Randomized evaluation of the effects of anacetrapib through lipid-modification

Plain English Summary

Background and study aims
Anacetrapib is a new cholesterol treatment which is being developed by MSD (known as Merck in the US and Canada). In previous studies anacetrapib reduced levels of ‘bad’ LDL cholesterol in the blood in addition to the reductions achieved with statin drugs, and it more than doubled ‘good’ HDL cholesterol levels. The aim of this study is to see whether fewer participants given anacetrapib have heart attacks, revascularisation procedures or die from coronary heart disease compared with participants treated with a placebo (dummy) drug.

Who can participate?
Men and women aged at least 50 with a history of heart attack, stroke or peripheral arterial disease.

What does the study involve?
All participants are given atorvastatin (a commonly used ‘statin’ drug) to ensure good control of LDL (‘bad’) cholesterol. In addition, they are randomly allocated to receive anacetrapib or matching placebo (dummy) tablets daily for at least 4 years. There is a further period of at least 2 years of off-treatment follow-up.

What are the possible benefits and risks of participating?
Statin treatment is known to reduce the risk of heart attacks and strokes and is generally well-tolerated. However, atorvastatin is associated with a small increase in the risk of liver enzyme abnormalities (although it is not thought to cause liver damage) and can also rarely (typically < 1 in 10,000 per year) cause muscle pain or weakness associated with blood test abnormalities showing muscle damage (known as myopathy). Blood tests are used to monitor liver function and, where indicated, muscle enzymes, throughout the study. Anacetrapib is not known to have any side effects and, in particular, has not been found to cause elevations in liver enzymes or muscle adverse effects. However, reliable assessment of the safety of anacetrapib in a large-scale study is essential before it can be used in routine practice. On the other hand, the lipid changes that are produced by anacetrapib might well reduce the risk of vascular events substantially and participants might potentially benefit from participating in the study.

Where is the study run from?
The Clinical Trial Service Unit (CTSU) at Oxford University (UK)

When is the study starting and how long is it expected to run for?
The study started in May 2011. All participants stopped study treatment prior to February 2017 and direct participant follow-up was completed in April 2019. However, in the UK the researchers will continue to collect information on health outcomes via registries and NHS sources for many years.

Who is funding the study?
Merck and Co, Inc. (USA)

Who is the main contact?
Dr Louise Bowman
reveal@ndph.ox.ac.uk

Study website

http://www.revealtrial.org

Type

Scientific

Contact name

Dr Louise Bowman

ORCID ID

Contact details

Clinical Trial Service Unit
Richard Doll Building
University of Oxford
Old Road Campus
Headington
Oxford
OX3 7LF
United Kingdom
+44 (0)1865 743875
reveal@ndph.ox.ac.uk

EudraCT/CTIS number

2010-023467-18

IRAS number

ClinicalTrials.gov number

NCT01252953

Protocol/serial number

CTSUREVEAL1

Scientific title

REVEAL: Randomized EValuation of the Effects of Anacetrapib through Lipid-modification. A large-scale, randomized placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease

Acronym

REVEAL

Study hypothesis

To determine whether lipid modification with anacetrapib 100mg daily reduces the risk of coronary death, myocardial infarction or coronary revascularization (collectively known as major coronary events) in patients with circulatory problems who have their LDL cholesterol level treated with a statin.

Ethics approval(s)

Oxfordshire REC B, 25/01/2011, ref: 10/H0605/83

Study design

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

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Study setting(s)

Hospital

Study type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a patient information sheet

Condition

Atherosclerotic cardiovascular disease

Intervention

Current interventions as of 19/05/2017:
Anacetrapib 100 mg daily or matching placebo. All participants receive background LDL-lowering with
atorvastatin. Both treatments taken orally. The median duration of on-treatment follow-up will be 4 years, and will vary depending on the patient's date of entry into the study. The maximum duration will be 6 years. There will be a further period of at least 2 years of off-treatment follow-up.

Previous interventions:
Anacetrapib 100 mg daily or matching placebo. All participants receive background LDL-lowering with atorvastatin. Both treatments taken orally. The median duration of treatment and follow-up will be 4 years, and vary depending on the patient's date of entry into the study. The maximum duration will be 6 years.

Intervention type

Drug

Pharmaceutical study type(s)

Phase

Phase III

Drug/device/biological/vaccine name(s)

Anacetrapib

Primary outcome measure

Intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib versus placebo on major coronary events (defined as the occurrence of coronary death, myocardial infarction or coronary revascularization procedure) during the scheduled treatment period.

Secondary outcome measures

Current secondary outcome measures as of 05/07/2016:
Intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period on:
1. Major atherosclerotic events (defined as coronary death, myocardial infarction or presumed ischaemic stroke; the key secondary outcome)
2. Presumed ischaemic stroke (i.e. not known to be haemorrhagic)
3. Major vascular events (defined as coronary death, myocardial infarction, coronary revascularization or presumed ischaemic stroke)
In addition, each of the individual components of the primary outcome (i.e. coronary death; myocardial infarction; and coronary revascularization) will be tested separately.

Previous secondary outcome measures:
Intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period on:
1. Coronary death or myocardial infarction (key secondary outcome)
2. Coronary revascularization procedure
3. Presumed ischaemic stroke (i.e. not known to be haemorrhagic)
4. Death from all cardiovascular causes

Overall study start date

01/05/2011

Overall study end date

31/01/2037

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Patients must be aged at least 50 at the time of initial invitation
2. At least one of the following inclusion criteria must be satisfied:
2.1. History of Myocardial Infarction (MI)
2.2. Cerebrovascular atherosclerotic disease (i.e. history of presumed ischaemic stroke or carotid revascularization)
2.3. Peripheral arterial disease (i.e. history of non-coronary revascularization, including aortic aneurysm repair or graft)
2.4. Diabetes mellitus with other evidence of symptomatic coronary heart disease (i.e. treatment or hospitalization for angina, or a history of coronary revascularization or acute coronary syndrome)

Participant type(s)

Patient

Age group

Senior

Sex

Both

Target number of participants

30,624

Total final enrolment

30449

Participant exclusion criteria

1. Acute MI, acute coronary syndrome or stroke within 4 weeks prior to Screening Visit or during Run-in (but such individuals may be entered later, if appropriate)
2. Planned coronary revascularization procedure within the next 6 months (such individuals may be entered later, if appropriate)
3. Definite history of chronic liver disease, or abnormal liver function (i.e. ALT >2x ULN). Note: Individuals with a history of acute hepatitis are eligible provided this ALT limit is not exceeded
4. Severe renal insufficiency (i.e. creatinine >200 µmol/L [2.3 mg/dL], dialysis or functioning renal transplant)
5. Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or CK >3x ULN
6. Previous significant adverse reaction to a statin or anacetrapib
7. Current treatment with any of the following lipid-lowering treatments:
7.1. A regimen considered to produce substantially greater LDL cholesterol reduction than atorvastatin 80 mg daily for individuals in non-Asian countries or 20 mg daily for those in North East Asia
7.2. Fibric acid derivative ('fibrate', including gemfibrozil)
7.3. Niacin (nicotinic acid) at doses above 100 mg daily
8. Concurrent treatment with a medication that is contraindicated with anacetrapib or atorvastatin:
8.1. Any potent CYP3A4 inhibitor, such as:
8.1.1. Macrolide antibiotics (erythromycin, clarithromycin, telithromycin)
8.1.2. Daptomycin
8.1.3. Systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole)
8.1.4. Protease inhibitors (e.g. atazanavir)
8.1.5. Nefazodone
8.2. Ciclosporin
8.3. Systemic use of fusidic acid
9. Known to be poorly compliant with clinic visits or prescribed medication
10. Medical history that might limit the individual’s ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; history of cancer or evidence of spread within last 5 years, other than non-melanoma skin cancer; or recent history of alcohol or substance misuse)
11. Women of child-bearing potential (unless using adequate contraception)
12. Current participation in a clinical trial with an unlicensed drug or device
13. Individuals will also be excluded at the Screening visit if it is considered unlikely that they will achieve total cholesterol <3.5 mmol/L (135 mg/dL) on the highest atorvastatin dose available in their region (atorvastatin 80 mg daily in non-Asian countries or 20 mg daily in North East Asia).
14. In addition, individuals will be excluded at the Randomization visit if any of the following are true:
14.1. Total cholesterol above 4 mmol/L [155 mg/dL]
14.2. Non-compliant with run-in treatment (<90% scheduled run-in medication taken)
14.3. Individual is no longer willing to be randomized into the 4-5 year trial
14.4. The individual’s doctor is of the view that their patient should not be randomized

Recruitment start date

22/08/2011

Recruitment end date

18/10/2013

Countries of recruitment

Canada, China, Denmark, England, Finland, Germany, Italy, Norway, Sweden, United Kingdom, United States of America

Study participating centre

University of Oxford
Oxford
OX3 7LF
United Kingdom

Organisation

University of Oxford (UK)

Sponsor details

Joint Research Office
Block 60
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
England
United Kingdom
+44 (0)1865 572221
reveal@ndph.ox.ac.uk

Sponsor type

University/education

Website

https://www.admin.ox.ac.uk/researchsupport/ctrg/

ROR

https://ror.org/052gg0110

Funder type

Industry

Funder name

Merck

Alternative name(s)

Merck & Co., Inc., Merck & Co.

Funding Body Type

government organisation

Funding Body Subtype

For-profit companies (industry)

Location

United States of America

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal in Autumn 2017.

Intention to publish date

01/09/2017

Individual participant data (IPD) sharing plan

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

IPD sharing plan summary

Data sharing statement to be made available at a later date

Study outputs