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

Primary Purpose

Hypercholesterolemia, Heterozygous Familial Hypercholesterolemia

Status

Completed

Phase

Phase 2

Locations

Japan

Study Type

Interventional

Intervention

Inclisiran sodium

Placebo

About this trial

This is an interventional treatment trial for Hypercholesterolemia focused on measuring inclisiran, siRNA, dyslipidemia, PCSK9, Hypercholesterolemia, LDL-C

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Other protocol-defined inclusion/exclusion criteria may apply.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Arm Label

300 mg inclisiran sodium

200 mg inclisiran sodium

100 mg inclisiran sodium

Placebo

Arm Description

Subcutaneous injection

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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

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

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

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

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

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

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

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

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.

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.

Full Information

NCT ID

NCT04666298

First Posted

December 7, 2020

Last Updated

April 17, 2023

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT04666298

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Completed

Study Start Date

January 29, 2021 (Actual)

Primary Completion Date

April 18, 2022 (Actual)

Study Completion Date

October 19, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypercholesterolemia, Heterozygous Familial Hypercholesterolemia

Keywords

inclisiran, siRNA, dyslipidemia, PCSK9, Hypercholesterolemia, LDL-C

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

312 (Actual)

8. Arms, Groups, and Interventions

Arm Title

300 mg inclisiran sodium

Arm Type

Experimental

Arm Description

Subcutaneous injection

Arm Title

200 mg inclisiran sodium

Arm Type

Experimental

Arm Description

Subcutaneous injection

Arm Title

100 mg inclisiran sodium

Arm Type

Experimental

Arm Description

Subcutaneous injection

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Subcutaneous injection

Intervention Type

Drug

Intervention Name(s)

Inclisiran sodium

Other Intervention Name(s)

KJX839

Intervention Description

Subcutaneously injected on Day 1, 90 and 270.

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

KJX839 placebo

Intervention Description

Subcutaneously injected on Day 1, 90, and 270.

Primary Outcome Measure Information:

Title

Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) to Day 180

Description

Time Frame

Baseline, Day 180

Secondary Outcome Measure Information:

Title

Percent Change From Baseline in PCSK9 by Visit

Description

Percent change from baseline in proprotein convertase subtilisin/kexin type 9 (PCSK9) was calculated to evaluate the effect of inclisiran over time.

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Percent Change From Baseline in LDL-C by Visit

Description

Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran over time.

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120 and day 150

Title

Absolute Change in LDL-C From Baseline at Day 180

Description

Absolute change from baseline in low-density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran until Day 180.

Time Frame

Baseline, Day 180

Title

Proportion of Participants With LDL-C Greater Than 80% of Baseline Value at Day 180

Description

Time Frame

Baseline, Day 180

Title

Proportion of Participants With Greater or Equal to 50% LDL-C Reduction From Baseline by Visit

Description

Proportion of participants with greater or equal to 50% LDL-C reduction from baseline was calculated to evaluate the effect of inclisiran over time.

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Percent Change From Baseline in Cholesterol by Visit

Description

Percent change from baseline in cholesterol by visit was calculated to evaluate the effect of inclisiran over time

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Percent Change From Baseline in Triglycerides by Visit

Description

Percent change from baseline in triglycerides by visit was calculated to evaluate the effect of inclisiran over time

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Percent Change From Baseline in HDL Cholesterol by Visit

Description

Percent change from baseline in high-density lipoprotein cholesterol (HDL-C) by visit was calculated to evaluate the effect of inclisiran over time

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Percent Change From Baseline in Non-HDL Cholesterol by Visit

Description

Percent change from baseline in non-HDL Cholesterol by visit was calculated to evaluate the effect of inclisiran over time

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Percent Change From Baseline in VLDL-C by Visit

Description

Percent change from baseline in very low-density lipoprotein cholesterol (VLDL - C) by visit was calculated to evaluate the effect of inclisiran over time

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Percent Change From Baseline in Apo- A1 by Visit

Description

Percent change from baseline in Apolipoprotein A1 (Apo-A1) by visit was calculated to evaluate the effect of inclisiran over time

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Percent Change From Baseline in Apo- B by Visit

Description

Percent change from baseline in Apolipoprotein B (Apo-B) by visit was calculated to evaluate the effect of inclisiran over time

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Percent Change From Baseline in Lipoprotein-a by Visit

Description

Percent change from baseline in Lipoprotein a (LP(a)) by visit was calculated to evaluate the effect of inclisiran over time

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

Title

Proportion of Participants Who Attain Lipid Control Target Pre-specified by JAS 2017 Guidelines for Their Level of Cardiovascular Risk at Day 180

Description

Time Frame

Day 180

Title

Number of Participants With LDL-C Levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL by Visit

Description

Number of participants by LDL-C levels was calculated to evaluate the effect of inclisiran.

Time Frame

Baseline, day 14, day 30, day 60, day 90, day 104, day 120, day 150, and day 180

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Nagoya

State/Province

Aichi

Country

Japan

Facility Name

Novartis Investigative Site

City

Matsudo city

State/Province

Chiba

ZIP/Postal Code

271 0077

Country

Japan

Facility Name

Novartis Investigative Site

City

Itoshima

State/Province

Fukuoka

ZIP/Postal Code

819-1104

Country

Japan

Facility Name

Novartis Investigative Site

City

Kitakyushu-city

State/Province

Fukuoka

ZIP/Postal Code

806-8501

Country

Japan

Facility Name

Novartis Investigative Site

City

Kitakyushu

State/Province

Fukuoka

ZIP/Postal Code

800-0057

Country

Japan

Facility Name

Novartis Investigative Site

City

Kitakyushu

State/Province

Fukuoka

ZIP/Postal Code

804-0025

Country

Japan

Facility Name

Novartis Investigative Site

City

Kitakyushu

State/Province

Fukuoka

ZIP/Postal Code

805-8508

Country

Japan

Facility Name

Novartis Investigative Site

City

Nakagawa

State/Province

Fukuoka

ZIP/Postal Code

811-1244

Country

Japan

Facility Name

Novartis Investigative Site

City

Sapporo-city

State/Province

Hokkaido

ZIP/Postal Code

006-8555

Country

Japan

Facility Name

Novartis Investigative Site

City

Sapporo

State/Province

Hokkaido

ZIP/Postal Code

062-8618

Country

Japan

Facility Name

Novartis Investigative Site

City

Sashima-gun

State/Province

Ibaraki

ZIP/Postal Code

306-0433

Country

Japan

Facility Name

Novartis Investigative Site

City

Tsuchiura

State/Province

Ibaraki

ZIP/Postal Code

300-0028

Country

Japan

Facility Name

Novartis Investigative Site

City

Kahoku-gun

State/Province

Ishikawa

ZIP/Postal Code

920-0293

Country

Japan

Facility Name

Novartis Investigative Site

City

Kanazawa-city

State/Province

Ishikawa

ZIP/Postal Code

920-8641

Country

Japan

Facility Name

Novartis Investigative Site

City

Kanazawa

State/Province

Ishikawa

ZIP/Postal Code

920 8650

Country

Japan

Facility Name

Novartis Investigative Site

City

Komatsu

State/Province

Ishikawa

ZIP/Postal Code

923-0961

Country

Japan

Facility Name

Novartis Investigative Site

City

Takamatsu city

State/Province

Kagawa

ZIP/Postal Code

760 8557

Country

Japan

Facility Name

Novartis Investigative Site

City

Fujisawa-city

State/Province

Kanagawa

ZIP/Postal Code

251-0041

Country

Japan

Facility Name

Novartis Investigative Site

City

Kawasaki-city

State/Province

Kanagawa

ZIP/Postal Code

216-8511

Country

Japan

Facility Name

Novartis Investigative Site

City

Kuse

State/Province

Kyoto

ZIP/Postal Code

613-0034

Country

Japan

Facility Name

Novartis Investigative Site

City

Sendai

State/Province

Miyagi

ZIP/Postal Code

983-0039

Country

Japan

Facility Name

Novartis Investigative Site

City

Omura

State/Province

Nagasaki

ZIP/Postal Code

856-8562

Country

Japan

Facility Name

Novartis Investigative Site

City

Izumisano-city

State/Province

Osaka

ZIP/Postal Code

598-8577

Country

Japan

Facility Name

Novartis Investigative Site

City

Matsubara-city

State/Province

Osaka

ZIP/Postal Code

580-0032

Country

Japan

Facility Name

Novartis Investigative Site

City

Osaka city

State/Province

Osaka

ZIP/Postal Code

530 0001

Country

Japan

Facility Name

Novartis Investigative Site

City

Osaka-city

State/Province

Osaka

ZIP/Postal Code

540-0006

Country

Japan

Facility Name

Novartis Investigative Site

City

Osaka-city

State/Province

Osaka

ZIP/Postal Code

543-0035

Country

Japan

Facility Name

Novartis Investigative Site

City

Suita-city

State/Province

Osaka

ZIP/Postal Code

565-0853

Country

Japan

Facility Name

Novartis Investigative Site

City

Suita

State/Province

Osaka

ZIP/Postal Code

564-8565

Country

Japan

Facility Name

Novartis Investigative Site

City

Iruma-gun

State/Province

Saitama

ZIP/Postal Code

350-0495

Country

Japan

Facility Name

Novartis Investigative Site

City

Sayama-city

State/Province

Saitama

ZIP/Postal Code

350-1305

Country

Japan

Facility Name

Novartis Investigative Site

City

Chiyoda

State/Province

Tokyo

Country

Japan

Facility Name

Novartis Investigative Site

City

Chuo-ku

State/Province

Tokyo

ZIP/Postal Code

103-0027

Country

Japan

Facility Name

Novartis Investigative Site

City

Chuo-ku

State/Province

Tokyo

ZIP/Postal Code

103-0028

Country

Japan

Facility Name

Novartis Investigative Site

City

Nerima-ku

State/Province

Tokyo

ZIP/Postal Code

176-8530

Country

Japan

Facility Name

Novartis Investigative Site

City

Shinagawa-ku

State/Province

Tokyo

ZIP/Postal Code

142-8666

Country

Japan

Facility Name

Novartis Investigative Site

City

Shinjuku ku

State/Province

Tokyo

ZIP/Postal Code

160-0008

Country

Japan

Facility Name

Novartis Investigative Site

City

Chuoh-ku

ZIP/Postal Code

104-0031

Country

Japan

Facility Name

Novartis Investigative Site

City

Gifu

ZIP/Postal Code

500-8384

Country

Japan

Facility Name

Novartis Investigative Site

City

Kyoto

ZIP/Postal Code

612-8555

Country

Japan

Facility Name

Novartis Investigative Site

City

Oita

ZIP/Postal Code

870-8511

Country

Japan

Facility Name

Novartis Investigative Site

City

Saga

ZIP/Postal Code

840-8571

Country

Japan

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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

Citations:

PubMed Identifier

33990512

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.

Results Reference

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

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

Hypercholesterolemia, Heterozygous Familial Hypercholesterolemia

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial