E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Hypercholesterolemia, specifically elevated low density lipoprotein cholesterol (LDL-C), is one of the major risk factors for the development of coronary heart disease (CHD) |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition 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, on top of ongoing individually optimized LLT, compared to placebo, on top of ongoing individually optimized LLT, on reaching a participant's individual LDL-C target as defined in 2019 ESC/EAS guidelines for the management of dyslipidemias (Mach et al 2020) |
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E.2.2 | Secondary objectives of the trial |
Inclisiran, on top of ongoing individually optimized LLT, compared to placebo, on top of ongoing individually optimized LLT, on: •Reducing mean LDL-C levels over the double-blind study period. •Muscle-related adverse events. •Annualized number of days pain is experienced using a pain diary. •Pain-related quality of life at day 360 using the Short-Form Brief Pain Inventory (SF-BPI). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
● Male or female participants ≥18 years of age. ● Participants meeting one of the following CV category: ●Very high risk participants with at least one of the following: ● Documented Atherosclerotic cardiovascular disease (ASCVD) i Acute coronary syndrome: Unstable angina or myocardial infarction. ii Stable angina. iii Coronary revascularization. iv Unequivocally documented ASCVD upon prior imaging. v Stroke and TIA. vi Peripheral artery disease (PAD). ● Diabetes mellitus (DM) with target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), or at least ≥ 3 major risk factors, or early onset of Type 1 DM of long duration (> 20 years). ● A calculated SCORE2 ≥ 7.5% for age <50 years; SCORE2 ≥10% for age 50-69 years; SCORE2-OP ≥15% for age ≥70 years to estimate 10- year risk of fatal and non-fatal cardiovascular disease (CVD). ● Pre-existing diagnosis of heterozygous familial hypercholesterolemia (HeFH) with ASCVD or with another major risk factor. OR ● High risk participants with at least one the following: ● Markedly elevated single risk factors, in particular total cholesterol >310 mg/dL, LDL-C > 190 mg/dL, or blood pressure ≥ 180/110 mmHg ● Pre-existing diagnosis of HeFH without other major risk factors. ● Diabetes Mellitus (DM) without target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), with DM duration ≥ 10 years or other additional risk factor. ● Moderate chronic kidney disease (eGFR 30-59 mL/min/1.73m2). ● A calculated SCORE2 2.5 to <7.5% for age < 50 years, SCORE2 5 to < 10% for age 50-69 years; SCORE2-OP 7.5 to < 15% for age ≥70 years to estimate 10-year risk of fatal and non-fatal CVD.
● LDL-C levels at screening and baseline: ● in participants with very high cardiovascular risk: serum LDL-C ≥=55mg/dL ● in participants with high cardiovascular risk: serum LDL-C ≥=70mg/dL. ● Participant on a stable dose of a statin for ≥ 30 days at screening. ● Participants on the individual MTD of statin for ≥ 30 days at baseline. ● Fasting triglyceride < 400 mg/dL at screening and baseline. |
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E.4 | Principal exclusion criteria |
● Participants on more than one other lipid-lowering drug on top of statin at screening visit. ● Participants with a known intolerance to rosuvastatin at screening or baseline visit. ● Previous (within 90 days of screening), current or planned treatment with a monoclonal antibody (mAb) directed towards PCSK9 (e.g. evolocumab, alirocumab) at screening or baseline visit. ● Previous exposure to inclisiran or any other non-mAb PCSK9 targeted therapy, either as an investigational or marketed drug within 2 years prior to screening or baseline visit. ● Previous, current or planned treatment with LDL-apheresis at screening or baseline visit. ● Liver and CK: (a) Active liver disease defined as any current infectious, neoplastic, or metabolic pathology of the liver or (b) unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST) elevation >3x ULN, or total bilirubin elevation > 2x ULN (except for participants with Gilbert's syndrome), or (c) creatine kinase (CK) >5x ULN at screening or baseline visit. ● Participant with severe renal impairment defined by eGFR <30 mL/min/1.73m2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula at screening or baseline visit. ● Acute coronary syndrome, ischemic stroke or TIA, coronary revascularization or peripheral arterial revascularization procedure or amputation due to atherosclerotic disease < 3 months prior to the screening or baseline visit. ● Heart failure New York Heart Association (NYHA) class IV at screening or baseline visit ● Pregnant or nursing (lactating) women at screening or baseline visit. ● Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing of study treatment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of participants achieving individual LDL-C target (< 55 mg/dL or < 70 mg/dL) at day 90 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Relative change (percentage from baseline to mean LDL-C level) over the double-blind treatment period. •Proportion of participants experiencing at least one muscle-related AE as defined in the Standardized MedDRA Queries (SMQ) rhabdomyolysis / myopathy from day 1 to day 360. •Proportion of participants experiencing self-reported pain. Annualized number of days participants experiencing self-reported pain from baseline to day 360. •Change from baseline in SF-BPI pain severity score to day 360 Change from baseline in SF-BPI pain interference score to day 360. Proportion of participants with clinically relevant change in SF-BPI pain severity score from baseline to day 360. Proportion of participants with clinically relevant change in SF-BPI pain interference score from baseline to day 360. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
quality of life; Tolerability |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 85 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 144 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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 | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |