Methods	Design: Randomised, double-blind, placebo-controlled trial. Multicentre international study. Follow-up period: 2 years.
Participants	N: 3680 patients randomised (high dose: 1827 versus low dose: 1853 patients) Sex (% male): high dose: 62.3% versus low dose: 62.8%. Age (mean±SD): high dose: 66.4 (10.8) versus low dose: 66.2 (10.8) Inclusion criteria: Nondisabling ischemic stroke(Modified Rankin Stroke Scale 3): Onset 120 days before randomization. Focal neurological deficit of likely atherothrombotic origin, classified as ischemic stroke by questionnaire/algorithm or confirmed as new cerebral infarction consistent with symptoms by cranial computed tomography or brainmagnetic resonance imaging, Total homocysteine level 25th percentile for North American stroke population, Age: ≥ 35 years, Accessibility for follow-up, Agreement to take study medication and not take other multivitamins or pills containing folic acid or vitamin B6, Written informed consent. Exclusion criteria: Potential sources of emboli (atrial fibrillation within 30 days of stroke, prosthetic cardiac valve, intracardiac thrombus or neoplasm, or valvular vegetation), Other major neurological illness that would obscure evaluation of recurrent stroke, Life expectancy 2 years, Renal failure requiring dialysis, Untreated anemia or untreated vitamin B12 deficiency, Systolic blood pressure 185mmHg or diastolic blood pressure 105 mm Hg on 2 readings 5 minutes apart at time of eligibility determination, Refractory depression, severe cognitive impairment, or alcoholism or other substance abuse, Use within the last 30 days of medications that affect total homocysteine level (methotrexate, tamoxifen, levodopa, niacin, or phenytoin) or bile acid sequestrants that can decrease folate levels, Childbearing potential, Participation in another trial with active intervention, General anesthesia or hospital stay of 3 days, any type of invasive cardiac instrumentation, or endarterectomy, stent placement, thrombectomy, or any other endovascular treatment of carotid artery within 30 days prior to randomization or scheduled to be performed within 30 days after randomization
Interventions	High dose multivitamin therapy 2.5 mg folic acid; 0.4 mg vitamin B12; 25 mg vitamin B6 per day Low dose multivitamin therapy 20 micrograms folic acid; 6 micrograms vitamin B12; 200 micrograms vitamin B6 per day Co-interventions: Risk factor control education Aspirin (325 mg/d). Duration Treatment: Not described
Outcomes	Primary outcome: Recurrent cerebral infarction. Secondary outcomes: Coronary heart disease, including: myocardial infarction requiring hospitalisation; coronary revascularization; and fatal coronary heart disease Death.
Notes	Study phase: III Sample size calculation a priori: Sample size calculation (80% power a .05 significance level for a 2-sided test) to detect a 30% reduction in the rate of primary endpoint over 2 years of follow up (assuming a 8% of events in the first year and a 4% at the second year, with a 20% of losses of follow up). These numbers resulted in an estimation of 1800 patients per group. Trialists planned up to 6 interim analyses Sponsors: Supported by the National Institute of Neurological Disorders and Stroke (grant RO1 NS34447). The study medication was provided by Roche Inc. They had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript Other: Elegible patients were tested for treatment compliance giving a 1-month low dose vitamins. Only persons taking at least 75% of treatment were randomised
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	The allocation of participants was programmed by the statistical coordinating center, encrypted, and entered into a data entry program installed on a studycomputer at each site
Allocation concealment?	Yes	Allocation programmed by the statistical coordinating centre. All the information on assignment were encrypted an entered in computers in study sites. After verification of eligibility participants were assigned in 1 of 20 medication codes
Blinding? All outcomes	Yes	The drug distributor centre bottled and distributed the vitamins, that were manufacture to be indistinguishable in colour, weight or ability to be dissolved in water The primary endpoint was reviewed by a local neurologist and two external independent review neurologists
Incomplete outcome data addressed? All outcomes	Unclear	132 patients in the low dose group, and 133 in the high dose were lost to follow up. Of these 18 and 13 patients respectively had no contact after randomisation, and were not included in the analysis. 186 patients in the low dose group, and 179 in the high dose discontinued the assigned treatment Patients that had not completed the planned follow up were invited to an exit visit