McMahon 2006.

Methods	2‐arms, placebo‐controlled, randomised clinical trial with intervention of 2 years and follow‐up duration of 2 years. No mean or median (range) follow‐up reported.
Participants	Location: Dunedin, New Zealand, number of centres involved unclear Recruitment: Department of Human Nutrition, University of Otago Number randomised: 138 in intervention, 138 in comparison Participant (baseline) characteristics: Age, years, mean (SD) placebo (n=126): 73.4 ± 5.7 vitamin (n=127): 73.6 ± 5.8 Female sex, n (%): placebo (n=126): 65 (52) vitamin (n=127): 47 (37) Inclusion criteria:· age of 65 years or older. Those with a fasting homocysteine concentration of at least 13 µmol/L and a normal plasma creatinine concentration (133 µmol/L (1.5 mg/dL) in men and 115 µmol/L (1.3 mg/dL) in women) were invited to participate in the trial. Exclusion criteria: ineligible if they had suspected dementia; were taking medications known to interfere with folate metabolism (e.g. oral hypoglycaemic agents or antiepileptic agents); were taking vitamin supplements containing folic acid, vitamin B12, or vitamin B6; were being treated for depression; had diabetes or had a history of stroke or transient ischaemic attacks. Quote: "Five participants (three in the placebo group and two in the vitamin group) had a baseline MMSE score of less than 26."
Interventions	Intervention (n=138): Treatment capsules contained the filler plus 1000 μg of folate (the calcium salt of l‐5‐methyltetrahydrofolate), 500 μg of vitamin B12 (cobalamin), and 10 mg of vitamin B6 (pyridoxine) (Merck Eprova). Comparator group (n=133): placebo. The placebo capsules contained a blend of magnesium stearate and microcrystalline cellulose as a filler. All capsules were gelatin‐coated, identical in colour and shape, and packaged in blister packs.
Outcomes	Primary outcomes: scores on tests of cognition including Mini–Mental State Examination, Wechsler Paragraph Recall test, Category Word Fluency test, Rey Auditory Verbal Learning Test, trials I–V, Rey Auditory Verbal Learning Test, trial VII, Raven’s Progressive Matrices, Controlled Oral Word Association Test, Part B of the Reitan Trail Making Test, the National Adult Reading Test (at baseline). Secondary Outcomes: biochemical measurements, including plasma concentrations of homocysteine, folate, and vitamin B12 Eligible cognitive outcomes: global cognitive function measured with MMSE at 1 and 2 years, with higher values indicating benefit executive functioning measured with Raven's Progressive Matrices at 1 and 2 years, with higher values indicating benefit executive functioning measured with Part B of the Reitan Trail Making at 1 and 2 years, with lower values indicating benefit executive function measured with Category Word Fluency test (total no. of words generated in three 1‐min tests) at 1 and 2 years, with higher values indicating benefit episodic memory measured with Rey Auditory Verbal Learning, Trials I‐V at 1 and 2 years, with higher values indicating benefit* episodic memory measured with Wechsler Paragraph Recall test at 1 and 2 years, with higher values indicating benefit episodic memory measured with Rey Auditory Verbal Learning, Trial VII at 1 and 2 years, with higher values indicating benefit
Notes	Funding sources: supported by an Otago Research Grant, Merck Eprova for providing the vitamin and placebo capsules Declarations of interest: No potential conflict of interest relevant to this article was reported. Treatment adherence: Compliance was assessed by counting returned capsules. Data on compliance were not reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Before randomization, all eligible participants were stratified according to the median values for age and homocysteine concentration in the screening population. Random decimals between 0 and 1 were generated for each person in each of the four strata. Those below the median of the random numbers in each stratum were assigned to the vitamin group, and the remainder were assigned to the placebo group." Comment: adequate method of sequence generation
Allocation concealment (selection bias)	Unclear risk	Quote: "Random decimals between 0 and 1 were generated for each person in each of the four strata. Those below the median of the random numbers in each stratum were assigned to the vitamin group, and the remainder were assigned to the placebo group." Comment: unclear method of allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "We conducted a two‐year, double‐blind, placebo‐controlled, randomized clinical trial". "All capsules were gelatin‐coated, identical in color and shape, and packaged in blister packs." Comment: Participants and personnel were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "One of the authors administered all the cognitive tests." Comment: unclear whether outcome assessment was blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: < 10% of randomised patients were not included in the analysis.
Selective reporting (reporting bias)	Low risk	Comment: All the primary and secondary outcomes mentioned in the Methods and protocol were reported.
Other bias	Low risk	Comment: none identified