Clinical trial NCT04666298: Study of Efficacy and Safety of Inclisiran in Japanese Participants With High Cardiovascular Risk and Elevated LDL-C
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypercholesterolemia
Heterozygous Familial Hypercholesterolemia
Keywords: inclisiran
siRNA
dyslipidemia
PCSK9
Hypercholesterolemia
LDL-C
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-12-14
Enrollment: 312
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) to Day 180
timeFrame: Baseline, Day 180
Secondary outcomes:
measure: Percent Change From Baseline in PCSK9 by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Percent Change From Baseline in LDL-C by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120 and day 150
measure: Absolute Change in LDL-C From Baseline at Day 180
timeFrame: Baseline, Day 180
measure: Proportion of Participants With LDL-C Greater Than 80% of Baseline Value at Day 180
timeFrame: Baseline, Day 180
measure: Proportion of Participants With Greater or Equal to 50% LDL-C Reduction From Baseline by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Percent Change From Baseline in Cholesterol by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Percent Change From Baseline in Triglycerides by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Percent Change From Baseline in HDL Cholesterol by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Percent Change From Baseline in Non-HDL Cholesterol by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Percent Change From Baseline in VLDL-C by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Percent Change From Baseline in Apo- A1 by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Percent Change From Baseline in Apo- B by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Percent Change From Baseline in Lipoprotein-a by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
measure: Proportion of Participants Who Attain Lipid Control Target Pre-specified by JAS 2017 Guidelines for Their Level of Cardiovascular Risk at Day 180
timeFrame: Day 180
measure: Number of Participants With LDL-C Levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL by Visit
timeFrame: Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180
Other outcomes:
Locations:
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Matsudo city
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Itoshima
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Kitakyushu-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Kitakyushu
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Kitakyushu
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Kitakyushu
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Nakagawa
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Sapporo-city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Sapporo
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Sashima-gun
country: Japan
facility: Novartis Investigative Site
state: Ibaraki
city: Tsuchiura
country: Japan
facility: Novartis Investigative Site
state: Ibaraki
city: Kahoku-gun
country: Japan
facility: Novartis Investigative Site
state: Ishikawa
city: Kanazawa-city
country: Japan
facility: Novartis Investigative Site
state: Ishikawa
city: Kanazawa
country: Japan
facility: Novartis Investigative Site
state: Ishikawa
city: Komatsu
country: Japan
facility: Novartis Investigative Site
state: Ishikawa
city: Takamatsu city
country: Japan
facility: Novartis Investigative Site
state: Kagawa
city: Fujisawa-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Kawasaki-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Kuse
country: Japan
facility: Novartis Investigative Site
state: Kyoto
city: Sendai
country: Japan
facility: Novartis Investigative Site
state: Miyagi
city: Omura
country: Japan
facility: Novartis Investigative Site
state: Nagasaki
city: Izumisano-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Matsubara-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Osaka city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Osaka-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Osaka-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Suita-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Suita
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Iruma-gun
country: Japan
facility: Novartis Investigative Site
state: Saitama
city: Sayama-city
country: Japan
facility: Novartis Investigative Site
state: Saitama
city: Chiyoda
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Nerima-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinagawa-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuoh-ku
country: Japan
facility: Novartis Investigative Site
city: Gifu
country: Japan
facility: Novartis Investigative Site
city: Kyoto
country: Japan
facility: Novartis Investigative Site
city: Oita
country: Japan
facility: Novartis Investigative Site
city: Saga
country: Japan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Warden BA, Duell PB. Inclisiran: A Novel Agent for Lowering Apolipoprotein B-containing Lipoproteins. J Cardiovasc Pharmacol. 2021 Aug 1;78(2):e157-e174. doi: 10.1097/FJC.0000000000001053.