Coronary Computed Tomography Study to Assess the Effect of Inclisiran in Addition to Maximally Tolerated Statin Therapy on Atherosclerotic Plaque Progression in Participants With a Diagnosis of Non-obstructive Coronary Artery Disease Without Previous Cardiovascular Events

Study Overview
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Brief Summary
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CKJX839D12303 is a research study to determine if the study treatment, called inclisiran, in comparison to placebo taken in addition to statin medication can effectively reduce the total amount of plaque formed in the heart's vessels as measured by coronary computed tomography angiography (CCTA) from baseline to month 24. This study is being conducted in eligible participants with a diagnosis of non-obstructive coronary artery disease (NOCAD), where the coronary arteries are blocked less than 50%, and with no previous cardiovascular events.

Detailed Description
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The purpose of this study is to evaluate the efficacy of inclisiran compared to placebo on top of maximally tolerated statin therapy in reducing total coronary atheroma volume assessed by coronary computed tomography angiography from baseline to month 24 in participants with a diagnosis of NOCAD without previous cardiovascular events, a CT-adapted Leaman score >5 and a FFRct >0.8. Participants will either receive inclisiran 300 mg subcutaneously administered on Day 1, Month 3 (Day 90), and every 6 months up until Month 21. The study duration is 24 months. Participants will have a CCTA performed at baseline and at the month 24/end of study visit.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel-group Phase IIIb Study Evaluating the Effect of Inclisiran on Atherosclerotic Plaque Progression Assessed by Coronary Computed Tomography Angiography (CCTA) in Participants With a Diagnosis of Non-obstructive Coronary Artery Disease Without Previous Cardiovascular Events (VICTORION-PLAQUE)

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Inclisiran sodium 300 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 years or ≤80 years of age at signing of informed consent. Fasting LDL-C local lab value at the Screening Visit of either i) ≥100 mg/dL if on statin therapy but not on a maximally tolerated statin therapy; ii) ≥150 mg/dL if statin naive and without documented statin intolerance; or iii) ≥70 mg/dL if on a stable (≥4 weeks) dose of maximally tolerated statin therapy or if statin intolerant. Participants may be pre-identified based on a CCTA or an invasive angiography that is performed as part of standard of care within 12 months prior to the participant's Screening Visit demonstrating: Presence of coronary artery plaque with visual diameter stenosis <50% or Coronary artery plaque with visual artery stenosis >50% but Fractional Flow Reserve (FFR) >0.8 by special wire measurement (CCTA or coronary angiography) Fasting LDL-C local lab value ≥70 mg/dL at the assessment performed during the Statin Optimization Period 3 Visit for participants going through the Statin Optimization Period. Participants having Non-Obstructive Coronary Artery (NOCA)* confirmed by CCTA with FFRct >0.8 and CT-adapted Leaman score >5** or coronary artery plaque with visual diameter stenosis >50% but with FFRct >0.8 and CT-adapted Leaman score >5 without previous cardiovascular events. *=NOCA is defined as the presence of coronary artery plaque with visual diameter stenosis <50%. **=CT-adapted Leaman score, which includes information on lesion localization, plaque composition, degree of stenosis by CCTA is demonstrated to be an independent long-term predictor of hard cardiac events. A standard of care CCTA may serve as the study baseline CCTA scan if it is performed within 3 months prior to the participant's Screening Visit and meets the inclusion criteria of FFRct >0.8 and CT-adapted Leaman score >5, which will be assessed by the Imaging Core Lab. At the Baseline Visit, participants must be on a stable (≥4 weeks) dose of maximally tolerated statin therapy. Participants not on maximally tolerated statin therapy and who do not have documented statin intolerance can be screened but must enter the study via a Statin Optimization Period. Exclusion Criteria: Previous cardiovascular events history including myocardial infarction (MI), or prior coronary revascularization [percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)]. Planned revascularization (PCI) or (CABG). Previous cerebrovascular events including: Prior ischemic stroke thought not to be caused by atrial fibrillation, valvular heart disease or mural thrombus. History of prior percutaneous or surgical carotid artery revascularization. History of Peripheral Artery Disease (PAD): Prior documentation of a resting ankle-brachial index <0.85. History of prior percutaneous or surgical revascularization of an iliac, femoral, or popliteal artery. Prior non-traumatic amputation of a lower extremity due to peripheral artery disease. Cardiac disorders, including any of the following: Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, atrial fibrillation) within 3 months prior to randomization that is not controlled by medication or via ablation at the time of the Screening Visit. Complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third-degree AV block) prior to randomization. NOCA participant who was prescreened by the Investigator with visual diameter stenosis >50% but FFR <0.8. Contraindication for CCTA (e.g., allergic reactions to the contrast dye) or CCTA not meeting entry standards after two attempts during the Baseline CCTA Visit as assessed by the Imaging Core Lab. Pacemaker or implantable cardioverter-defibrillator (ICD) in situ. Systolic Left Ventricle Ejection Fraction <30% at the Screening Visit. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization (assessed at the Screening Visit) despite antihypertensive therapy. Heart failure New York Heart Association (NYHA) class III or class IV at the Screening Visit. Renal insufficiency (eGFR <30 mL/min/1.73m2) as measured by the Modification of Diet in Renal Disease (MDRD) formula at the Screening Visit and at the Statin Optimization 3 Visit. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver at the Screening Visit. Participants who enter the Statin Optimization Period must have AST and ALT ≤3x ULN (as defined by local laboratory reference ranges collected at the Screening Visit) and reported by the Statin Optimization Telephone Visit 1 to be allowed to continue in the Statin Optimization Period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-center, randomized, double-blind, placebo-controlled, parallel-group
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subcutaneous injection | Drug: Placebo<br>* Subcutaneously administered on Day 1, Month 3 (Day 90), and every 6 months thereafter.<br>|
| Experimental: Inclisiran sodium<br>Subcutaneous injection | Drug: Inclisiran sodium 300 mg<br>* Subcutaneously administered on Days 1, Month 3 (Day 90), and every 6 months thereafter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change in total coronary atheroma volume | Evaluating inclisiran compared to placebo both on top of maximally tolerated statin therapy in reducing total coronary atheroma volume assessed by coronary computed tomography angiography (CCTA) in participants with a diagnosis of non-obstructive coronary artery disease (NOCAD) without previous cardiovascular events. | From baseline to month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change in LDL-C | Full fasting lipid panel will be collected throughout the study beginning at baseline. | From baseline to month 24 | 
| Percentage change in low attenuation plaque volume evaluated by CCTA | Evaluating inclisiran compared to placebo in percentage change in low attenuation plaque volume evaluated by CCTA. | From baseline to month 24 | 
| Percentage of participants with progression, regression, or no change of total plaque atheroma volume | Evaluating inclisiran compared to placebo in percentage of participants experiencing progression, regression, or no change of total atheroma volume. | From baseline to month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inclisiran, KJX839, Atherosclerotic plaques, CCTA, CT-adapted Leaman score, LDL-C, FFRct, NOCAD, PCSK9 inhibitor, TAV