Grodstein 2013.

Methods	Substudy of the Physicians’ Health Study II, a randomised, double‐blind, placebo‐controlled, 2 x 2 x 2 x 2 factorial trial testing ß‐carotene, vitamin E, ascorbic acid, and a multivitamin for their role in preventing chronic diseases including total and prostate cancer, cardiovascular disease, and age‐related eye disease among 14641 male physicians aged 50 years or older. The trial was done from 1997 to 1 June 2011. The cognitive function substudy began in 1998.
Participants	Location: not reported Recruitment: The Physicians’ Health Study II. Quote: "In July 1997, invitations to enrol in PHS II were mailed to eligible participants from PHS I who had been part of an earlier trial of aspirin and beta‐carotene among 22,071 physicians aged 40 to 84 years in 1982. Second, in July 1999, invitation letters were mailed to a new group of male physicians identified from a list provided by the American Medical Association." The substudy of cognitive function was conducted among PHS II participants aged 65 years or older. Number randomised: 2980 in multivitamin, 2967 in placebo Participant (baseline) characteristics: All participants were men. Age, mean (SD): multivitamin: 71.6 (6.0) placebo: 71.6 (5.9) Inclusion criteria: not reported Exclusion criteria: history of cirrhosis or active liver disease, patients receiving anticoagulants, or reported a serious illness that may interfere with study participation Men were also required to forgo current use of multivitamins or individual supplements containing more than 100% of the recommended daily allowance of vitamin E, vitamin C, ß‐carotene, or vitamin A during PHS II follow‐up. For those newly recruited: no history of cancer, active liver disease, current renal disease, peptic ulcer, or gout. Quote: "Only physicians who comply with the pill‐taking regimen at least two‐thirds of the time and remain willing and eligible to participate will be subsequently randomized".
Interventions	Intervention: ß‐carotene (Lurotin, 50 mg on alternate days, or its placebo; BASF, Florham Park, New Jersey); vitamin E (synthetic alfa‐tocopherol, 400 IU on alternate days, or its placebo; BASF); ascorbic acid (synthetic ascorbic acid, 500 mg daily, or its placebo; BASF); multivitamin (Centrum Silver or its placebo daily; Pfizer, New York, New York) NB: Grodstein 2007 reported on the ß‐carotene and Grodstein 2013 on multivitamin supplementation. Comparator group: placebo multivitamin Use of additional interventions (common to both treatment arms): Because of the factorial design, some participants were also taking vitamin E and/or vitamin C. Exposure to study intervention: Mean time from randomisation to initial cognitive assessment was 2.5 years (range, 0.18 to 5.3 years) and mean time from randomisation to the final cognitive assessment was 8.5 years (range, 0.3 to 14.2 years).
Outcomes	Primary Outcomes: A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The cognitive battery included the Telephone Interview for Cognitive Status (TICS); immediate and delayed recall on the East Boston Memory Test (EBMT) (verbal memory); the delayed recall of a 10‐word list (verbal memory); and a category fluency task. The cognitive function substudy began in 1998. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years. Quote: "The beta‐carotene group of the PHS II continued as planned through May 2003... Treatment and follow‐up of the vitamin E and C components continued through August 2007...The multivitamin intervention continued through 1 June 2011.." Eligible cognitive outcomes: global cognitive function measured with TICS episodic memory (verbal memory) measured using an average of z‐scores* for immediate and delayed recall on the EBMT and delayed recall of a 10‐word list executive functioning measured with category fluency: animals named during 1 minute Function outcome extracted: none reported Quality of life outcome extracted: none reported Safety outcome extracted: none reported
Notes	Funding sources, Quote: “National Institutes of Health, BASF, Pfizer, and DSM Nutritional Products." "By grants CA 097193, CA 34944, CA 40360, HL 26490, HL 34595, AG 15933, and T32‐AG000158 from the National Institutes of Health, and an investigator‐initiated grant from BASF. Study agents and packaging were provided by BASF and Pfizer, and study packaging was provided by DSM Nutritional Products." Declarations of interest, quote: “Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum_M13‐1340." Several authors reported some conflicts of interest. Treatment adherence: "83.5% of the multivitamin group and 84.2% of the placebo group reported taking at least two thirds of their study pills".
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “The PHS II is a randomized, double‐blind, placebo‐controlled, 2x2x2x2 factorial trial". "Randomization..using a computer‐generated list of random numbers". Comment: adequate method of random generation
Allocation concealment (selection bias)	Low risk	Quote: “The PHS II is a randomized, double‐blind, placebo‐controlled, 2x2x2x2 factorial trial". Comment: method of allocation concealment not reported, but likely to be adequate
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: “The PHS II is a randomized, double‐blind, placebo‐controlled, 2x2x2x2 factorial trial". Comment: method of blinding not reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: “The PHS II is a randomized, double‐blind, placebo‐controlled, 2x2x2x2 factorial trial". "An Endpoint Committee of physicians blinded to the participants' treatment assignment, will review the medical records for final confirmation of a reported diagnosis". Comment: The method of blinding of outcome assessment for the cognitive substudy was not reported. The statement about the Endpoint Committee is contained in the design paper which, however, does not mention any cognitive outcome.
Incomplete outcome data (attrition bias) All outcomes	Low risk	There was good retention of participants from the first to the second (96%) and the third (90%) assessments. Quote: “the fourth assessment was not attempted in many participants because of trial completion (that is, 2700 (45%) of the initial 5947 who completed the initial interview were invited to participate at the fourth assessment before the trial closed on 1 June 2011)". Comment: 3623 (61%) patients had none of the assessments at last visit so we considered there was a high risk of attrition bias for the final assessment only (time point > 5 to 10 years).
Selective reporting (reporting bias)	Low risk	Comment: No differences identified between the protocol ClinicalTrials.gov: NCT00270647) and the article. All outcomes specified in the Methods were reported in the Results.
Other bias	Low risk	No other risks identified