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

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ClinicalTrials.gov Identifier: NCT00124072
Recruitment Status : Completed
First Posted : July 26, 2005
Results First Posted : June 9, 2010
Last Update Posted : February 1, 2012
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by:
University of Oxford

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Factorial Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition Cardiovascular Disease
Interventions Drug: Simvastatin 20 mg daily
Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily
Drug: Simvastatin 80 mg daily
Drug: Placebo
Enrollment 12064
Recruitment Details First Patient In: 28-SEP-1998, Last Patient Last Visit: 22-May-2008 Eighty-eight (88) sites in 3 countries: England 72, Scotland 12 and Wales 4.
Pre-assignment Details Patients entered a run-in period during which they received simvastatin 20 mg daily and placebo-vitamin tablets for 2 months. Eligible patients who completed run-in were then randomized in a 2x2 factorial blinded design between simvastatin 80 mg daily versus simvastatin 20 mg daily and folic acid 2 mg + vitamin B12 1 mg daily versus placebo.
Arm/Group Title Simvastatin 20 mg + Folic Acid and B12 Simvastatin 80 mg + Folic Acid and B12 Simvastatin 20 mg + Placebo Simvastatin 80 mg + Placebo
Hide Arm/Group Description Participants received 20 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily Participants received 80 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily
Period Title: Overall Study
Started 3017 3016 3016 3015
Completed 2503 2504 2524 2515
Not Completed 514 512 492 500
Reason Not Completed
Lost to Follow-up for Mortality             0             3             2             2
Lost to Follow-up for Morbidity             15             25             19             18
Death             499             484             471             480
Arm/Group Title Simvastatin 20 mg + Folic Acid and B12 Simvastatin 80 mg + Folic Acid and B12 Simvastatin 20 mg + Placebo Simvastatin 80 mg + Placebo Total
Hide Arm/Group Description Participants received 20 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily Participants received 80 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily Total of all reporting groups
Overall Number of Baseline Participants 3017 3016 3016 3015 12064
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3017 participants 3016 participants 3016 participants 3015 participants 12064 participants
64.2  (8.9) 64.2  (8.9) 64.2  (8.9) 64.2  (8.9) 64.2  (8.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3017 participants 3016 participants 3016 participants 3015 participants 12064 participants
Female
513
  17.0%
514
  17.0%
513
  17.0%
512
  17.0%
2052
  17.0%
Male
2504
  83.0%
2502
  83.0%
2503
  83.0%
2503
  83.0%
10012
  83.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United Kingdom Number Analyzed 3017 participants 3016 participants 3016 participants 3015 participants 12064 participants
3017 3016 3016 3015 12064
1.Primary Outcome
Title Major Vascular Events (MVE)
Hide Description 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.
Time Frame 6.7 years median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin 20 mg Daily Simvastatin 80 mg Daily Folic Acid 2 mg + Vitamin B12 1 mg Daily Placebo
Hide Arm/Group Description:
Simvastatin 20 mg tablet once daily in the following arms: simvastatin 20 mg daily + folic acid 2 mg and vitamin B12 1 mg daily (active); simvastatin 20 mg daily + placebo vitamin B12/folic acid
Simvastatin 80 mg tablet once daily in the following arms: simvastatin 80 mg daily + folic acid 2 mg and vitamin B12 1 mg daily (active); simvastatin 80 mg daily + placebo vitamin B12/folic acid
Folic acid 2 mg + vitamin B12 1 mg tablet once daily in the following arms: simvastatin 20 mg daily + folic acid 2 mg and vitamin B12 1 mg daily (active); simvastatin 80 mg daily + folic acid 2 mg and vitamin B12 1 mg daily (active)
Placebo vitamin B12/folic acid tablet once daily in the following arms: simvastatin 20 mg daily + placebo vitamin B12/folic acid; simvastatin 80 mg daily + placebo vitamin B12/folic acid
Overall Number of Participants Analyzed 6033 6031 6033 6031
Measure Type: Number
Unit of Measure: Participants
1553 1477 1537 1493
2.Secondary Outcome
Title MVEs Separately in Year 1 and in Later Years
Hide Description [Not Specified]
Time Frame 6.7 years median follow-up
Outcome Measure Data Not Reported
3.Secondary Outcome
Title MVEs in Patients Subdivided Into 3 Groups by Baseline Low-density Lipoprotein (LDL)
Hide Description [Not Specified]
Time Frame 6.7 years median follow-up
Outcome Measure Data Not Reported
4.Secondary Outcome
Title MVEs in Presence and Absence of the Other Factorial Treatment
Hide Description [Not Specified]
Time Frame 6.7 years median follow-up
Outcome Measure Data Not Reported
5.Secondary Outcome
Title Major Coronary Events
Hide Description Non-fatal MI, coronary death or coronary revascularisation
Time Frame 6.7 years median follow-up
Outcome Measure Data Not Reported
6.Secondary Outcome
Title Total Strokes
Hide Description [Not Specified]
Time Frame 6.7 years median follow-up
Outcome Measure Data Not Reported
Time Frame 6.7 years median follow-up
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Simvastatin 20 mg Daily Simvastatin 80 mg Daily Folic Acid 2 mg + Vitamin B12 1 mg Daily Placebo
Hide Arm/Group Description Simvastatin 20 mg tablet once daily in the following arms: simvastatin 20 mg daily + folic acid 2 mg and vitamin B12 1 mg daily (active); simvastatin 20 mg daily + placebo vitamin B12/folic acid Simvastatin 80 mg tablet once daily in the following arms: simvastatin 80 mg daily + folic acid 2 mg and vitamin B12 1 mg daily (active); simvastatin 80 mg daily + placebo vitamin B12/folic acid Folic acid 2 mg + vitamin B12 1 mg tablet once daily in the following arms: simvastatin 20 mg daily + folic acid 2 mg and vitamin B12 1 mg daily (active); simvastatin 80 mg daily + folic acid 2 mg and vitamin B12 1 mg daily (active) Placebo vitamin B12/folic acid tablet once daily in the following arms: simvastatin 20 mg daily + placebo vitamin B12/folic acid; simvastatin 80 mg daily + placebo vitamin B12/folic acid
All-Cause Mortality
Simvastatin 20 mg Daily Simvastatin 80 mg Daily Folic Acid 2 mg + Vitamin B12 1 mg Daily Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Simvastatin 20 mg Daily Simvastatin 80 mg Daily Folic Acid 2 mg + Vitamin B12 1 mg Daily Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5037/6033 (83.49%)   5024/6031 (83.30%)   5068/6033 (84.00%)   4993/6031 (82.79%) 
General disorders         
Other   3484/6033 (57.75%)  3547/6031 (58.81%)  3531/6033 (58.53%)  3500/6031 (58.03%) 
Vascular disorders         
MVE   1553/6033 (25.74%)  1477/6031 (24.49%)  1537/6033 (25.48%)  1493/6031 (24.76%) 
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2.5%
Simvastatin 20 mg Daily Simvastatin 80 mg Daily Folic Acid 2 mg + Vitamin B12 1 mg Daily Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   479/6033 (7.94%)   493/6031 (8.17%)   480/6033 (7.96%)   492/6031 (8.16%) 
Gastrointestinal disorders         
Abdominal pain or indigestion *  143/6033 (2.37%)  167/6031 (2.77%)  156/6033 (2.59%)  154/6031 (2.55%) 
General disorders         
Tiredness or lethargy *  165/6033 (2.73%)  152/6031 (2.52%)  162/6033 (2.69%)  155/6031 (2.57%) 
Other and unspecified symptom or problem *  171/6033 (2.83%)  174/6031 (2.89%)  162/6033 (2.69%)  183/6031 (3.03%) 
*
Indicates events were collected by non-systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: CTSU Reception
Organization: CTSU, University of Oxford
Phone: 01865 743743
Responsible Party: Professor Rory Collins, University of Oxford
ClinicalTrials.gov Identifier: NCT00124072     History of Changes
Other Study ID Numbers: CTSUSEARCH1
First Submitted: July 22, 2005
First Posted: July 26, 2005
Results First Submitted: March 29, 2010
Results First Posted: June 9, 2010
Last Update Posted: February 1, 2012