Phase IIIb Randomized Study of Inclisiran on Atherosclerotic Plaque Progression in Non-obstructive Coronary Artery Disease with Statin Therapy

Trial ID: 2024-511126-31-00
Protocol: CKJX839D12303
Sponsor: Novartis Pharma AG

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Diseases & Conditions

Coronary artery disease

Objectives

The primary objective of this study is to demonstrate the superiority of **inclisiran** versus placebo, administered on top of maximally tolerated statin therapy, in reducing the total coronary atheroma volume assessed by coronary computed tomography angiography (CCTA) from baseline to Month 24. This is clinically relevant as it aims to address the progression of atherosclerotic plaque in patients with non-obstructive coronary artery disease, potentially reducing the risk of future cardiovascular events.

Secondary objectives include: - Demonstrating the superiority of inclisiran versus placebo in reducing LDL-C from baseline to Month 24. - Evaluating inclisiran versus placebo in percentage change in low attenuation plaque volume evaluated by CCTA. - Evaluating inclisiran versus placebo in the percentage of participants experiencing progression, regression, or no change of total plaque atheroma volume. - Assessing the safety and tolerability profile of inclisiran.

Participants

The clinical trial involves a total of **355 participants** diagnosed with **Non-obstructive Coronary Artery Disease**. The study population includes both male and female subjects, aged between 18 and 80 years. Participants were selected based on specific criteria, including their fasting LDL-C levels and their status regarding statin therapy. The trial population is characterized by individuals who are on a stable dose of maximally tolerated statin therapy or those who are statin naive but meet the LDL-C criteria. Lifestyle considerations such as diet and physical activity are not explicitly detailed in the trial data. The study includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants. The selection process ensures that participants have not experienced previous cardiovascular events, aligning with the study's focus on individuals with non-obstructive coronary conditions.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled, parallel-group Phase IIIb study. The primary objective is to evaluate the effect of **inclisiran** on atherosclerotic plaque progression in participants diagnosed with non-obstructive coronary artery disease (NOCAD) without previous cardiovascular events. The trial will assess the superiority of inclisiran versus placebo, administered alongside maximally tolerated statin therapy, in reducing total coronary atheroma volume as measured by coronary computed tomography angiography (CCTA) from baseline to Month 24. The trial is expected to conclude by September 2026, with recruitment having commenced in November 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, fasting LDL-C levels, and the presence of NOCAD. Following the screening, eligible participants will enter a statin optimization period if not already on a stable dose of maximally tolerated statin therapy. The baseline visit will mark the start of the treatment phase, where participants will be randomized to receive either inclisiran or placebo. Subsequent follow-up visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will occur at Month 24, where the final assessments will be conducted to evaluate the primary and secondary endpoints, including changes in LDL-C levels and plaque volume.

The expected duration of participant involvement is approximately 24 months, aligning with the trial's primary endpoint assessment timeline. Conditions that may lead to early termination from the study include the occurrence of serious adverse events (SAEs) related to the study drug, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial will ensure rigorous monitoring and adherence to ethical standards throughout its duration to safeguard participant well-being and data integrity.

Treatment

The clinical trial involves the administration of several treatments, including **rosuvastatin**, **inclisiran**, and **atorvastatin**, as well as a placebo. **Rosuvastatin** is provided in the form of a tablet, with a maximum daily dose of 40 mg and a total maximum dose of 31,320 mg over a treatment period of 111 days. The route of administration is oral. The active substance, rosuvastatin, is of chemical origin. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Inclisiran** is administered as a solution for injection, with a maximum daily dose of 300 mg and a total maximum dose of 1,500 mg over a treatment period of 24 months. The route of administration is subcutaneous, utilizing a pre-filled syringe. The active substance, inclisiran, is of nucleic acid origin. The clinical dossier includes alternative packaging sites for clinical trial supplies, which are not part of the marketing authorization dossier. The drug substance has a retest period of 36 months, and the drug product has a shelf life of 36 months.

**Atorvastatin** is also provided in tablet form, with a maximum daily dose of 80 mg and a total maximum dose of 62,640 mg over a treatment period of 111 days. The route of administration is oral. The active substance, atorvastatin, is of chemical origin. Participant compliance with the dosing schedule will be monitored throughout the trial.

The placebo used in the trial is a solution for injection in a pre-filled syringe, designed to match the administration of inclisiran. It contains no active substance and is used to maintain the double-blind nature of the study. The placebo is administered subcutaneously, and participant compliance with the dosing schedule will be monitored throughout the trial.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the **percentage change from baseline to Month 24 in total coronary atheroma volume**. This will be evaluated using coronary computed tomography angiography (CCTA). Secondary endpoints include the percentage change in LDL-C from baseline to Month 24, the percentage change in low attenuation plaque volume evaluated by CCTA, and the percentage of participants with progression, regression, or no change of total plaque atheroma. Additionally, the incidence, severity, and relationship to the study drug of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) will be monitored.

The primary and secondary endpoints will be measured at specified timepoints, with the primary endpoint being assessed at Month 24. The trial will utilize validated imaging techniques and laboratory tests to ensure accurate and consistent data collection across study sites. The trial is designed to demonstrate the superiority of inclisiran versus placebo, administered on top of maximally tolerated statin therapy, in reducing coronary atheroma volume in participants with non-obstructive coronary artery disease (NOCAD) without previous cardiovascular events.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent must be obtained before any assessment is performed.
Male or female ≥ 18 to ≤ 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 (2.6 mmol/L) if on statin therapy but not on a maximally tolerated statin therapy; ii) ≥150 mg/dL (3.9 mmol/L) if statin naive and without documented statin intolerance; or iii) ≥55 mg/dL (1.4 mmol/L) if on a stable (≥4 weeks) dose of maximally tolerated statin therapy or if statin intolerant. Local laboratory values should be calculated using the Friedewald formula for consistency across study sites if the Screening visit occurs prior to the Baseline CCTA Visit. If the Screening and Baseline Visits occur on the same day, then the LDL-C value will be assessed on the central laboratory sample. If the center can only perform the direct LDL-C test, then the local lab should also obtain the total cholesterol, HDL-C, and triglycerides results so that the LDL-C can be calculated using the Friedewald estimation..
Fasting LDL-C local lab value ≥55 mg/dL (1.4 mmol/L) at the assessment performed during the Statin Optimization Period 3 Visit for participants going through the Statin Optimization Period. Local laboratory values should be calculated using the Friedewald formula for consistency across study sites. If the center can only perform the direct LDL-C test, then the local lab should also obtain the total cholesterol, HDL-C, and triglycerides results so that the LDL-C can be calculated using the Friedewald estimation.
Participants having NOCAD without previous cardiovascular events: NOCAD is defined as: 1) Participants with a CT-adapted Leaman score >5 and a diameter stenosis of <50%. OR 2) Participants with a CT-adapted Leaman score >5, a diameter stenosis ≥50%* but with FFRCT ≥0.76**. Notes: *=In case of left main CAD, diameter stenosis is ≥40%. **=In case of FFRCT between ≥0.76 and 0.80, participant eligibility will be assessed and determined by the Imaging Core Lab based on the location of the lesion, proximality of the lesion, delta FFRCT and diffuseness of coronary artery disease, (Cury et al 2022). FFRCT and CT-adapted Leaman score will be determined by the Imaging Core Lab. 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 as described above and as 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.
Fasting LDL-C lab value ≥55 mg/dL (1.4 mmol/L) at the Baseline Visit, measured at the central laboratory. If the Baseline and Screening Visits occur on the same day, then the LDL-C assessment will be assessed on the central laboratory sample. If a participant qualifies at Screening but the fasting central lab LDL-C value at the Baseline visit does not meet eligibility, then eligibility will be determined based on the central lab result.
Fasting triglycerides value <400 mg/dL (4.52 mmol/L) based on the local lab results at the Screening visit and on the central lab results at the CCTA Baseline Visit.

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Exclusion Criteria

Previous myocardial infarction (MI), or prior coronary revascularization [percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)].
Planned revascularization (PCI or CABG).
Previous ischemic cerebrovascular event 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.
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: mean systolic blood pressure >180 mmHg or mean 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 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3x upper limit of normal (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.
Local creatine kinase (CK) values of either, unless a more stringent threshold is mandated by a local regulatory authority (e.g., ≥3x ULN in Korea according to MFDS internal guideline): • CK values ≥5x ULN at the Screening Visit for participants on maximally tolerated statin therapy or who are statin intolerant. • CK values ≥5x ULN at Screening and before entering the Statin Optimization Period and confirmed by repeat test within 7 days at Screening or based on Investigator’s judgement for participants entering the Statin Optimization Period (who will be switched to or initiated on the protocol-specified dose of high-intensity statin of atorvastatin ≥40 mg QD or rosuvastatin ≥20 mg QD during the Statin Optimization Period).
Local CK values ≥5x ULN at the Statin Optimization 3 Visit unless a more stringent threshold is mandated by a local regulatory authority (e.g., ≥3x ULN in Korea according to MFDS internal guideline) and monitored according to national guidelines and statin label during the Statin Optimization Period
Participant with myopathy at the Statin Optimization 3 Visit.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	24 Nov 2022	27
France	Not Recruiting	24 Nov 2022	25
Hungary	Not Recruiting	24 Nov 2022	12
Ireland	Not Recruiting	24 Nov 2022	50
Italy	Not Recruiting	24 Nov 2022	25
Spain	Not Recruiting	24 Nov 2022	34

Sites & Investigators

Research sites

Hospital Vall d’Hebron IRCCS Humanitas Research Hospital Instituto Medico Quirurgico San Rafael S.A.Assistance Publique Hopitaux De Paris

Investigators

Bela M.Fabian D.Juan Carlos C. D.Lorenzo F. R.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
ROSUVASTATIN	Other	—	ORAL USE	40	111	SUB20634
ROSUVASTATIN	Other	—	ORAL USE	40	111	SUB20634
INCLISIRAN	Test	—	SUBCUTANEOUS USE	300	24	SUB182427
Placebo to KJX839 (Inclisiran sodium) 0 mg/1.5 mL solution for injection in pre-filled syringe	Placebo	N/A	—	—	—	N/A
ROSUVASTATIN	Other	—	ORAL USE	40	111	SUB20634
ATORVASTATIN	Other	—	ORAL USE	80	111	SUB05600MIG
ATORVASTATIN	Other	—	ORAL USE	80	111	SUB05600MIG
ROSUVASTATIN	Other	—	ORAL USE	40	111	SUB20634
ATORVASTATIN	Other	—	ORAL USE	80	111	SUB05600MIG
ATORVASTATIN	Other	—	ORAL USE	80	111	SUB05600MIG