Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine - Full Text View

Sponsor:	University of Oxford
Collaborator:	Merck
Information provided by:	University of Oxford
ClinicalTrials.gov Identifier:	NCT00124072

Purpose

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.

Condition	Intervention	Phase
Cardiovascular Disease	Drug: Simvastatin 20 mg daily Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily Drug: Simvastatin 80 mg daily Drug: Placebo	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Factorial Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Prevention
Official Title:	SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine

Resource links provided by NLM:

MedlinePlus related topics: B Vitamins Cholesterol Heart Attack

Drug Information available for: Cholest-5-en-3-ol (3beta)- Folic acid Vitamin B 12 Hydroxocobalamin Simvastatin Homocysteine

U.S. FDA Resources

Further study details as provided by University of Oxford:

Primary Outcome Measures:

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.

Secondary Outcome Measures:

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 ]

Enrollment:	12064
Study Start Date:	July 1998
Study Completion Date:	May 2008
Primary Completion Date:	May 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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	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
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	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
Active Comparator: Simvastatin 20 mg + placebo Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily	Drug: Simvastatin 20 mg daily Simvastatin 20 mg tablet once daily Drug: Placebo Placebo vitamin B12/folic acid tablet once daily
Active Comparator: Simvastatin 80 mg + placebo Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily	Drug: Simvastatin 80 mg daily Simvastatin 80 mg tablet once daily Drug: Placebo Placebo vitamin B12/folic acid tablet once daily

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.

Eligibility

Ages Eligible for Study:	18 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00124072

Locations

United Kingdom
CTSU, Richard Doll Building, University of Oxford
Oxford, Oxon, United Kingdom, OX3 7LF

Sponsors and Collaborators

University of Oxford

Merck

Investigators

Study Director:

Rory Collins, MB BS FRCP

University of Oxford

More Information

Additional Information:

SEARCH study website (primarily for dissemination of the results) This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Professor Rory Collins, University of Oxford
ClinicalTrials.gov Identifier:	NCT00124072 History of Changes
Other Study ID Numbers:	CTSUSEARCH1
Study First Received:	July 22, 2005
Results First Received:	March 29, 2010
Last Updated:	January 31, 2012
Health Authority:	United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Oxford:

Myocardial infarction
Coronary heart disease
Cholesterol
Stroke

Additional relevant MeSH terms:

Cardiovascular Diseases
Folic Acid
Vitamin B 12
Hydroxocobalamin
Vitamin B Complex
Hematinics
Vitamins
Simvastatin
Micronutrients
Growth Substances
Physiological Effects of Drugs

Pharmacologic Actions
Hematologic Agents
Therapeutic Uses
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on February 09, 2012