Sano 1996

Methods	Design: randomised, placebo‐controlled, double‐blind study Duration: 24 months
Participants	Country: US Multicentre: 23 sites Diagnosis: probable AD according to NINCDS‐ADRDA Number of participants: 341 total randomised (completers: 85 in vitamin E group, 84 in placebo group, 87 in selegiline group, 85 in selegiline + vitamin E group) Gender: 65% women Age: mean 73 years Ethnicity: not described Cognitive status: mean MMSE 12.6 Inclusion criteria: diagnosis of probable AD, aged ≥ 45 years, fluent in English or Spanish, CDR score 2, modified Hachinski score 4, supervised by a responsible carer. Exclusion criteria: other central nervous system or psychiatric diagnosis; achieving end point on any primary outcome measure at time of entry; participation in any other investigational drug study or treatment with a psychoactive medication within 2 months of initiation of this trial; treatment with antiparkinsonian medications; recent initiated treatment for a non‐psychiatric condition with an agent to have psychoactive properties (e.g. beta‐blockers, calcium channel blockers). Entry permitted if medication and dose had been stable for 3 months prior to entry into the protocol; antilipaemic drugs specifically contradicted with selegiline (i.e. cholestyramine or colestipol) within 2 weeks of enrolment; some narcotics: demerol has been reported to interact with selegiline; ancillary vitamin E (alpha tocopherol) other than the 30 IU to 32 IU included in a standard multivitamin.
Interventions	Treatment 1: placebo Treatment 2: vitamin E (2000 IU total daily dose divided into 2 doses) Treatment 3: selegiline (10 mg total daily dose divided into 2 doses) Treatment 4: vitamin E (2000 IU total daily dose divided into 2 doses) + selegiline (10 mg total daily dose divided into 2 doses)
Outcomes	Delay in any of 4 end points: death; institutionalisation; severity of dementia; loss of ADL ADAS‐Cog (1 month after enrolment and at 3‐month intervals) MMSE (1 month after enrolment and at 3‐month intervals) BDS (1 month after enrolment and at 3‐month intervals) DS (1 month after enrolment and at 3‐month intervals) BRSD (1 month after enrolment and at 3‐month intervals) Adverse events
Notes	‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were "...randomly assigned (after stratification according to center with the use of a permuted‐block procedure)..." to receive vitamin E or placebo.
Allocation concealment (selection bias)	Unclear risk	Method in which allocation concealment was ensured was not reported.
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 and vitamin E treatment capsules were visually identical.
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	High risk	Attrition was only able to be reported up until the point a participant reached 1 of the primary end points of the study. Loss to follow‐up was defined as those who did not reach an end point and did not complete the study: 6/84 for the placebo group and 8/85 for the vitamin E group. The reasons for withdrawal were not described in each treatment group.
Selective reporting (reporting bias)	Unclear risk	All outcome measures were reported as per the protocol paper. No SDs reported for change scores.
Other bias	Low risk	No evidence of other bias.

AD: Alzheimer's dementia; ADAS‐Cog: Alzheimer's Disease Assessment Scale ‐ Cognitive subsection; ADCS: Alzheimer's Disease Cooperative Study; ADL: activities of daily living; APoE: apolipoprotein E; BDS: Blessed Dementia Scale; BRSD: Behavior Rating Scale for Dementia; CDR: Clinical Dementia Rating; CT: computer tomography; DS: Dependence Scale; DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ECG: electrocardiography; GDS: Global Deterioration Scale; ITT: intention to treat; MCI: mild cognitive impairment; MMSE: Mini‐Mental State Examination; MRI: magnetic resonance imaging; n: number of participants; NINCDS‐ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association; NPI: Neuropsychiatric Inventory; RPR: rapid plasmin reagin; SD: standard deviation.