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 (V-PLAQUE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

16 Aug 2022 → ongoing

Decision date (initial)

2024-07-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-511126-31-00

EudraCT number

2021-004601-47

ClinicalTrials.gov

NCT05360446

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

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 CCTA from baseline to Month 24.

Secondary objectives 4

1. Demonstrate the superiority of inclisiran versus placebo in reducing the LDL-C from baseline to Month 24
2. Evaluate inclisiran versus placebo in percentage change in low attenuation plaque volume evaluated by CCTA
3. Evaluate inclisiran versus placebo in percentage of participants experiencing progression, regression, or no change of total plaque atheroma volume
4. Assess the safety and tolerability profile of inclisiran

Conditions and MedDRA coding

Non-obstructive Coronary Artery Disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Written informed consent must be obtained before any assessment is performed.
2. Male or female ≥ 18 to ≤ 80 years of age at signing of informed consent.
3. 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..
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.

Exclusion criteria 15

1. Previous myocardial infarction (MI), or prior coronary revascularization [percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)].
2. Planned revascularization (PCI or CABG).
3. 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.
4. 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.
5. 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.
6. 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.
7. Pacemaker or implantable cardioverter-defibrillator (ICD) in situ.
8. Systolic Left Ventricle Ejection Fraction <30% at the Screening Visit.
9. 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.
10. Heart failure New York Heart Association (NYHA) class III or class IV at the Screening Visit.
11. 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.
12. 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.
13. 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).
14. 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
15. Participant with myopathy at the Statin Optimization 3 Visit.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage change from baseline to Month 24 in total coronary atheroma volume

Secondary endpoints 4

1. Percentage change in LDL-C from baseline to Month 24
2. Percentage change in low attenuation plaque volume evaluated by CCTA
3. Percentage of participants with progression, regression, or no change of total plaque atheroma
4. incidence, severity, and relationship to study drug of TEAEs and Serious Adverse Events (SAEs)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 11

Locations

6 EU/EEA countries · 27 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 43 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications