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A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease (ORION-4)

Primary Purpose

Atherosclerotic Cardiovascular Disease

Status

Recruiting

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Inclisiran

Placebo

About this trial

This is an interventional prevention trial for Atherosclerotic Cardiovascular Disease focused on measuring Inclisiran, PCSK9, Cardiovascular, LDL Cholesterol, Cholesterol, Lipid, RNA interference

Eligibility Criteria

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

Inclusion Criteria

History or evidence of at least one of the following:

Prior MI; or
Prior ischemic stroke; or
Peripheral artery disease as evident by prior lower extremity artery revascularization or aortic aneurysm repair.

Minimum age is 40 years for men and 55 years for women

Exclusion Criteria

None of the following must be satisfied (based on self-reported medical history):

Acute coronary syndrome or stroke less than 4 weeks before the Screening visit or during the Run-in period;
Coronary revascularization procedure planned within the next 6 months;
Known chronic liver disease;
Current or planned renal dialysis or transplantation;
Previous exposure to inclisiran or participation in a randomized trial of inclisiran;
Previous (within about 3 months), current or planned treatment with a monoclonal antibody targeting PCSK9, or with a drug known to be contra-indicated with inclisiran (none currently known);
Known to be poorly compliant with clinic visits or prescribed medication;
Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; cancer or evidence of spread within approximately the last 5 years, other than non-melanoma skin cancer; or history of alcohol or substance misuse) or may put the individual at significant risk in the opinion of the investigator (or their authorised deputy) if he/she were to participate in the trial;
Women of child-bearing potential, current pregnancy, or lactation;
Current participation in a clinical trial with an unlicensed drug or device; or
Staff personnel directly involved with the study and any family member of the investigational study staff.

Sites / Locations

TIMI Study GroupRecruiting
CTSU, University of OxfordRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Inclisiran

Placebo

Arm Description

Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection at randomization, 3 months and then every 6 months.

Placebo will be administered as SC injections of saline solution at randomization, 3 months and then every 6 months.

Outcomes

Primary Outcome Measures

Number of participants with a major adverse cardiovascular event (MACE)

Defined as time to first occurrence - during the scheduled treatment period - of: Coronary heart disease (CHD) death; Myocardial infarction; Fatal or non-fatal ischemic stroke; or Urgent coronary revascularization procedure.

Secondary Outcome Measures

Number of participants with MACE among those recorded to be taking high-intensity statin at baseline

Number of participants with a composite of CHD death or myocardial infarction

Number of participants with cardiovascular death

Full Information

NCT ID

NCT03705234

First Posted

October 10, 2018

Last Updated

September 14, 2022

Sponsor

University of Oxford

Collaborators

The TIMI Study Group, Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT03705234

Brief Title

A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease

Acronym

ORION-4

Official Title

HPS-4/TIMI 65/ORION-4: A Double-blind Randomized Placebo-controlled Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Atherosclerotic Cardiovascular Disease

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Recruiting

Study Start Date

October 30, 2018 (Actual)

Primary Completion Date

July 2026 (Anticipated)

Study Completion Date

December 2049 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Oxford

Collaborators

The TIMI Study Group, Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

ORION-4 is a research study coordinated by the University of Oxford and co-sponsored by The University of Oxford and Novartis (Protocol: CTSU_MDCO-PCS-17-01 (CKJX839B12301)). The study aims to find out if a new cholesterol-lowering injection (inclisiran) safely lowers the risk of heart attacks and strokes in people who have already had one of these conditions, or who have had an operation or procedure to treat blocked arteries.

Detailed Description

The ORION-4 study aims to provide evidence about both the efficacy and safety of inclisiran. Inclisiran is a PCKS9 synthesis inhibitor which has been found to reduce LDL-cholesterol by about 50-60%. ORION-4 will investigate the effects of inclisiran on major adverse cardiovascular events. The study is intended to be conducted at approximately 180 clinical sites in the UK and the USA. Approximately 15,000 participants aged 40 years or older for men, and 55 years or older for women, with pre-existing atherosclerotic cardiovascular disease will be randomized between inclisiran sodium 300 mg and matching placebo (given by subcutaneous injection on the day of randomization, at 3 months and then every 6-months) in a 1:1 ratio for a planned median duration of about 5 years.

6. Conditions and Keywords

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

Atherosclerotic Cardiovascular Disease

Keywords

Inclisiran, PCSK9, Cardiovascular, LDL Cholesterol, Cholesterol, Lipid, RNA interference

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

15000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Inclisiran

Arm Type

Experimental

Arm Description

Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection at randomization, 3 months and then every 6 months.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo will be administered as SC injections of saline solution at randomization, 3 months and then every 6 months.

Intervention Type

Drug

Intervention Name(s)

Inclisiran

Intervention Description

Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Saline solution

Intervention Description

Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).

Primary Outcome Measure Information:

Title

Number of participants with a major adverse cardiovascular event (MACE)

Description

Time Frame

Median follow-up of 5-years

Secondary Outcome Measure Information:

Title

Number of participants with MACE among those recorded to be taking high-intensity statin at baseline

Time Frame

Median follow-up of 5-years

Title

Number of participants with a composite of CHD death or myocardial infarction

Time Frame

Median follow-up of 5-years

Title

Number of participants with cardiovascular death

Time Frame

Median follow-up of 5-years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria History or evidence of at least one of the following: Prior MI; or Prior ischemic stroke; or Peripheral artery disease as evident by prior lower extremity artery revascularization or aortic aneurysm repair. Minimum age is 40 years for men and 55 years for women Exclusion Criteria None of the following must be satisfied (based on self-reported medical history): Acute coronary syndrome or stroke less than 4 weeks before the Screening visit or during the Run-in period; Coronary revascularization procedure planned within the next 6 months; Known chronic liver disease; Current or planned renal dialysis or transplantation; Previous exposure to inclisiran or participation in a randomized trial of inclisiran; Previous (within about 3 months), current or planned treatment with a monoclonal antibody targeting PCSK9, or with a drug known to be contra-indicated with inclisiran (none currently known); Known to be poorly compliant with clinic visits or prescribed medication; Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; cancer or evidence of spread within approximately the last 5 years, other than non-melanoma skin cancer; or history of alcohol or substance misuse) or may put the individual at significant risk in the opinion of the investigator (or their authorised deputy) if he/she were to participate in the trial; Women of child-bearing potential, current pregnancy, or lactation; Current participation in a clinical trial with an unlicensed drug or device; or Staff personnel directly involved with the study and any family member of the investigational study staff.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Louise Bowman

Phone

+44 (0)1865 743743

orion4@ndph.ox.ac.uk

First Name & Middle Initial & Last Name or Official Title & Degree

Marion Mafham

Phone

+44 (0)1865 743743

orion4@ndph.ox.ac.uk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Louise Bowman

Organizational Affiliation

University of Oxford

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Marion Mafham

Organizational Affiliation

University of Oxford

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

David Preiss

Organizational Affiliation

University of Oxford

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Martin Landray

Organizational Affiliation

University of Oxford

Official's Role

Principal Investigator

Facility Information:

Facility Name

TIMI Study Group

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

David Morrow, MD, MPH

Phone

617-278-0145

TIMI@partners.org

First Name & Middle Initial & Last Name & Degree

Michelle O'Donoghue, MD, MPH

Phone

617-278-0145

TIMI@partners.org

Facility Name

CTSU, University of Oxford

City

Oxford

State/Province

Oxfordshire

ZIP/Postal Code

OX3 7LF

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Louise Bowman

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Proposals for substudies must be approved by the Steering Committee. Procedure for accessing the data for this study are available on https://www.ndph.ox.ac.uk/data-access

IPD Sharing Time Frame

After the main study results have been announced and published

IPD Sharing Access Criteria

See URL

IPD Sharing URL

https://www.ndph.ox.ac.uk/data-access

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

derived

Links:

URL

https://www.orion4trial.org

Description

Study website

Learn more about this trial

A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease

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