Ting 2017.

Methods	Substudy of the VITATOPS trial, a randomised, 2‐arm, parallel group, placebo‐controlled trial.
Participants	Location: VITATOPS was an international, multicentre (20 countries from 4 continents). This substudy took place in a single study centre of the VITATOPS trial in Singapore. Sample size Number randomised: 8164 participants with recent stroke or TIA randomised in VITATOPS. This substudy was of the 230 subjects with recent lacunar stroke and cognitive impairment no dementia (CIND). 118/230 allocated to B vitamins, 112/230 allocated to placebo. Participant baseline characteristics: Age in years (mean (range)): 67 (61‐73) Female sex: 39.6% Cognitive function ‐ MMSE score (median (IQR)): B vitamins 24 (22‐27), placebo 25 (21‐27). Inclusion criteria: "patients presenting within 7 months of stroke (ischaemic or haemorrhagic) or TIA (eye or brain), as defined by standard criteria, are eligible" for VITATOPS. For this substudy, which took place in a single VITATOPS centre, "patients with recent lacunar stroke and cognitive impairment no dementia (CIND) who were followed up every 6 months for 1 to 5 years as per VITATOPS trial protocol were included. CIND was defined as impairment in at least one domain of the neuropsychological test battery using education adjusted cut‐off values of 1.5 SDs below the established normal means on individual tests." Patients who consented for extended cognition study. Exclusion criteria: Taking folic acid or vitamin B6 on medical advice; Taking methotrexate for any reason; Pregnant or at risk of pregnancy; Limited life expectancy.
Interventions	Intervention: Folic acid 2 mg, vitamin B6 25 mg, vitamin B12 500 μg once daily. Comparator: Placebo.
Outcomes	"Neuropsychological tests results focusing on attention and executive functions derived from a standardized cognitive assessment battery that validated for Singaporean elderly was analysed." Standardized MMSE; Digit span forward; Digit span backward; Visual memory span forward; Visual memory span backward; Category naming ‐ animals; Digit cancellation; Frontal assessment battery. Other: serum homocysteine.
Source of Funding	Singapore Biomedical Research Council and Singapore National Medical Research Council.
Declaration of Interest	6/8 authors: no disclosures. "Dr Chen has received support from the Biomedical Research Council, Singapore for current study of vitamin therapy in the prevention of dementia and cognitive deterioration following stroke from 2004 to 2008." "Dr EK Tan has received support from the National Medical Research Council, Duke NUS Graduate Medical school, and has received honoraria for duties as an editor of European Journal of Neurology (Wiley publisher) and Parkinsonism Related Disorders (Elsevier Publisher), and sponsorship from Novartis Pharmaceuticals, GSK Pharmaceuticals and Lundbeck Pharmaceuticals."
Notes	5 of 235 potentially eligible subjects did not consent to participate in this extended cognition substudy.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Parent study (VITATOPS), quote: "a central 24‐hour telephone service or an interactive website ... uses random permuted blocks stratified by hospital to allocate a treatment pack number."
Allocation concealment (selection bias)	Low risk	Parent study (VITATOPS), quote: "a central 24‐hour telephone service or an interactive website ... uses random permuted blocks stratified by hospital to allocate a treatment pack number."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "double‐blind". Parent study (VITATOPS), quote "the tablets being either vitamin supplements or matching placebo".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	No specific information about site investigators. Likely blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	"The number of the study participants at the end of each study year from year one till year five for active and placebo group was 97, 83, 73, 45, 33 and 93, 75, 59, 38, 27 respectively."
Selective reporting (reporting bias)	Unclear risk	Quote: "Neuropsychological tests (sic) results focusing on attention and executive functions derived from a standardized cognitive assessment battery that validated (sic) for Singaporean elderly was analysed." No protocol for substudy identified. Not clear if any outcomes were measured in addition to those reported.
Other bias	Low risk	No other sources of bias identified.