Study to understand if inclisiran is better than a placebo at lowering LDL-cholesterol, is safe and can have an impact on patient quality of life, when given along with other lipid lowering medications.

Phase 1

• Conditions: MedDRA version: 21.0Level: LLTClassification code 10020604Term: HypercholesterolemiaSystem Organ Class: 100000004861; Hypercholesterolemia; Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

• Registration Number: EUCTR2021-003759-40-LV
• Lead Sponsor: ovartis Pharma AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2022-06-14
• Last Update Posted: 9 January 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 1760

Inclusion Criteria

? Male or female participants =18 years of age.
? Participants meeting one of the following CV category:
?Very high risk participants with 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.

? High risk participants with the following:
? Markedly elevated single risk factors, in particular total cholesterol > 8mmol/L (>310 mg/dL), LDL-C > 4.9 mmol/dL (> 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 =1.4 mmol/l (=55 mg/dL).
? in participants with high cardiovascular risk: serum LDL-C =1.8 mmol/l (=70 mg/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 (< 4.52 mmol/L) at screening and baseline.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 792
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 968

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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 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);Secondary Objective: Inclisiran, on top of ongoing individually optimized LLT, compared to placebo, on top of ongoing individually optimized LLT, on:<br>•Reducing mean LDL-C levels over the double-blind study period.<br>•Muscle-related adverse events.<br>•Annualized number of days pain is experienced using a pain diary.<br>•Pain-related quality of life at day 360 using the Short-Form Brief Pain Inventory (SF-BPI). <br>;Primary end point(s): Proportion of participants achieving individual LDL-C target (< 55 mg/dL or < 70 mg/dL) at day 90;Timepoint(s) of evaluation of this end point: Day 90

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): •Relative change (percentage from baseline to mean LDL-C level) over the double-blind treatment period.<br>•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.<br>•Proportion of participants experiencing self-reported pain.<br>Annualized number of days participants experiencing self-reported pain from baseline to day 360.<br>•Change from baseline in SF-BPI pain severity score to day 360<br>Change from baseline in SF-BPI pain interference score to day 360.<br>Proportion of participants with clinically relevant change in SF-BPI pain severity score from baseline to day 360.<br>Proportion of participants with clinically relevant change in SF-BPI pain interference score from baseline to day 360.<br>;Timepoint(s) of evaluation of this end point: From baseline to day 360.