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

Hypercholesterolemia Clinical Trial

— ORION-15  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04666298
• Other study ID #: CKJX839A11201
• Status: Completed
• Phase: Phase 2
• Start date: January 29, 2021
• Est. completion date: October 19, 2022

Study information

• Verified date: April 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 312
• Est. completion date: October 19, 2022
• Est. primary completion date: April 18, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Heterozygous Familial Hypercholesterolemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

Drug:
• Inclisiran sodium
Subcutaneously injected on Day 1, 90 and 270.
• Placebo
Subcutaneously injected on Day 1, 90, and 270.

Locations

Country	Name	City	State
Japan	Novartis Investigative Site	Chiyoda	Tokyo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Chuoh-ku
Japan	Novartis Investigative Site	Fujisawa-city	Kanagawa
Japan	Novartis Investigative Site	Gifu
Japan	Novartis Investigative Site	Iruma-gun	Saitama
Japan	Novartis Investigative Site	Itoshima	Fukuoka
Japan	Novartis Investigative Site	Izumisano-city	Osaka
Japan	Novartis Investigative Site	Kahoku-gun	Ishikawa
Japan	Novartis Investigative Site	Kanazawa	Ishikawa
Japan	Novartis Investigative Site	Kanazawa-city	Ishikawa
Japan	Novartis Investigative Site	Kawasaki-city	Kanagawa
Japan	Novartis Investigative Site	Kitakyushu	Fukuoka
Japan	Novartis Investigative Site	Kitakyushu	Fukuoka
Japan	Novartis Investigative Site	Kitakyushu	Fukuoka
Japan	Novartis Investigative Site	Kitakyushu-city	Fukuoka
Japan	Novartis Investigative Site	Komatsu	Ishikawa
Japan	Novartis Investigative Site	Kuse	Kyoto
Japan	Novartis Investigative Site	Kyoto
Japan	Novartis Investigative Site	Matsubara-city	Osaka
Japan	Novartis Investigative Site	Matsudo city	Chiba
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Nakagawa	Fukuoka
Japan	Novartis Investigative Site	Nerima-ku	Tokyo
Japan	Novartis Investigative Site	Oita
Japan	Novartis Investigative Site	Omura	Nagasaki
Japan	Novartis Investigative Site	Osaka city	Osaka
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	Saga
Japan	Novartis Investigative Site	Sapporo	Hokkaido
Japan	Novartis Investigative Site	Sapporo-city	Hokkaido
Japan	Novartis Investigative Site	Sashima-gun	Ibaraki
Japan	Novartis Investigative Site	Sayama-city	Saitama
Japan	Novartis Investigative Site	Sendai	Miyagi
Japan	Novartis Investigative Site	Shinagawa-ku	Tokyo
Japan	Novartis Investigative Site	Shinjuku ku	Tokyo
Japan	Novartis Investigative Site	Suita	Osaka
Japan	Novartis Investigative Site	Suita-city	Osaka
Japan	Novartis Investigative Site	Takamatsu city	Kagawa
Japan	Novartis Investigative Site	Tsuchiura	Ibaraki

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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