Cardiovascular DiseasePhase 3SEARCHNCT00124072
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine
A Phase 3 study testing Simvastatin 20 mg daily, Folic acid 2 mg + vitamin B12 1 mg daily and Simvastatin 80 mg daily in people with Cardiovascular Disease, run by University of Oxford at 1 site in United Kingdom.
Trial summary
SEARCH is a randomised, double-blind, multi-centre United Kingdom (UK) trial of 12,064 patients with myocardial infarction (MI) prior to study entry which aims to demonstrate whether a more intensive cholesterol lowering regimen using 80 mg simvastatin daily produces a larger and worthwhile reduction in cardiovascular… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Cardiovascular Disease
- What is being tested?
- Simvastatin 20 mg daily, Folic acid 2 mg + vitamin B12 1 mg daily and Simvastatin 80 mg daily
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12,064 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jul 1998to May 2008
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Prior myocardial infarction
- Statin therapy indicated
- No clear indication for folic acid
Who cannot join
- No clear contraindication to study treatments
- Screening plasma total cholesterol <3.5 mmol/l in patient already on statin therapy, or <4.5 mmol/l in patient not on statin therapy
- Chronic liver disease
- Severe renal disease or evidence of renal impairment
- Inflammatory muscle disease
- Concurrent treatment with fibrates or high-dose niacin
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- Concurrent treatment with cyclosporin (or condition likely to result in organ transplantation and the need for cyclosporin), nefazodone, methotrexate, systemic azole antifungal or systemic macrolide antibiotics
- Child bearing potential
- No other predominant medical problem (other than coronary heart disease [CHD]) which might limit compliance with 5 years of study treatment
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
CTSU, Richard Doll Building, University of Oxford
Oxford, Oxon, OX3 7LF
About this study
Official title: SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine
SEARCH is a randomised, double-blind, multi-centre United Kingdom (UK) trial of 12,064 patients with myocardial infarction (MI) prior to study entry which aims to demonstrate whether a more intensive cholesterol lowering regimen using 80 mg simvastatin daily produces a larger and worthwhile reduction in cardiovascular events compared with a standard 20 mg daily regimen and whether reducing blood homocysteine levels with a daily dose of folic acid 2 mg + vitamin B12 1 mg compared with matching placebo produces a worthwhile reduction in vascular disease.
Read the detailed description
In observational studies, lower blood cholesterol concentrations are associated with lower coronary risk, without any clear threshold below which lower levels are not associated with lower risk. Cholesterol reduction with statins reduces such risk but there is uncertainty about whether greater reductions with more intensive statin therapy will produce greater benefits. Elevated blood homocysteine levels appear to be an independent marker of cardiovascular risk, but it is unknown whether taking vitamins to reduce homocysteine concentrations will translate into cardiovascular benefit.
12,064 survivors of myocardial infarction have been randomised in a 2x2 factorial design to more intensive versus standard cholesterol-lowering treatment, using 80 mg or 20 mg daily simvastatin, and separately to homocysteine-lowering with folic acid plus vitamin B12 or matching placebo. Follow-up will continue until there are at least 2800 confirmed major vascular events (MVE), defined as non-fatal myocardial infarction, coronary death, stroke or arterial revascularisation. The primary outcome is the incidence of first MVE during the scheduled treatment period.
SEARCH should provide reliable evidence of the effectiveness and safety of more intensive cholesterol-lowering for the reduction of major vascular events in a high-risk population, and of the effects of homocysteine-lowering with folic acid plus vitamin B12.
- Conditions
- Cardiovascular Disease
- Being tested
- Simvastatin 20 mg daily, Folic acid 2 mg + vitamin B12 1 mg daily, Simvastatin 80 mg daily, Placebo
- Keywords
- Myocardial infarction, Coronary heart disease, Cholesterol, Stroke
- Medical subject headings
- Cardiovascular Diseases, Myocardial Infarction, Coronary Disease, Stroke
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Simvastatin 20 mg dailyDrug
Simvastatin 20 mg tablet once daily
Folic acid 2 mg + vitamin B12 1 mg dailyDietary supplement
Folic acid 2 mg + vitamin B12 1 mg tablet once daily
Simvastatin 80 mg dailyDrug
Simvastatin 80 mg tablet once daily
PlaceboDrug
Placebo vitamin B12/folic acid tablet once daily
| Study group | Role | What they receive |
|---|---|---|
| Simvastatin 20 mg + folic acid and B12 | Active comparator | Participants received 20 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily Receives: Drug: Simvastatin 20 mg daily; Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily |
| Simvastatin 80 mg + folic acid and B12 | Active comparator | Participants received 80 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily Receives: Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily; Drug: Simvastatin 80 mg daily |
| Simvastatin 20 mg + placebo | Active comparator | Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily Receives: Drug: Simvastatin 20 mg daily; Drug: Placebo |
| Simvastatin 80 mg + placebo | Active comparator | Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily Receives: Drug: Simvastatin 80 mg daily; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Major Vascular Events (MVE)
Major vascular events (MVE) defined as major coronary events (MCE [non-fatal MI, coronary death or coronary revascularisation]), non-fatal or fatal stroke, or peripheral revascularization (peripheral artery angioplasty or arterial surgery, including amputations), during the scheduled study treatment period.
Measured: 6.7 years median follow-up
Secondary outcomes (5)
MVEs Separately in Year 1 and in Later Years
Measured: 6.7 years median follow-up
MVEs in Patients Subdivided Into 3 Groups by Baseline Low-density Lipoprotein (LDL)
Measured: 6.7 years median follow-up
MVEs in Presence and Absence of the Other Factorial Treatment
Measured: 6.7 years median follow-up
Major Coronary Events
Non-fatal MI, coronary death or coronary revascularisation
Measured: 6.7 years median follow-up
Total Strokes
Measured: 6.7 years median follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jul 2005 (estimated)
- Study startJul 1998
- Primary completionMay 2008
- Study completionMay 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Cardiovascular DiseaseStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 12,064 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Investigators
- Rory Collins, MB BS FRCP, Study director, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00124072
- Sponsor's protocol ID
- CTSUSEARCH1
- Acronym
- SEARCH
- Status last verified
- Jan 2012
- First submitted
- 22 Jul 2005
- Last updated
- 1 Feb 2012
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine
- ClinicalTrials.gov ID
- NCT00124072
- Acronym / sponsor ID
- SEARCH / CTSUSEARCH1
- Conditions
- Cardiovascular Disease
- Keywords
- Myocardial infarction, Coronary heart disease, Cholesterol, Stroke
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12,064 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- Jul 1998
- Primary completion
- May 2008 (actual)
- Study completion
- May 2008 (actual)
- First posted
- 26 Jul 2005 (estimated)
- Results
- Posted 9 Jun 2010
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
SEARCH is a randomised, double-blind, multi-centre United Kingdom (UK) trial of 12,064 patients with myocardial infarction (MI) prior to study entry which aims to demonstrate whether a more intensive cholesterol lowering regimen using 80 mg simvastatin daily produces a larger and worthwhile reduction in cardiovascular events compared with a standard 20 mg daily regimen and whether reducing blood homocysteine levels with a daily dose of folic acid 2 mg + vitamin B12 1 mg compared with matching placebo produces a worthwhile reduction in vascular disease.
Detailed description
In observational studies, lower blood cholesterol concentrations are associated with lower coronary risk, without any clear threshold below which lower levels are not associated with lower risk. Cholesterol reduction with statins reduces such risk but there is uncertainty about whether greater reductions with more intensive statin therapy will produce greater benefits. Elevated blood homocysteine levels appear to be an independent marker of cardiovascular risk, but it is unknown whether taking vitamins to reduce homocysteine concentrations will translate into cardiovascular benefit.
12,064 survivors of myocardial infarction have been randomised in a 2x2 factorial design to more intensive versus standard cholesterol-lowering treatment, using 80 mg or 20 mg daily simvastatin, and separately to homocysteine-lowering with folic acid plus vitamin B12 or matching placebo. Follow-up will continue until there are at least 2800 confirmed major vascular events (MVE), defined as non-fatal myocardial infarction, coronary death, stroke or arterial revascularisation. The primary outcome is the incidence of first MVE during the scheduled treatment period.
SEARCH should provide reliable evidence of the effectiveness and safety of more intensive cholesterol-lowering for the reduction of major vascular events in a high-risk population, and of the effects of homocysteine-lowering with folic acid plus vitamin B12.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Simvastatin 20 mg + folic acid and B12 | Active comparator | Drug: Simvastatin 20 mg daily, Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg dailyParticipants received 20 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily |
| Simvastatin 80 mg + folic acid and B12 | Active comparator | Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily, Drug: Simvastatin 80 mg dailyParticipants received 80 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily |
| Simvastatin 20 mg + placebo | Active comparator | Drug: Simvastatin 20 mg daily, Drug: PlaceboParticipants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily |
| Simvastatin 80 mg + placebo | Active comparator | Drug: Simvastatin 80 mg daily, Drug: PlaceboParticipants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Prior myocardial infarction
- Statin therapy indicated
- No clear indication for folic acid
Key exclusion criteria (9 listed)
- No clear contraindication to study treatments
- Screening plasma total cholesterol <3.5 mmol/l in patient already on statin therapy, or <4.5 mmol/l in patient not on statin therapy
- Chronic liver disease
- Severe renal disease or evidence of renal impairment
- Inflammatory muscle disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Simvastatin 20 mg dailySimvastatin 20 mg tablet once daily | Drug | Simvastatin 20 mg + folic acid and B12, Simvastatin 20 mg + placebo |
| Folic acid 2 mg + vitamin B12 1 mg dailyFolic acid 2 mg + vitamin B12 1 mg tablet once daily | Dietary supplement | Simvastatin 20 mg + folic acid and B12, Simvastatin 80 mg + folic acid and B12 |
| Simvastatin 80 mg dailySimvastatin 80 mg tablet once daily | Drug | Simvastatin 80 mg + folic acid and B12, Simvastatin 80 mg + placebo |
| PlaceboPlacebo vitamin B12/folic acid tablet once daily | Drug | Simvastatin 20 mg + placebo, Simvastatin 80 mg + placebo |
Primary outcome
Major Vascular Events (MVE)
Time frame: 6.7 years median follow-up
Major vascular events (MVE) defined as major coronary events (MCE [non-fatal MI, coronary death or coronary revascularisation]), non-fatal or fatal stroke, or peripheral revascularization (peripheral artery angioplasty or arterial surgery, including amputations), during the scheduled study treatment period.
5 secondary outcomes
MVEs Separately in Year 1 and in Later Years
Time frame: 6.7 years median follow-up
MVEs in Patients Subdivided Into 3 Groups by Baseline Low-density Lipoprotein (LDL)
Time frame: 6.7 years median follow-up
MVEs in Presence and Absence of the Other Factorial Treatment
Time frame: 6.7 years median follow-up
Major Coronary Events
Time frame: 6.7 years median follow-up
Total Strokes
Time frame: 6.7 years median follow-up
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- SEARCH study website (primarily for dissemination of the results)Link provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rory Collins, MB BS FRCP study director
University of Oxford
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Simvastatin 20 mg daily, Folic acid 2 mg + vitamin B12 1 mg daily and Simvastatin 80 mg daily in people with Cardiovascular Disease, run by University of Oxford at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Feb 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Jun 2010). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Major Vascular Events (MVE) (time frame: 6.7 years median follow-up). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2012; AzTrials last refreshed its copy on 26 Oct 2026.