Petersen 2005.

Methods	3‐arm, parallel group, randomised, controlled trial, duration 3 years
Participants	Location: United States and Canada. Setting of recruitment and treatment: 69 ADCS sites in the United States and Canada, between March 1999 and January 2004. Sample size: · Number randomised: 257 in intervention, 259 in comparison. · Number completed: 185 in intervention, 193 in comparison. Participant baseline characteristics: Age in years (mean ± SD): placebo 72.9 ± 7.6, vitamin E 72.8 ± 7.3. Female sex: placebo 121 (47%), vitamin E 119 (46%). Cognitive function ‐ MMSE score (mean ± SD): placebo 27.35 ± 1.8, vitamin E 27.20 ± 1.9 Inclusion criteria: Amnestic mild cognitive impairment of a degenerative nature (insidious onset and gradual progression); Age 55‐90 years, inclusive; Study informant available; MMSE 24‐30; Adequate vision and hearing for neuropsychological testing; Normal vitamin B12 level and thyroid function studies and non‐reactive RPR; Electrocardiogram normal or no clinically significant abnormalities; CDR 0.5 ‐ Memory box score 0.5 or 1 and No box score greater than 1; All subjects and study informants signed. Exclusion criteria: Significant cerebral vascular disease ‐ Modified Hachinski > 4; Depression ‐ Hamilton Depression Rating Scale > 12; Central nervous system infarct, infection, or focal lesions of clinical significance on CT or MRI scans; Medical diseases or psychiatric disorders that could interfere with study participation; Pregnant, lactating, or of child bearing potential; Taking vitamin supplements, other supplements, or a multivitamin; Restrictions on concomitant medication usage, including those with significant cholinergic or anticholinergic effects or potential adverse effects on cognition.
Interventions	Active intervention: 2000 IU of vitamin E and multivitamin containing 15 IU of vitamin E daily. Intial vitamin E dose was 1000 IU daily, increased to 2000 IU (1000 IU twice daily) after 6 weeks. Comparator group: Placebo vitamin E and multivitamin containing 15 IU of vitamin E daily. Note: There was a third arm in which participants received donepezil. Both groups of interest in this review received placebo donepezil.
Outcomes	Outcomes of interest in the review: Progression to possible or probable Alzheimer’s disease, defined according to the clinical criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer’s Disease and Related Disorders Association. Overall cognitive function: MMSE (also measured: ADAS‐cog). Specific cognitive subdomain: episodic memory: standardised composite z‐score incorporating ADAS immediate and delayed word‐recall scores and the New York University immediate and delayed paragraph‐recall scores. Specific cognitive subdomain: executive function: standardised composite z‐score incorporating the digits‐backward test, Symbol Digit Modalities Test, and number‐cancellation test. Clinical global impression: CDR sum of boxes, Global Deterioration Scale. Functional performance: ADCS Mild Cognitive Impairment Activities of Daily Living Scale. Adverse events: rates of adverse events that occurred in at least 5% of subjects in the donepezil or vitamin E group and at least two times in the placebo group during the double‐blind phase.
Source of Funding	Supported by a grant from the National Institute on Aging (UO1 AG10483) (50% of funding), and by Pfizer and Eisai (50% of funding). DSM Nutritional Products donated the vitamin E.
Declaration of Interest	Most authors were either employees of a pharmaceutical company funding the study, or had received fees for various engagements from pharmaceutical companies.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "We used an adaptive allocation scheme for the treatment assignment, with the MMSE score, age, and APOE ϵ4 status as balancing covariates. Comment: Adequate sequence generation in the study.
Allocation concealment (selection bias)	Low risk	Comment: Insufficient information given. Should be adequate in a large multicentre well designed study.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “In this multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study, which was conducted between March 1999 and January 2004”. Comment: Insufficient information on the process of double‐blinding. Should be adequate in a large multicentre RCT. Placebos used and identical treatment regimens in all groups.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "A data and safety monitoring board reviewed the blinded safety data every three months during the trial.".. "verification by a central review committee that a participant met these clinical criteria for Alzheimer’s disease..." Comment: Should be adequate in a large trial with safety and central review committees for main outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	Only 185/257 (72%) in intervention and 193/259 (75%) completed review. Comment: More than 25% dropout from each arm.
Selective reporting (reporting bias)	High risk	No protocol identified. Cognitive results reported as composite z‐scores, individual test results not reported. Number of participants in each analysis not reported.
Other bias	Low risk	No other potential biases detected.