Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH)

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by:
University of Oxford
ClinicalTrials.gov Identifier:
NCT00124072
First received: July 22, 2005
Last updated: January 31, 2012
Last verified: January 2012

July 22, 2005
January 31, 2012
July 1998
May 2008   (final data collection date for primary outcome measure)
Major Vascular Events (MVE) [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
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.
Major vascular events (MVE)
Complete list of historical versions of study NCT00124072 on ClinicalTrials.gov Archive Site
  • MVEs Separately in Year 1 and in Later Years [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
  • MVEs in Patients Subdivided Into 3 Groups by Baseline Low-density Lipoprotein (LDL) [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
  • MVEs in Presence and Absence of the Other Factorial Treatment [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
  • Major Coronary Events [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
    Non-fatal MI, coronary death or coronary revascularisation
  • Total Strokes [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
  • MVEs separately in year 1 and in later years
  • MVEs in patients subdivided into 3 groups by baseline LDL
  • MVEs in presence & absence of the other factorial treatment
  • Major coronary events
  • Total strokes
Not Provided
Not Provided
 
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine
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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Cardiovascular Disease
  • Drug: Simvastatin 20 mg daily
    Simvastatin 20 mg tablet once daily
  • Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily
    Folic acid 2 mg + vitamin B12 1 mg tablet once daily
  • Drug: Simvastatin 80 mg daily
    Simvastatin 80 mg tablet once daily
  • Drug: Placebo
    Placebo vitamin B12/folic acid tablet once daily
  • Active Comparator: Simvastatin 20 mg + folic acid and B12
    Participants received 20 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily
    Interventions:
    • Drug: Simvastatin 20 mg daily
    • Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily
  • Active Comparator: Simvastatin 80 mg + folic acid and B12
    Participants received 80 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily
    Interventions:
    • Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily
    • Drug: Simvastatin 80 mg daily
  • Active Comparator: Simvastatin 20 mg + placebo
    Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily
    Interventions:
    • Drug: Simvastatin 20 mg daily
    • Drug: Placebo
  • Active Comparator: Simvastatin 80 mg + placebo
    Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily
    Interventions:
    • Drug: Simvastatin 80 mg daily
    • Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
12064
May 2008
May 2008   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Prior myocardial infarction
  • Statin therapy indicated
  • No clear indication for folic acid

Exclusion Criteria:

  • 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
  • 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
Both
18 Years to 80 Years
No
Contact information is only displayed when the study is recruiting subjects
United Kingdom
 
NCT00124072
CTSUSEARCH1
Yes
Professor Rory Collins, University of Oxford
University of Oxford
Merck Sharp & Dohme Corp.
Study Director: Rory Collins, MB BS FRCP University of Oxford
University of Oxford
January 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP