Condition category
Circulatory System
Date applied
25/06/2018
Date assigned
10/10/2018
Last edited
23/05/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
This study aims to find out if a new cholesterol-lowering injection (called 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-up arteries.

Who can participate?
People aged at least 55 years or older who have known vascular disease (that is they have had a heart attack, a stroke, a leg artery bypass, an angioplasty or an aortic aneurysm repair)

What does the study involve?
Participants attend the study clinic 3 times in the first 5 months and every 6 months after that. At each visit, a trained researcher (usually a nurse) asks them about their health, takes a blood sample and gives an injection of either inclisiran or placebo (dummy drug). Participants are asked to remain in the study for about 5 years. Wherever possible, the study team may like to stay in touch with participants after the end of the scheduled 5-year study follow-up, possibly with a simple questionnaire or phone call once or twice a year. Also, the study scientists would like to continue to get information about participant health, such as details of any admissions to hospital from NHS digital or other central registries after the end of the scheduled study follow-up period. This may include health information recorded throughout a person’s lifetime. Participants can opt out of this if they choose.

What are the possible benefits and risks of participating?
Participants will be helping doctors and scientists improve treatment for people who have had heart attacks or strokes, or who may be at risk of having one. If successful, results from this study might help to prevent many thousands of heart attacks, strokes and bypass procedures around the world.
Most treatments have side effects, which some people may experience, and others may not. If participants experience any side effects during the study, they will be recorded so that scientists can learn from this. Participants can stop receiving the study injections at any time if they want. Inclisiran is an unlicensed drug. In a previous study including about 350 people treated with inclisiran for 6 months, about 1 in 20 people noticed some redness or soreness where the injection was given, but no other side effects were found. Inclisiran has also been given to over 1500 people in other ongoing studies, but at this stage scientists cannot rule out the possibility of side effects. All drugs have a potential risk of an allergic reaction, which if not treated promptly, could become life-threatening. Throughout the study participants will be carefully monitored for possible side effects. At every visit, the study nurse will discuss any new information about the drug.

Where is the study run from?
1. Oxford University Clinical Trial Service Unit (CTSU) (UK)
2. Brigham and Women’s Hospital (USA)

When is the study starting and how long is it expected to run for?
December 2017 to December 2049

Who is funding the study?
The Medicines Company (USA)

Who is the main contact?
Prof. Louise Bowman
orion4@ndph.ox.ac.uk

Trial website

www.orion4trial.org

Contact information

Type

Scientific

Primary contact

Prof Louise Bowman

ORCID ID

http://orcid.org/0000-0003-1125-8616

Contact details

CTSU
Richard Doll Building
Roosevelt Drive
Oxford
OX3 7LF
United Kingdom
+44 (0)1865 743743
orion4@ndph.ox.ac.uk

Additional identifiers

EudraCT number

2017-005066-22

ClinicalTrials.gov number

NCT03705234

Protocol/serial number

38382; CTSU_MDCO-PCS-17-01

Study information

Scientific title

A double-blind randomized placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease (ORION-4)

Acronym

HPS-4/TIMI 65/ORION-4

Study hypothesis

Does inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis with the small interfering ribonucleic acid (siRNA) inclisiran prevent cardiovascular events among people with cardiovascular disease?

Ethics approval

Oxfordshire C Research Ethics Committee, 31/05/2018, ref: 18/SC/0243

Study design

Multicentre multinational double-blind randomised placebo-controlled parallel-group trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Prevention

Patient information sheet

See additional files

Condition

Myocardial infarction and stroke in people with atherosclerosis

Intervention

Screening and pre-randomization run-in:
Local investigators in UK hospitals will appoint research coordinators (usually nurses) to run local study clinics. Clinics will be run by the co-ordinator with the local investigator retaining medical oversight for the study. Potentially eligible patients will be identified (after obtaining the necessary approvals), from hospital-based computerised medical records or other NHS bodies such as NHS Digital.
Potentially eligible participants will be sent an invitation letter on behalf of the local investigator together with information about the study, and will be invited to attend a local study clinic and asked to call the coordinating centre in Oxford to confirm their appointment.

When they call the co-ordinating centre, trained staff will check key eligibility criteria over the phone in order to avoid a wasted visit to the clinic. Medical staff will be available to answer any questions about the study.

At their first visit (screening) they will be asked questions to assess their eligibility. After documenting written consent for the blood test, the nurse will collect a capillary blood sample and will measure a point-of-care total cholesterol level. Those with a total cholesterol level of less than 4 mmol/l are not able to continue with the study. For eligible individuals the nurse will explain the study in detail and they will be asked to sign an informed consent form. Optional consent will be sought for long-term storage of samples for genetic and, separately, for non-genetic analyses and for post-trial follow-up. Details of the participant’s cholesterol lowering medication will be collected and an injection of placebo inclisiran will be administered. The participant's Randomization appointment will be scheduled for 8 weeks time and they will be provided with a 24-hour Freephone telephone number for any trial-related queries. Participants will be observed in the clinic for 30 minutes after the injection for any injection site reactions. The participant now enters the pre-randomization run-in period of the trial.

After the screening visit each participant's general practitioner will be informed by letter of their patient's possible involvement in the study and asked to review their patient's usual cholesterol lowering medication.

Final check of eligibility and randomization:
Participants returning for their Randomization visit will be asked about any circulatory or other problems since the Screening visit, about any problems following the injection given at Screening, and if they are happy to continue in the trial. Those individuals who remain willing and eligible to continue in the trial will have a venous blood sample taken for processing for central laboratory analysis and storage. Details of all non-study treatments will be recorded and information about smoking history and alcohol intake will be sought and a quality of life questionnaire will be completed. Those who consent to continue in the trial will be assigned at random (like tossing a coin) to receive either inclisiran sodium 300 mg or placebo injection which will then be administered by the study coordinator. The follow-up appointment in 3 months is scheduled and the participant is reminded to contact the Freephone number if they have any concerns or questions about the study.

Post-randomization follow-up at 3 months, and then 6-monthly:
Participants will be asked to attend the ORION-4 clinic initially 3 months after randomization and then 6-monthly for a median of 5 years. At each visit serious medical events will be recorded along with any changes to their concurrent medication and a venous blood sample will be taken for processing for central laboratory analysis and storage. At each visit, participants will be asked if they are willing to continue with the study injections and, if so, the inclisiran or placebo injection will be given. If the participant is not willing to continue the study injections, the reason will be recorded. At the final study visit an assessment of quality of life will be made.

Additional "early recall" visits to clinic might be arranged for individuals who need to be reviewed before their planned appointment. This may occur in the case of symptoms possibly related to study treatment or if a participant has particular concerns.

Confirmation of reported events:
Data will be collected by the study coordinators directly onto a secure web-based case report form using specially designed and validated computer programs. Data will be stored securely on computers at the University of Oxford. All reports of possible cardiovascular events (heart attacks, strokes, revascularization procedures, etc) and other relevant serious adverse events will be independently confirmed or refuted by seeking further information about the event from the GP and hospital medical records. Participants will be flagged for mortality, cancer and other health outcomes through central registries, but will have the opportunity to opt out of this at any point during the trial.

Follow up of non-attenders:
Participants will be encouraged to continue attending study clinics even if study treatment is no longer being given. Those who are unwilling or unable to attend study clinics will be followed up by telephone if appropriate. If this is not appropriate, follow-up information will be obtained from their own doctor or central registries unless consent for this is withdrawn.

Post-trial follow-up:
Extended follow-up of all surviving randomized participants may continue for several years beyond the final study visit in order to provide valuable information on the longer term safety and efficacy of the study treatment. Data will continue to be requested from NHS Digital (or eDRIS in Scotland) after the final study visit and this is made clear in the Participant Information Leaflet and the Consent Form and participants will have the opportunity to opt out of this if they choose. As well as seeking long term follow-up information via routine data sources, participant questionnaires may be administered by telephone, by mail or by electronic means (e.g. secure web-based survey tools) where consent is provided for this.

Intervention type

Drug

Phase

Phase III

Drug names

Inclisiran

Primary outcome measure

Major adverse cardiovascular event, defined as occurrence of:
1. Coronary heart disease (CHD) death
2. Myocardial infarction
3. Fatal or non-fatal ischemic stroke, or
4. Urgent coronary revascularization procedure
Collected with a secure web-based case report form. Timeframe: median follow-up of 5 years

Secondary outcome measures

Occurrence of:
1. A composite of CHD death or myocardial infarction, or
2. Cardiovascular death
Collected with a secure web-based case report form. Timeframe: median follow-up of 5 years

Overall trial start date

07/12/2017

Overall trial end date

31/12/2049

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

History or evidence of at least one of the following:
1. Prior MI
2. Prior ischemic stroke
3. Peripheral artery disease as evident by prior lower extremity artery revascularization or aortic aneurysm repair

Participant type

Patient

Age group

Senior

Gender

Both

Target number of participants

15000

Participant exclusion criteria

None of the following must be satisfied (based on self-reported medical history):
1. Acute coronary syndrome or stroke less than 4 weeks before the Screening visit or during the Run-in period
2. Coronary revascularization procedure planned within the next 6 months
3. Known chronic liver disease
4. Current or planned renal dialysis or transplantation
5. Previous exposure to inclisiran or participation in a randomized trial of inclisiran
6. Previous, current or planned treatment with a monoclonal antibody targeting PCSK9, or with a drug known to be contra-indicated with inclisiran (none currently known)
7. Known to be poorly compliant with clinic visits or prescribed medication
8. 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 nonmelanoma 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
9. Women of child-bearing potential, current pregnancy, or lactation
10. Current participation in a clinical trial with an unlicensed drug or device
11. Staff personnel directly involved with the study and any family member of the investigational study staff

Recruitment start date

28/10/2018

Recruitment end date

31/12/2019

Locations

Countries of recruitment

United Kingdom, United States of America

Trial participating centre

CTSU
Richard Doll Building Roosevelt Drive
Oxford
OX3 7LF
United Kingdom

Trial participating centre

TIMI Study Group
350 Longwood Avenue Office Level One
Boston
MA 02115
United States of America

Sponsor information

Organisation

University of Oxford

Sponsor details

CTSU
Richard Doll Building
Roosevelt Drive
Oxford
OX3 7LF
United Kingdom
+44 (0)1865 743743
orion4@ndph.ox.ac.uk

Sponsor type

University/education

Website

Organisation

The Medicines Company

Sponsor details

8 Sylvan Way
Parsippany
NJ 07054
United States of America
+1 (0)973 290 6103
david.sampson@themedco.com

Sponsor type

Industry

Website

Funders

Funder type

Industry

Funder name

The Medicines Company

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Results will be published in health or scientific journals and be discussed at major conferences. The protocol and data analysis plan will be available at a later date.

IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/12/2025

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

23/05/2019: ClinicalTrials.gov number added. 25/03/2019: The condition has been changed from "Specialty: Cardiovascular Disease, Primary sub-specialty: Atherothrombosis; UKCRC code/ Disease: Cardiovascular/ Ischaemic heart diseases" to "Myocardial infarction and stroke in people with atherosclerosis" following a request from the NIHR. 10/10/2018: The participant information sheet has been uploaded.