Sano 1996

Methods	Randomised, placebo‐controlled, double‐blind study Duration: 2 years
Participants	Country: US Multicentre: 23 sites Diagnosis: probable AD according to NINCDS‐ADRDA Number of subjects: 341 (65% females) Age: mean 73 years Inclusion criteria: CDR score: 2, Hachinski score > 4, dementia of moderate severity, living at home with responsible carer, good general health Exclusion criteria: neurological diagnoses other than AD, psychiatric DSM‐III‐R diagnoses other than primary progressive dementia of Alzheimer's type, recent history of psychoactive medication use, no antipsychotic/neuroleptic medications, no antidepressants
Interventions	1. Placebo 2. Vitamin E (2000 IU total daily dose divided into 2 doses) 3. Selegiline (10 mg total daily dose divided into 2 doses) 4. Vitamin E (2000 IU total daily dose divided into 2 doses) plus selegiline (10 mg total daily dose divided into 2 doses)
Outcomes	1. Delay in any of 4 end points: death; institutionalisation; severity of dementia; loss of activities of daily living 2. ADAS‐Cog (Rosen 1984) evaluates cognition across 11 tests: spoken language ability, comprehension of spoken language, recall of test instructions, word finding difficulty, following commands, naming objects construction drawing, ideational praxis, orientation, word recall, and word recognition 3. MMSE (Folstein 1975) evaluates cognition in five areas; orientation, immediate recall, attention and calculation, delayed recall and language 4. BDS (Blessed 1968) is composed of a series of scales split into 6 sections: the first 3 measure changes in performance of everyday activities, habits, personality, interests and drive. The second 3 sections form the cognitive test 5. DS (Stern 1994), a 7‐point scale that rates the need for care and supervision 6. BRSD (Tariot 1995). The BRSD measures psychopathological signs and symptoms frequently seen in mild to moderate dementia. The covers the domains of depressive features, psychotic features, defective self‐regulation, irritability and agitation, vegetative features, apathy, aggression and affective lability 7. Adverse events
Notes	‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A random assignment of patients followed stratification according to centre using a permuted‐block procedure. This is one of the most widely used sequential allocation procedure and is designed to achieve stratum balance. This method ensures an equal distribution of all variables in the different groups
Allocation concealment (selection bias)	Unclear risk	The method in which allocation concealment was ensured was not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants and personnel were blinded prior to the beginning of trial. No reference is made to whether they remained blinded throughout
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	There was no reference of how the outcome assessors were blinded to the allocated condition
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	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, 4/87 for selegiline and 5/85 for vitamin E plus selegiline. The reasons for withdrawal were not described in each treatment group
Selective reporting (reporting bias)	Low risk	All outcome measures were reported
Other bias	Low risk	No evidence of other bias

AD: Alzheimer's dementia; ADAS‐Cog: Alzheimer's Disease Assessment Scale ‐ Cognitive section; ADCS: Alzheimer's Disease Cooperative Study; APoE: apolipoprotein E; BDS: Blessed Dementia Scale; BRSD: Behavior Rating Scale for Dementia; CDR: Clinical Dementia Rating; CT: computer tomography; DS: Dependence Scale; DSM‐III‐R: Diagnostic and Statistical Manual of Mental Disorders, Third Edition; ECG: electrocardiography; GDS: Global Deterioration Scale; MCI: mild cognitive impairment; MMSE: Mini‐Mental State Examination; MRI: magnetic resonance imaging; NINCDS‐ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association; RPR: rapid plasmin reagin; SD: standard deviation.