely, patients with a history of prior MI, coronary revascularization, ischemic cerebrovascular events, or peripheral artery disease are excluded from the trial. A detailed list of exclusion criteria is provided in YY.
Material online, Supplementary Table I. Pretest probability for CAD will be calculated after obtaining patient consent and trial enrolment, with the score recorded as a baseline parameter.
Aligning with the 2022 CAD-RADS 2.0 guidelines, recent amendments to the study design protocol have updated the eligibility criteria. The updated imaging criteria reflect the NOCAD patient population defined by a visual diameter stenosis of <50% and require baseline CCTA and a CT-LeSc of >5. Additionally, the visual diameter stenosis threshold for left main disease was reduced from ≥50% to ≥40%, and the duration of statin observations was extended by up to 4 weeks, showing additional benefits from further LDL-C lowering. The threshold for ischemia was also lowered from <0.80 to <0.76 for lesions with a visual diameter stenosis of ≥50% . , For cases where the FFR CT falls between ≥0.76 and 0.80, participant eligibility is determined by the Imaging Core Lab, taking into account factors such as the lesion’s location, proximality, delta FFR CT and diffuseness of coronary artery disease.
Study site selection and compliance
A site feasibility survey was conducted to evaluate sites’ readiness for a clinical trial by gathering information on the Principal Investigator’s (PI) qualifications and experience, staff availability, and technical capabilities, especially regarding computed tomography (CT) scanners for cardiac imaging. Key considerations, included the volume of cardiac CT scans performed, the prevalence of nonobstructive coronary artery disease (CAD), the use of contrast agents, and the feasibility of follow-up cardiac CT scans and sample collection for site inclusion.
To ensure consistency across multiple centers, CT scanner specifications were enforced. Additionally, an imaging guide was issued providing clear guidelines on performing a CCTA, submitting images, and receiving assessments of the Imaging Core Lab. Sites submitted anonymized test images to the Imaging Core Lab for approval, ensuring accurate and consistent coronary imaging assessments throughout the study. At the baseline visit, CCTA was performed to assess the CT-LeSc and FFR CT to confirm patient’s eligibility. A final CCTA is to be conducted at Month 24, integrating baseline and Month 24 data for analysis. Once approved, the standardized imaging protocol was programmed into the CT scanners for consistent application across all study patients.
Study design
The VICTORION-PLAQUE study ( ClinicalTrials.gov number: NCT05360446 ) is a 24-month multicenter, randomized, parallel-group, placebo-controlled, double-blind trial conducted in 18 countries (refer to Figures 1 and 2 and Supplementary material online, Supplementary Table II for further details).
VICTORION-PLAQUE: Participating countries.
Study design. The baseline CCTA visit *should not be performed until a participant has been on a stable dose of maximally tolerated statin therapy for at least 4 weeks (unless participant has documented statin intolerance or if the highest locally approved dose for one of stated statins is lower than the protocol-specified high-intensity statin dose or the national guideline recommends a lower dose than the protocol-specified high-intensity statin dose). ⁎⁎ Study drug is administered on Day 1, Day 90 (Month 3), Day 270 (Month 9), Day 450 (Month 15), and Day 630 (Month 21).– Solid line indicates mandatory study periods.– Dashed line only applies to participants not on the prespecified dose of high-intensity statin therapy at the time of the screening visit, who need to enter the statin optimization period. △ Open triangles are telephone visits. △ Pattern triangles are hybrid trial design visits, where off-site visits may occur if needed by the protocol and allowed by national and local/site regulations. Otherwise, physical on-site visits will be performed if mandated by national and local/site regulations and by the protocol. ▲ Solid triangles are physical, in-person visits at the study site.
This study includes a one-week screening period to evaluate inclusion and exclusion criteria, during which a fasting blood sample is collected to measure LDL-C, estimated glomerular filtration rate (eGFR), liver function tests, and creatine kinase (CK). At screening, participants are assigned a unique identification number via an interactive response technology (IRT) system, and their current use of statins and LLT is recorded. Participants not receiving a maximally tolerated dose of high-intensity statin therapy (defined as atorvastatin ≥40 mg once a day [QD] or rosuvastatin ≥20 mg QD) without documented statin intolerance during the screening period proceed to a 5- to 7-week statin optimization period. During statin optimization period, the investigator prescribes either atorvastatin (≥40 mg/day) or rosuvastatin (≥20 mg/day), depending on local availability at investigator’s discretion. This period involves three visits (two telephonic and one in-person) to monitor statin tolerance and to adjust statin dosage, if necessary. After completing the screening and statin optimization period (if required), eligible participants transition to a baseline period, during which participants undergo CCTA. The baseline period may be extended by 2 weeks to allow for repeat imaging if there are quality issues with the images. A CCTA obtained as part of the routine clinical care within the previous 3 months of the participants screening visit can also be used as a baseline image and sent to the Imaging Core Lab for evaluation. Participant eligibility is confirmed based on assessments of the CT-LeSc and/or FFR CT .
Eligible participants who meet all entry criteria after the baseline period ( Figure 3 ) are randomized in a 1:1 ratio to receive either a subcutaneous injection of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) or a matching placebo on Day 1, at Month 3 and then every six-month until Month 21 in addition to maximally tolerated statin therapy. The Interactive Response Technology (IRT)-based assignment of randomization numbers is stratified by country and by the prior use of maximally tolerated statin dose for at least 4 weeks or documented statin intolerance prior to the statin optimization period (yes/no). The double-blind treatment period spans of 24 months and concludes in a follow-up CCTA. A safety follow-up phone visit is conducted within 30 days after the final study visit to record any serious adverse events (SAEs) experienced by participants. All study sponsor personnel directly overseeing the conduct and management of the trial, as well as the investigator, study site personnel and participants, remain blinded to the treatment throughout the study. The study design is illustrated in Figure 2 .
