Kesse‐Guyot 2011.

Methods	Substudy of the SU.VI.MAX, a randomised, double‐blind, placebo‐controlled, primary prevention trial
Participants	Location: France, number of sites not reported for the cognitive substudy Recruitment: selected French participants aged 45–60 years who were enrolled in the SU.VI.MAX study (1994–2002). Quote: "A total of 12,741 individuals were included for a planned follow‐up of 8 y. At the end of the supplementation (2002), a total of 6850 subjects who agreed to participate in a post‐supplementation follow‐up were included in the SU.VI.MAX 2 study, which sought to investigate the effect of nutrition on the quality of aging." Sample size: Number randomised: 6850 of the 12741 people randomised in the SU.VI.MAX study had agreed to participate in the follow‐up study (SU.VI.MAX 2), which included a cognitive evaluation, but the authors reported only on the 5583 participants who were aged 45‐60 years at the onset of the treatment period. Number completed: 4447 (see Inclusion criteria below*) Participant (baseline) characteristics: Age at baseline: placebo (n = 2071): 52.1 ± 4.6, supplementation (n = 2376): 52.1 ± 4.5 Age at cognitive evaluation: placebo (n = 2071): 65.5 ± 4.6, supplementation (n = 2376): 65.5 ± 4.5 Male sex: placebo: 52.2% (n = 1080), supplementation: 51.7% (n = 1229) *Inclusion criteria: Quote: "Of the 6850 participants in the SU.VI.MAX 2 study, for the current analysis we selected participants who were 45–60 y old at baseline, had undergone a cognitive evaluation, and had available baseline data for serum antioxidants, smoking status, and alcohol consumption." Exclusion criteria: not reported
Interventions	Intervention (n = 2376): daily vitamin C (120 mg), beta‐carotene (6 mg), vitamin E (30 mg), selenium (100 µg), and zinc (20 mg) in combination Comparison (n = 2071): placebo N.B. Intervention period was 8 years (1994‐2002). Cognitive outcomes in SU.VI.MAX 2 were measured in 2007‐9, a mean of 5.9 (± 0.4) years after the end of the intervention in both groups.
Outcomes	Outcomes of interest in the review: Episodic memory: RI‐48 test Executive function: category fluency Speed of processing: time taken to complete the Delis‐Kaplan trail‐making test (TMT)
Notes	Funding source: "Supported by the Agence Nationale de Recherche (no. ANR‐05‐PNRA‐ 010), Direction Générale de la Santé (Ministry of Health), Mederic, Sodexo, Ipsen, the Mutuelle Générale de l’Education Nationale (MGEN), and Pierre Fabre. Mederic and MGEN are French health insurance organizations that are complementary to the national health insurance system. Ipsen and Pierre Fabre are private pharmaceutical companies. They provided financial support for the overall implementation of the research project. Sodexo, a catering company, provided financial support for several teamwork events with researchers and study participants. Because French public research is independent, the sponsors were not involved in the analysis or interpretation of the findings." Declarations of interest: "None of the authors had a conflict of interest". Treatment adherence: "At the end of the trial phase (2002), 84% of the participants reported having taken at least three‐fourths of the capsules independent of the allocated supplementation group".
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Random treatment allocation was performed by block‐sequence generation stratified by sex and age group." Comment: Should be adequate, since team included statisticians and computing staff who handled the data.
Allocation concealment (selection bias)	Low risk	Quote: “Randomization was concealed from subjects and all investigators except for the few who were in charge of capsule labelling." Comment: Should be adequate.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Capsules were prepared in 52 weekly packages of 7 capsules and delivered each year in a box labelled with the participant’s number and a 10‐digit lot number" "..a matching placebo". "The absence of an easy way to distinguish antioxidant from placebo capsules was tested in a pilot study", "double‐blind" Comment: Blinding of participants and personnel seemed adequate.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “Once a possible event is suspected, all relevant records,...are collected from the hospitals, laboratories, or institutions or from the participants by the SU.VI.MAX medical investigators and are examined at the study coordinating centre". Comment: It was not reported if outcome assessment was blinded for adverse events. However, the blinding should be adequate for cognitive function since the patients and investigators were well blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 1136 of 5583 (20%) of the eligible patients were not included in the analysis because of missing cognitive data.
Selective reporting (reporting bias)	Unclear risk	Comment: Cognitive outcomes were not mentioned in the protocol of the main study.
Other bias	High risk	Participants in this study were those who responded to an invitation 6 years after the end of the parent study. The authors described this subsample of the original trial population as "more compliant and health conscious, as shown by the comparison between included and excluded subjects." This may work to reduce any difference between groups.