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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Placebo-controlled, Double-blind, Randomized Trial to Evaluate the Effect of Different Doses of Inclisiran Given as Subcutaneous Injections in Japanese Participants With High Cardiovascular Risk and Elevated LDL-C

Conditions
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Hypercholesterolemia, Heterozygous Familial Hypercholesterolemia

Intervention / Treatment
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* Drug: Inclisiran sodium
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 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.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 300 mg inclisiran sodium<br>Subcutaneous injection | Drug: Inclisiran sodium<br>* Subcutaneously injected on Day 1, 90 and 270.<br>* Other names: KJX839;|
| Experimental: 200 mg inclisiran sodium<br>Subcutaneous injection | Drug: Inclisiran sodium<br>* Subcutaneously injected on Day 1, 90 and 270.<br>* Other names: KJX839;|
| Experimental: 100 mg inclisiran sodium<br>Subcutaneous injection | Drug: Inclisiran sodium<br>* Subcutaneously injected on Day 1, 90 and 270.<br>* Other names: KJX839;|
| Placebo Comparator: Placebo<br>Subcutaneous injection | Drug: Placebo<br>* Subcutaneously injected on Day 1, 90, and 270.<br>* Other names: KJX839 placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) to 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. | Baseline, Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in PCSK9 by Visit | Percent change from baseline in proprotein convertase subtilisin/kexin type 9 (PCSK9) was calculated to evaluate the effect of inclisiran over time. | Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180 | 
| Percent Change From Baseline in LDL-C by Visit | Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran over time. | Baseline, day 14, day 30, day 60, day 90, day 104, day 120 and day 150 | 
| Absolute Change in LDL-C From Baseline at Day 180 | Absolute change from baseline in low-density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran until Day 180. | Baseline, Day 180 | 
| Proportion of Participants With LDL-C Greater Than 80% of Baseline Value at 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. | Baseline, Day 180 | 
| Proportion of Participants With Greater or Equal to 50% LDL-C Reduction From Baseline by Visit | Proportion of participants with greater or equal to 50% LDL-C reduction from baseline was calculated to evaluate the effect of inclisiran over time. | 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 | Percent change from baseline in cholesterol by visit was calculated to evaluate the effect of inclisiran over time | 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 | Percent change from baseline in triglycerides by visit was calculated to evaluate the effect of inclisiran over time | Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180 | 
| Percent Change From Baseline in HDL Cholesterol by Visit | Percent change from baseline in high-density lipoprotein cholesterol (HDL-C) by visit was calculated to evaluate the effect of inclisiran over time | 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 | Percent change from baseline in non-HDL Cholesterol by visit was calculated to evaluate the effect of inclisiran over time | Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180 | 
| Percent Change From Baseline in VLDL-C by Visit | Percent change from baseline in very low-density lipoprotein cholesterol (VLDL - C) by visit was calculated to evaluate the effect of inclisiran over time | Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180 | 
| Percent Change From Baseline in Apo- A1 by Visit | Percent change from baseline in Apolipoprotein A1 (Apo-A1) by visit was calculated to evaluate the effect of inclisiran over time | Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180 | 
| Percent Change From Baseline in Apo- B by Visit | Percent change from baseline in Apolipoprotein B (Apo-B) by visit was calculated to evaluate the effect of inclisiran over time | 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 by Visit | Percent change from baseline in Lipoprotein a (LP(a)) by visit was calculated to evaluate the effect of inclisiran over time | Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180 | 
| Proportion of Participants Who Attain Lipid Control Target Pre-specified by JAS 2017 Guidelines for Their Level of Cardiovascular Risk at 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. | Day 180 | 
| Number of Participants With LDL-C Levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL by Visit | Number of participants by LDL-C levels was calculated to evaluate the effect of inclisiran. | Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inclisiran, siRNA, dyslipidemia, PCSK9, Hypercholesterolemia, LDL-C