E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-obstructive coronary artery disease |
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E.1.1.1 | Medical condition in easily understood language |
atherosclerotic plaque (fatty deposits that can lead to heart disease) in the heart with less than 50% obstruction of blood flow |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011078 |
E.1.2 | Term | Coronary artery disease |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Inclisiran compared to placebo, on top of maximally tolerated statin therapy, in reducing the total coronary atheroma volume assessed by CCTA from baseline to month 24 |
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E.2.2 | Secondary objectives of the trial |
- Inclisiran compared to placebo, administered on top of maximally tolerated statin therapy, in reducing the LDL-C from baseline to month 24 - Inclisiran compared to placebo in percentage change in low attenuation plaque volume evaluated by CCTA - Inclisiran compared to placebo in percentage of participants experiencing progression, regression, or no change of total plaque atheroma volume (progression, regression, or no change will be defined in the SAP) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained before any assessment is performed. 2. Male or female ≥18 years or ≤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 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. 4. 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) 5. 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. 6. Participants having 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. 7. 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. |
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E.4 | Principal exclusion criteria |
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. NOCA participant who was prescreened by the Investigator with visual diameter stenosis >50% but FFR <0.8. 7. 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. 8. Pacemaker or implantable cardioverter-defibrillator (ICD) in situ. 9. Systolic Left Ventricle Ejection Fraction <30% at the Screening Visit. 10. 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. 11. Heart failure New York Heart Association (NYHA) class III or class IV at the Screening Visit. 12. 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. 13. 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.
Please refer to Section 5.2 of the study protocol for the complete list of exclusion criteria
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage change from baseline to month 24 in total coronary atheroma volume |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to month 24. |
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E.5.2 | Secondary end point(s) |
-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 of total plaque atheroma volume |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to month 24. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
Chile |
China |
India |
Japan |
Korea, Republic of |
United States |
Belgium |
France |
Germany |
Hungary |
Ireland |
Italy |
United Kingdom |
Spain |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |