Petersen 2005

Methods	Randomised, placebo‐controlled, double‐blind study
Participants	Country: US and Canada Multicentre Diagnosis: amnestic type of MCI Subjects: 769 (46% females) Age: 55 to 90 years, mean 73 years 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, a score of 24 to 30 on the MMSE, and an age of 55 to 90 years. 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 multi‐vitamin. Restriction on concomitant medication usage, including those with significant cholinergic or anticholinergic effects or potential adverse effects on cognition
Interventions	Both vitamin E and donepezil were tested using a parallel group design, with 3 groups, vitamin E group (vitamin E 2000 IU, placebo donepezil and a multivitamin daily), donepezil group (donepezil 10 mg, placebo vitamin E and a multivitamin daily), and placebo group (placebo vitamin E, placebo donepezil and a multivitamin daily). The multivitamin contained vitamin E 15 IU N.B. 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
Outcomes	1. The time to possible or probable development of AD 2. MMSE 3. ADAS‐Cog 4. Global CDR 5. ADCS Mild Cognitive Impairment Activities of Daily Living Scale 6. GDS 7. 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 8. Adverse events
Notes	‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random assignment of participants using an adaptive allocation scheme with MMSE score, age and APoE A4 status as a balancing covariates
Allocation concealment (selection bias)	Unclear risk	No reference was made to the method in which allocation concealment was ensured
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants and personnel were blinded, though no evidence was presented to suggest if this was maintained throughout the study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	There was no information presented about how the study controlled for detection bias
Incomplete outcome data (attrition bias) All outcomes	Low risk	This was an intention‐to‐treat analysis with 230 subjects withdrawing during the double‐blind phase and 539 subjects completing the double‐blind or the open‐label phase, or both phases. A sensitivity analysis was carried out that showed no significant difference in the results regarding vitamin E and placebo groups
Selective reporting (reporting bias)	Low risk	All outcomes reported sufficiently
Other bias	Low risk	No evidence of other bias