Study of Efficacy and Safety of Inclisiran in Japanese Participants With High Cardiovascular Risk and Elevated LDL-C (ORION-15)

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

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).

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia; Heterozygous Familial Hypercholesterolemia
• Intervention / Treatment: Drug: Inclisiran sodium; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 312
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Chuoh-ku, Japan, 104-0031
    • Novartis Investigative Site
  • Gifu, Japan, 500-8384
    • Novartis Investigative Site
  • Kyoto, Japan, 612-8555
    • Novartis Investigative Site
  • Oita, Japan, 870-8511
    • Novartis Investigative Site
  • Saga, Japan, 840-8571
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan
      • Novartis Investigative Site
  • Chiba
    • Matsudo city, Chiba, Japan, 271 0077
      • Novartis Investigative Site
  • Fukuoka
    • Itoshima, Fukuoka, Japan, 819-1104
      • Novartis Investigative Site
    • Kitakyushu, Fukuoka, Japan, 800-0057
      • Novartis Investigative Site
    • Kitakyushu, Fukuoka, Japan, 804-0025
      • Novartis Investigative Site
    • Kitakyushu, Fukuoka, Japan, 805-8508
      • Novartis Investigative Site
    • Kitakyushu-city, Fukuoka, Japan, 806-8501
      • Novartis Investigative Site
    • Nakagawa, Fukuoka, Japan, 811-1244
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 062-8618
      • Novartis Investigative Site
    • Sapporo-city, Hokkaido, Japan, 006-8555
      • Novartis Investigative Site
  • Ibaraki
    • Sashima-gun, Ibaraki, Japan, 306-0433
      • Novartis Investigative Site
    • Tsuchiura, Ibaraki, Japan, 300-0028
      • Novartis Investigative Site
  • Ishikawa
    • Kahoku-gun, Ishikawa, Japan, 920-0293
      • Novartis Investigative Site
    • Kanazawa, Ishikawa, Japan, 920 8650
      • Novartis Investigative Site
    • Kanazawa-city, Ishikawa, Japan, 920-8641
      • Novartis Investigative Site
    • Komatsu, Ishikawa, Japan, 923-0961
      • Novartis Investigative Site
  • Kagawa
    • Takamatsu city, Kagawa, Japan, 760 8557
      • Novartis Investigative Site
  • Kanagawa
    • Fujisawa-city, Kanagawa, Japan, 251-0041
      • Novartis Investigative Site
    • Kawasaki-city, Kanagawa, Japan, 216-8511
      • Novartis Investigative Site
  • Kyoto
    • Kuse, Kyoto, Japan, 613-0034
      • Novartis Investigative Site
  • Miyagi
    • Sendai, Miyagi, Japan, 983-0039
      • Novartis Investigative Site
  • Nagasaki
    • Omura, Nagasaki, Japan, 856-8562
      • Novartis Investigative Site
  • Osaka
    • Izumisano-city, Osaka, Japan, 598-8577
      • Novartis Investigative Site
    • Matsubara-city, Osaka, Japan, 580-0032
      • Novartis Investigative Site
    • Osaka city, Osaka, Japan, 530 0001
      • Novartis Investigative Site
    • Osaka-city, Osaka, Japan, 543-0035
      • Novartis Investigative Site
    • Osaka-city, Osaka, Japan, 540-0006
      • Novartis Investigative Site
    • Suita, Osaka, Japan, 564-8565
      • Novartis Investigative Site
    • Suita-city, Osaka, Japan, 565-0853
      • Novartis Investigative Site
  • Saitama
    • Iruma-gun, Saitama, Japan, 350-0495
      • Novartis Investigative Site
    • Sayama-city, Saitama, Japan, 350-1305
      • Novartis Investigative Site
  • Tokyo
    • Chiyoda, Tokyo, Japan
      • Novartis Investigative Site
    • Chuo-ku, Tokyo, Japan, 103-0028
      • Novartis Investigative Site
    • Chuo-ku, Tokyo, Japan, 103-0027
      • Novartis Investigative Site
    • Nerima-ku, Tokyo, Japan, 176-8530
      • Novartis Investigative Site
    • Shinagawa-ku, Tokyo, Japan, 142-8666
      • Novartis Investigative Site
    • Shinjuku ku, Tokyo, Japan, 160-0008
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2021
• Primary Completion (Actual): April 18, 2022
• Study Completion (Actual): October 19, 2022

Study Registration Dates

• First Submitted: December 7, 2020
• First Submitted That Met QC Criteria: December 7, 2020
• First Posted (Actual): December 14, 2020

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: April 17, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Hypercholesterolemia; PCSK9; LDL-C; siRNA; dyslipidemia; inclisiran
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II
• Other Study ID Numbers: CKJX839A11201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes