Stott 2005.

Methods	Factorial 2 X 2 x 2, randomised, placebo‐controlled, double‐blind study with 3 active treatments with 12‐week treatment and 1‐year follow‐up
Participants	Location: United Kingdom and the Netherlands, 2 centres Recruitment: hospital‐based Number randomised: 185 Participant (baseline) characteristics: Age, mean ± SD: placebo: 72.8 ± 5.4 folic acid plus vitamin B12: 72.9 ± 6.0 riboflavin (vitamin B2): 74.6 ± 5.3 vitamin B6: 74.7 ± 6.1 folic acid plus vitamin B12 plus vitamin B2: 76.5 ± 8.0 folic acid plus vitamin B12 plus vitamin B6: 72.6 ± 6.4 vitamin B6 plus vitamin B2: 74.2 ± 6.8 folic acid plus vitamin B12 plus vitamin B2 plus vitamin B6: 74.0 ± 6.5 Gender (male/female): placebo: 14/10 folic acid plus vitamin B12: 12/11 riboflavin (vitamin B2): 10/13 vitamin B6: 11/12 folic acid plus vitamin B12 plus vitamin B2: 10/13 folic acid plus vitamin B12 plus vitamin B6: 12/11 vitamin B6 plus vitamin B2: 10/13 folic acid plus vitamin B12 plus vitamin B2 plus vitamin B6: 9/14 · Main diagnosis: patients aged "65 y with ischemic vascular disease" Inclusion criteria: age ≥ 65 y and Ischaemic vascular disease, defined as one or more of the following: history of angina pectoris, previous acute myocardial infarction, evidence of major ischaemia or previous acute myocardial infarction on the basis of a 12‐lead electrocardiogram, ischaemic stroke, transient ischaemic attack, intermittent claudication, or surgery for peripheral arterial disease Exclusion criteria: acute vascular event < 1 wk previously; major surgery < 1 mo previously; any other major acute illness < 1 mo previously; severe renal impairment (serum creatinine > 400 µmol/L); severe hepatic impairment; malignancy within the previous year (excluding local skin cancer); severe congestive heart failure (New York Heart Association class IV); total anterior cerebral infarct with major residual disability; malabsorption; inability to give informed consent (e.g. due to dementia or dysphasia); major cognitive impairment (Mini‐Mental State Examination score < 19); existing treatment with riboflavin, vitamin B6, vitamin B12, or folic acid preparations; haemoglobin concentration < 10 g/dL; and mean cell volume > 100 fL plus either a low red blood cell folate concentration (< 280 ng/mL) or a low serum vitamin B12 concentration (< 250 pg/mL)
Interventions	Intervention: Folic acid 2.5 mg plus vitamin B12 400 mcg; vitamin B6 25 mg; riboflavin (vitamin B2) 25 mg; placebo in a 2 x 2 x 2 factorial design folic acid plus vitamin B12: 23 vitamin B6: 23 riboflavin (vitamin B2): 23 folic acid plus vitamin B12 plus vitamin B2: 23 folic acid plus vitamin B12 plus vitamin B6: 23 vitamin B6 plus vitamin B2: 23 folic acid plus vitamin B12 plus vitamin B2 plus vitamin B6: 23 Comparator: placebo: 24 Intervention or placebo were continued for 12 weeks. The daily dose was provided in a total of 2 capsules (1 red and 1 white), irrespective of patient group. Quote: "The patients initially entered a single‐blind, placebo, run‐in phase lasting between 2 and 4 weeks. Patients who successfully completed the run‐in phase were randomly allocated". Use of additional interventions (common to both treatment arms): not reported
Outcomes	Overall cognitive function was assessed by using the Telephone Interview for Cognitive status (TICSm) at both baseline visits and at 6 and 12 months; attention and speed of information processing were assessed by using the Letter Digit Coding Test (at both baseline visits and 12 months). Serious adverse events, including incident vascular events, were recorded at each review.
Notes	Funding sources, quote: “Supported by a grant from the Healthcare Foundation (reference 112/57)." Declarations of interest, quote: “None of the authors had any conflicting or competing interests, and the funder of the study had no role in data collection, analysis, or interpretation of the data or in the writing of the report."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Allocation was determined at a site remote from the clinical study (Robertson Centre for Biostatistics) in randomized permuted blocks of 8, stratified by hospital center." Comment: adequate method of random sequence generation
Allocation concealment (selection bias)	Low risk	Quote: “Allocation was determined at a site remote from the clinical study (Robertson Centre for Biostatistics) in randomized permuted blocks of 8, stratified by hospital center." Comment: adequate method of allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “Treatment allocation was concealed from the patients and the investigators (double‐blind)." Comment: adequate method of participants and personnel blinding
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “Treatment allocation was concealed from the patients and the investigators (double‐blind)." Comment: adequate method of outcome assessment blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: Numbers of participants missing outcome data calculated from tables. 18/185 (10%) missing data for TICSm at 1 year. 39/185 (21%) missing data for LDCT at 1 year. Dropouts not mentioned in paper. No reasons for missing data given. Presumed completers analysis.
Selective reporting (reporting bias)	High risk	Quote: from ISRCTN registry “Retrospectively registered” “Primary outcome measures: 1. Serum HCY, plasma von Willebrand factor, vitamin levels (red cell folate, serum vitamin B12, B2, and B6) 2. Piloting of telephone follow‐up of cognition (Telephone Interview for Cognitive Status (TICSm)) and of disability (Barthel Index and short Instrumental Activities for Daily Living (ADL) scale). Secondary outcome measures: not provided at time of registration." Comment: Disability and IADL (relevant to this review) not reported in paper.
Other bias	Low risk	Comment: no other risks identified