Study of Efficacy and Safety of Inclisiran in Asian Participants With Atherosclerotic Cardiovascular Disease (ASCVD) or ASCVD High Risk and Elevated Low Density Lipoprotein Cholesterol (LDL-C)

A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Inclisiran in Asian Patients With ASCVD or ASCVD High Risk and Elevated Low-density Lipoprotein Cholesterol as an Adjunct to Diet and Maximally Tolerated Statins With or Without Additional Lipid-lowering Therapy (ORION-18)

A multicenter study to evaluate safety and efficacy of inclisiran in Asian patients with ASCVD or ASCVD high risk and elevated LDL-C

Study Overview

• Status: Active, not recruiting
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Placebo; Drug: inclisiran sodium

Detailed Description

The purpose of the study is to demonstrate the efficacy and safety of inclisiran sodium 300mg to support the indication for LDL-C reduction of inclisiran in Asian patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-high risk patients with elevated LDL-C as an adjunct to diet and maximally tolerated dose statins with or without additional lipid-lowering therapy.

A core part (2-week screening period and a 12-month double-blinded treatment period), and an extension part (until reasonable access to the IMP post product launch provided for the participants)

• Study Type: Interventional
• Enrollment (Actual): 345
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100034
    • Novartis Investigative Site
  • Beijing, China, 100050
    • Novartis Investigative Site
  • Beijing, China, 100191
    • Novartis Investigative Site
  • Beijing, China, 100039
    • Novartis Investigative Site
  • Shanghai, China, 200080
    • Novartis Investigative Site
  • Shanghai, China, 200040
    • Novartis Investigative Site
  • Shanghai, China, 200120
    • Novartis Investigative Site
  • Shijiazhuang, China, 050000
    • Novartis Investigative Site
  • Tianjin, China, 300052
    • Novartis Investigative Site
  • Tianjin, China, 300140
    • Novartis Investigative Site
  • Xiamen, China, 361004
    • Novartis Investigative Site
  • Gansu
    • Lanzhou, Gansu, China, 730030
      • Novartis Investigative Site
  • Guangdong
    • Foshan, Guangdong, China, 528000
      • Novartis Investigative Site
    • Guangzhou, Guangdong, China, 51000
      • Novartis Investigative Site
  • Inner Mongolia
    • Baotou, Inner Mongolia, China, 014040
      • Novartis Investigative Site
    • Hohhot, Inner Mongolia, China, 010017
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210008
      • Novartis Investigative Site
    • Nanjing, Jiangsu, China, 211166
      • Novartis Investigative Site
    • Nantong, Jiangsu, China, 226000
      • Novartis Investigative Site
    • Suzhou, Jiangsu, China, 215006
      • Novartis Investigative Site
    • Xuzhou, Jiangsu, China, 221003
      • Novartis Investigative Site
  • Jilin
    • Chang Chun, Jilin, China, 130021
      • Novartis Investigative Site
    • Changchun, Jilin, China, 130021
      • Novartis Investigative Site
  • Shandong
    • Jinan, Shandong, China, 250013
      • Novartis Investigative Site
  • Shanghai
    • Jinshan, Shanghai, China, 201508
      • Novartis Investigative Site
    • Shanghai, Shanghai, China, 200032
      • Novartis Investigative Site
  • Shanxi
    • Taiyuan, Shanxi, China, 030002
      • Novartis Investigative Site
    • Xian, Shanxi, China, 710061
      • Novartis Investigative Site
  • Tianjin
    • Tianjin, Tianjin, China, 300121
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310014
      • Novartis Investigative Site
• Korea, Republic of
  • Gwangju, Korea, Republic of, 61469
    • Novartis Investigative Site
  • Incheon, Korea, Republic of, 405 760
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 02841
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 05505
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 110-746
    • Novartis Investigative Site
  • Gangwon-do
    • Wonju, Gangwon-do, Korea, Republic of, 26427
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169609
    • Novartis Investigative Site
  • Singapore, Singapore, 117549
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung, Taiwan, 80756
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
  • Taipei, Taiwan, 11220
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

-At screening participants with: ASCVD (including acute coronary syndrome (ACS), stable coronary heart disease, post revascularization, ischemic cardiomyopathy, ischemic stroke, transient ischemic attack (TIA), and peripheral atherosclerosis) and Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL) OR ASCVD high risk (LDL-C ≥4.9 mmol/L, diabetes, high 10-year ASCVD risk assessed by Chinese ASCVD Risk Assessment Flow Chart , or high risk per local guidelines with a target LDL-C of <100 mg/dL) and Serum LDL-C ≥2.6 mmol/L (≥100 mg/dL)

• Fasting triglyceride < 400 mg/dL (< 4.52 mmol/L) at screening.
• Participants on statins should be receiving a maximally tolerated dose . Maximum tolerated dose is defined as the maximum dose of statin that can be taken on a regular basis without intolerable AE. Intolerance to any dose of statin must be documented as historical AEs attributed to the statin in question on the source documentation and on the Medical history page of the eCRF
• Participants not receiving statin must have a documented evidence of intolerance to all doses of at least 2 different statins(or the corresponding local definition of complete intolerance to statins)
• Participants following lifestyle modification should be on the therapy of LDL-C lowering (such as statin monotherapy, or statin incombination with ezetimibe) with a stable dose for ≥30 days before screening and have no planned medication or dose change during study participation.
• Participants are willing and able to give informed consent before initiation of any study related procedures and willing to comply with all required study procedures.

Exclusion Criteria:

• New York Heart Association (NYHA) class IV heart failure or last known left ventricular ejection fraction <25%.
• Cardiac arrhythmia with clinical significance within 3 months prior to randomization that is not controlled by medication or via ablation.
• Major adverse cardiovascular event within 3 months prior to randomization.
• Uncontrolled severe hypertension: systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg prior to randomization despite antihypertensive therapy.
• Calculated glomerular filtration rate ≤30 mL/min by estimated glomerular filtration rate (eGFR) using standardized clinical methodology.
• Severe concomitant non-cardiovascular disease that carries the risk of reducing life expectancy to less than 2 years.
• History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or systemic therapy during the three years prior to randomization.
• Barrier method: Condom or Occlusive cap (e.g. diaphragm or cervical/vault caps).
• Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subcutaneous injection	Drug: Placebo; Subcutaneously injected on Day 1, 90, and 270.
Experimental: inclisiran sodium 300 mg; Subcutaneous injection	Drug: inclisiran sodium; Subcutaneously injected on Day 1, 90 and 270 (Core Part). Subcutaneously injected on Day 360 and every 6 months thereafter until EOS visit (Extension Part); Other Names: KJX839

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Core: Percentage change in low- density lipoprotein cholesterol (LDL-C)	Superiority of inclisiran compared to placebo in reducing LDL-C from baseline to Day 330	Baseline, Day 330
Extension: Number of participants with Adverse Events	Evaluation of the safety and tolerability of inclisiran, treatment emergent Adverse events and Serious Adverse Events	Day 360 until study completion, an average of 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Core: Time adjusted percentage change in LDL-C	The superiority of inclisiran compared to placebo in reducing LDL-C from baseline to Day 330 and over time	From baseline after Day 90 and up to Day 360
Core: Absolute change in LDL-C	The superiority of inclisiran compared to placebo in reducing LDL-C from baseline to Day 330 and over time	From baseline to Day 330
Core: Time adjusted absolute change in LDL-C	The superiority of inclisiran compared to placebo in reducing LDL-C from baseline to Day 330 and over time	From baseline after Day 90 and up to Day 360
Core: Percentage change in PCSK9	The superiority of inclisiran compared to placebo in reducing PCSK9 from baseline to Day 330	From baseline to Day 330
Core: Absolute change in PCSK9	The superiority of inclisiran compared to placebo in reducing PCSK9 from baseline to Day 330	From baseline to Day 330
Core: Proportion of participants reaching LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL	The superiority of inclisiran compared to placebo in individual response rate for lipid controlling	Day 330
Core: Proportion of participants in each group with ≥ 50% LDL-C reduction	The superiority of inclisiran compared to placebo in individual response rate for lipid controlling	From baseline to Day 330
Core: Proportion of participants in each group who attain global lipid targets for their level of ASCVD risk (55mg/dl for ASCVD patients, 70mg/dl for ASCVD high risk patients)	The superiority of inclisiran compared to placebo in individual response rate for lipid controlling	Day 330
Core: Percentage change in total cholesterol, ApoB, non-HDL-C, ApoA1, HDL-C, Lp(a) and triglycerides	The superiority of inclisiran compared to placebo in reducing other lipids, lipoproteins and apolipoproteins	From baseline to Day 330
Core: Absolute change in total cholesterol, ApoB, non-HDL-C, ApoA1, HDL-C, Lp(a) and triglycerides	The superiority of inclisiran compared to placebo in reducing other lipids, lipoproteins and apolipoproteins	From baseline to Day 330

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Actual): June 9, 2022
• Study Completion (Estimated): December 28, 2026

Study Registration Dates

• First Submitted: February 5, 2021
• First Submitted That Met QC Criteria: February 19, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 31, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: siRNA; dyslipidemia; inclisiran; KJX839
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia
• Other Study ID Numbers: CKJX839A12307

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: No
• Studies a U.S. FDA-regulated device product: No