Study of Efficacy and Safety of Inclisiran in Japanese Participants With High Cardiovascular Risk and Elevated LDL-C

Phase 2

Completed

• Conditions: Hypercholesterolemia; Heterozygous Familial Hypercholesterolemia
• Interventions: Drug: Inclisiran sodium; Drug: Placebo

• Registration Number: NCT04666298
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

This was a placebo-controlled, double-blind, randomized trial in Japanese participants with history of coronary artery disease (CAD) or participants categorized in 'high risk' by JAS 2017 guideline, or Japanese participants with heterozygous familial hypercholesterolemia (HeFH) and elevated Low-density lipoprotein cholesterol (LDL-C) despite maximum tolerated dose of statin(s) to evaluate the efficacy, safety, tolerability, and PK of subcutaneous inclisiran injection(s).

Detailed Description

The expected duration of the participants' involvement in the study was approximately 374 days which included screening (up to 14 days), Day 1 study drug administration, two additional injections on Day 90 and Day 270, and the follow-up period to Day 360.

The primary analysis was conducted after all participants had finished Day 180 visit assessments or discontinued before Day 180 visit.

After the primary analysis, double-blind treatment period were maintained to Day 360, although specific sponsor members (except for blinded monitors) were unblinded for the regulatory submission in Japan.

Study Timeline

• Study First Submitted: 2020-12-07
• Study First Submitted QC: 2020-12-07
• Study First Posted: 2020-12-14
• Study Start: 2021-01-29
• Primary Completion: 2022-04-18
• Study Completion: 2022-10-19
• Results First Submitted: 2023-04-17
• Results First Submitted QC: 2023-04-17
• Results First Posted: 2023-05-10
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-17
• Last Update Posted: 2024-06-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 312

Inclusion Criteria

• Participants with history of CAD or participants categorized in 'high risk' by Japan Atherosclerosis Society (JAS) 2017 guidelines or participants with heterozygous familial hypercholesterolemia (HeFH)
• As per the JAS 2017 guideline, participants not meeting the LDL-C management targets.
• Participants on statins should be receiving a maximally tolerated dose.
• Participants not receiving statins must have documented evidence of intolerance to at least one statin.
• The lipid-lowering therapy should have remained stable for ≥ 30 days before screening with no planned medication/ dose change until Day 180

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Exclusion Criteria

• Participants diagnosed with homozygous familial hypercholesterolemia (HoFH).
• Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9.
• New York Heart Association (NYHA) class IV heart failure or last known left ventricular ejection fraction <25%.
• Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation.
• Uncontrolled hypertension: systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg prior to randomization despite antihypertensive therapy.
• Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), >3x the upper limit of normal (ULN), or total bilirubin >2x ULN at screening.
• Severe concomitant non-cardiovascular disease that carries the risk of reducing life expectancy to less than 2 years.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
300 mg inclisiran sodium	Inclisiran sodium	Subcutaneous injection
200 mg inclisiran sodium	Inclisiran sodium	Subcutaneous injection
100 mg inclisiran sodium	Inclisiran sodium	Subcutaneous injection
Placebo	Placebo	Subcutaneous injection

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) to Day 180	Baseline, Day 180	Percent change from baseline in LDL-C was calculated to evaluate the effect of inclisiran at Day 180.; Difference between different inclisiran dose groups and the placebo group in percentage change in LDL-C levels from baseline to Day 180 were calculated to capture both, the effect of the study drug and the effect of additional medications, mirroring the conditions in clinical practice.; An MMRM (Mixed-effect Model with Repeated Measurement) was used as the primary analysis model, with treatment group, visits, interaction between visits and treatment groups, current use of statins or other lipid-modifying therapies as fixed effects, and baseline LDL-C as a continuous covariate.

Secondary Outcome Measures

Name	Time	Method
Absolute Change in LDL-C From Baseline at Day 180	Baseline, Day 180	Absolute change from baseline in low-density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran until Day 180.
Proportion of Participants With LDL-C Greater Than 80% of Baseline Value at Day 180	Baseline, Day 180	Proportion of participants with LDL-C greater than 80% of baseline value at Day 180 was calculated to evaluate the effect of inclisiran until Day 180.; Subjects are counted if the LDL-C value is greater than '0.8\*(LDL-C at Baseline - LDL-C at Day180) + LDL-C at Day180', or the LDL-C value is greater than or equal to the LDL-C at Baseline.
Proportion of Participants With Greater or Equal to 50% LDL-C Reduction From Baseline by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Proportion of participants with greater or equal to 50% LDL-C reduction from baseline was calculated to evaluate the effect of inclisiran over time.
Percent Change From Baseline in Non-HDL Cholesterol by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Percent change from baseline in non-HDL Cholesterol by visit was calculated to evaluate the effect of inclisiran over time
Percent Change From Baseline in PCSK9 by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Percent change from baseline in proprotein convertase subtilisin/kexin type 9 (PCSK9) was calculated to evaluate the effect of inclisiran over time.
Percent Change From Baseline in Cholesterol by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Percent change from baseline in cholesterol by visit was calculated to evaluate the effect of inclisiran over time
Percent Change From Baseline in Triglycerides by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Percent change from baseline in triglycerides by visit was calculated to evaluate the effect of inclisiran over time
Percent Change From Baseline in Apo- A1 by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Percent change from baseline in Apolipoprotein A1 (Apo-A1) by visit was calculated to evaluate the effect of inclisiran over time
Percent Change From Baseline in Lipoprotein-a by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Percent change from baseline in Lipoprotein a (LP(a)) by visit was calculated to evaluate the effect of inclisiran over time
Percent Change From Baseline in LDL-C by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120 and day 150	Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran over time.
Proportion of Participants Who Attain Lipid Control Target Pre-specified by JAS 2017 Guidelines for Their Level of Cardiovascular Risk at Day 180	Day 180	Proportion of participants who attain lipid control target pre-specified by Japan Atherosclerosis Society(JAS) 2017 guidelines for their level of cardiovascular risk at Day 180 was calculated to evaluate the effect of inclisiran.
Percent Change From Baseline in HDL Cholesterol by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Percent change from baseline in high-density lipoprotein cholesterol (HDL-C) by visit was calculated to evaluate the effect of inclisiran over time
Percent Change From Baseline in VLDL-C by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Percent change from baseline in very low-density lipoprotein cholesterol (VLDL - C) by visit was calculated to evaluate the effect of inclisiran over time
Percent Change From Baseline in Apo- B by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Percent change from baseline in Apolipoprotein B (Apo-B) by visit was calculated to evaluate the effect of inclisiran over time
Number of Participants With LDL-C Levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL by Visit	Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180	Number of participants by LDL-C levels was calculated to evaluate the effect of inclisiran.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇯🇵 Saga, Japan