Petersen 2005

Methods	Design: randomised, placebo‐controlled, double‐blind study Duration: 36 months
Participants	Country: US and Canada Number of centres: 69 Diagnosis: amnestic type of MCI Number of participants: 769 total randomised (ITT: 257 in vitamin E group, 259 in placebo group, 253 in donepezil group) Gender: 46% women Age: 55 to 90 years, mean 73 years Cognitive status: MMSE 24 to 30, mean MMSE 27.3 Inclusion criteria: amnestic MCI of a degenerative nature, impaired memory, a Logical Memory delayed‐recall score approximately 1.5 to 2 SD below an education adjusted‐norm, a CDR of 0.5, MMSE score 24 to 30, and 55 to 90 years of age. adequate vision and hearing for neuropsychological testing, normal vitamin B12 and thyroid function studies and non‐reactive RPR. ECG normal or no clinical significant abnormalities. Study informant available. Exclusion criteria: significant cerebral vascular disease, modified Hachinski > 4; Hamilton Depression Rating Scale > 12; central nervous system infarct, infection or focal lesions of clinical significance on CT or MRI scan. Medical diseases or psychiatric disorders that could interfere with study participation. Pregnant, lactating or of child‐bearing potential; taking vitamin supplements, other supplements or multivitamin. Restriction on concomitant medication usage, including those with significant cholinergic or anticholinergic effects or potential adverse effects on cognition.
Interventions	Treatment 1: vitamin E group (2000 IU total daily dose divided into 2 doses, placebo donepezil and a multivitamin daily) Treatment 2: donepezil group (donepezil 10 mg, placebo vitamin E and a multivitamin daily) Treatment 3: placebo group (placebo vitamin E, placebo donepezil and a multivitamin daily) Note: the initial dose of vitamin E was 1000 IU/day, and the dose was increased to 2000 IU (1000 IU twice daily) after 6 weeks. The multivitamin contained vitamin E 15 IU
Outcomes	Time to possible or probable development of AD MMSE (months 0, 6, 12, 18, 24, 30, 36) ADAS‐Cog (months 0, 6, 12, 18, 24, 30, 36) Global CDR (months 0, 6, 12, 18, 24, 30, 36) ADCS Mild Cognitive Impairment Activities of Daily Living Scale (months 0, 6, 12, 18, 24, 30, 36) GDS (months 0, 6, 12, 18, 24, 30, 36) Neuropsychological battery including; New York University paragraph‐recall test, the Symbol Digit Modalities Test, the category‐fluency test, a number‐cancellation test, the Boston Naming Test, the digits‐backward test, the Clock Drawing Test, and a maze‐tracing task (months 0, 6, 12, 18, 24, 30, 36) Adverse events
Notes	‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants randomly assigned to treatment groups. The authors used "…an adaptive allocation scheme for the treatment assignment, with the MMSE score, age, and APOE e4 status as balancing covariates."
Allocation concealment (selection bias)	Unclear risk	No reference made to the method in which allocation concealment was ensured.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Study described as 'double blind' but authors did not describe how blinding was maintained and whether it was successful. Unclear whether the placebo was identical in appearance to the vitamin E treatment.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Study described as 'double blind' but authors did not describe how blinding was maintained and whether it was successful.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	"The primary analysis was conducted according to the intention‐to‐treat principle." During the double‐blind phase, 72 participants discontinued in the vitamin E group, and 66 in placebo group. Sensitivity analyses suggested no impact of dropouts on the results regarding vitamin E and placebo groups. 76 participants in the vitamin E group and 73 in the placebo group developed AD and switched to open label donepezil. It is not clear how subsequent data from these participants was handled.
Selective reporting (reporting bias)	Low risk	All outcomes reported in accordance with the methods section.
Other bias	Low risk	No evidence of other bias.