Dangour 2015.

Methods	2‐arm, double‐blinded, multicentre, parallel group RCT, with 12 months of treatment and follow‐up
Participants	Location: 7 general practices in South East England Recruitment: recruited at GP by mail, baseline appointment and 12‐month follow‐up at King’s College Hospital, London, treatment one tablet daily at home Sample size: · Number randomised: 99 in intervention, 102 in comparison · Number completed: 91 in intervention, 92 in comparison Group A (B vitamins) baseline characteristics: age (mean ± SD): 79.9±3.5 gender (n) : 46 males, 54 females main diagnosis: no diagnosis Group B (placebo) baseline characteristics: age: 80.1 ± 3.7 gender: 48 males, 54 females main diagnosis: no diagnosis (Inclusion criteria:) Age: ≥ 75 years, Participants with a Mini‐Mental State Examination score > 24 (maximum score 30) were asked to provide a blood sample to assess serum vitamin B12 and haemoglobin concentration. Those with moderate vitamin B12 deficiency who did not have anaemia (serum vitamin B12 concentrations ≥ 107 and < 210 pmol/L were eligible to join the trial. The diagnostic criterion used for dementia/cognitive impairment screening was the MMSE. Only those with a score > 24 were eligible to join the trial. (Exclusion criteria:) Diabetes, dementia, epilepsy, alcohol addiction, pacemakers (and other implanted metallic devices where central neurophysiologic testing was contraindicated), residents of nursing homes, diagnosis of pernicious anaemia, current consumption of vitamin B12 supplements and those who had received a vitamin B12 injection within the previous 6 months. Individuals with very low vitamin B12 concentrations (< 107 pmol/L, which is a cutoff typically used for deficiency) or who were shown to have anaemia (haemoglobin concentration, 110 g/L for women and 120 g/L for men) were excluded.
Interventions	Intervention (n = 97): vitamin B12 (cyanocobalamin), oral administration, 1 mg tablet/day, 12 months Comparator group (n = 97): placebo tablet administered once daily identical to intervention in shape, size, colour, smell, taste, and identically packaged Use of additional interventions (common to both treatment arms): not reported
Outcomes	Outcomes of interest in the review: Episodic memory measured with California Verbal Learning Test at delayed recall, with higher values indicating benefit Executive function measured with verbal fluency, with higher values indicating benefit Speed of processing measured with Choice Reaction time, with lower values indicating benefit
Notes	Funding sources: Supported by the Food Standards Agency (N05072) and the Department of Health. National Health Service. Research and Development and King’s College Hospital Trust Research and Development provided service support costs. Declarations of interest: none declared Treatment adherence: Adherence was measured by counting the number of tablets returned at the end of the study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Allocation codes were obtained from a central computerized randomization service." Comment: adequate method of random sequence generation
Allocation concealment (selection bias)	Low risk	Quote: “Allocation codes were obtained from a central computerized randomization service." Comment: adequate method of allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “All study personnel were blinded to the treatment allocation." “Allocated treatment consisted of a single tablet administered daily that was identical in size, shape, color, smell, and taste for both the intervention and placebo and packaged into identical pots.” Comment: As all participants were given identical tablets this ensured blinding was maintained.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “All study personnel were blinded to the treatment allocation." “Allocated treatment consisted of a single tablet administered daily that was identical in size, shape, color, smell, and taste for both the intervention and placebo and packaged into identical pots.” Comment: Study mentions personnel were blinded to treatment allocation and due to identical tablets this would have maintained appropriate blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: Cognitive outcome data were available for 184/201 participants (92%). Dropout rates and reasons were similar in both groups.
Selective reporting (reporting bias)	Low risk	Comment: followed study protocol, no reporting bias found
Other bias	Low risk	Comment: none found