Holmes 2004.

Study characteristics
Methods	24‐week, double‐blind randomised placebo‐controlled withdrawal study
Participants	Setting: 16 sites in the United Kingdom Sample size: 134 patients entered the study, 96 were randomised at 12 weeks to receive placebo (N = 55) or donepezil 10mg/day (N = 41) Age: mean age entering randomisation phase = 78.8 ± 1.5 years (placebo) and 78.6 ± 1.4 years (donepezil) Inclusion criteria ≥ 55 years Probable AD of more than 6 months' duration, according to NINDS‐ADRDA criteria NPI score ≥ 11 points arising from at least three domains of neuropsychiatric status as assessed by the NPI Carer able to monitor compliance with drug regimen and report on the neuropsychiatric features of the patient and on their own distress Exclusion criteria MMSE below 10 or above 27 Previous exposure to a cholinesterase inhibitor Any clinically relevant disease that might contraindicate use of a cholinesterase inhibitor
Interventions	Patients were treated in an open‐label phase with 5 mg/day donepezil for 6 weeks followed by 10mg/day donepezil for a further 6 weeks. Patients were then randomised to placebo or 10 mg/day donepezil on a 3:2 ratio for a further 6 weeks. Provided there was no further deterioration in cognitive function (defined as a loss of greater than 2 points on the MMSE compared with baseline), then the randomised treatment with placebo or 10 mg/day donepezil was continued for a further 6 weeks.
Outcomes	1. NPI 2. NPI‐D 3. MMSE 4. Safety and tolerability Psychometric evaluations, medication compliance checks and adverse event monitoring was undertaken at screening, at baseline, and at weeks 6, 12, 18 and 24.
Source of funding	Unrestricted project grant in excess of $10,000 from Pfizer/Eisai to Drs C Holmes and D Wilkinson
Declaration of interest	Both Dr C Holmes and Dr D Wilkinson have received sponsorship from Pfizer/Eisai to attend educational meetings and as speakers.
Notes	AD: Alzheimer's disease NINCDS‐ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association MMSE: Mini‐Mental State Examination NPI: Neuropsychiatry Inventory NPI‐D: Neuropsychiatry Inventory caregiver Distress
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patients were randomised by an independent pharmacist using a computer‐generated randomisation protocol.
Allocation concealment (selection bias)	Unclear risk	Methods used to conceal the allocation sequence were not described; therefore it was not possible to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	All participants were blind to the treatment being offered in the randomisation phase of the study. An independent pharmacist provided numbered containers of identical tablets for each patient. Blinding of personnel was not described; the authors only mentioned that patients were blind to the treatment. It seems likely that carers, clinicians and trial personnel were blinded to the assigned treatment due to the use of central randomisation and matching placebo tablets, but this was not explicitly stated. There may be a small risk of unblinding due to the relatively high proportion of participants with marked cognitive deterioration (6/10 = 60% placebo vs. 2/6 = 33% donepezil).
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details were provided of how blinding of outcome assessment was undertaken, although the use of central randomisation and identical placebo make blinding seem likely.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	96 patients were included in the randomisation phase of the study, 16 patients withdrew during the randomisation phase (10 subjects on placebo and 6 subjects on donepezil). Completion rates were 82% and 85% for patients taking placebo and donepezil, respectively. The authors reported that placebo and donepezil treatment groups were similar with respect to demographic characteristics and psychometric test scores. Data for the primary outcome (NPI) were available for 83% of randomised participants (82% placebo, 85% donepezil). The remaining 17% missing data were imputed using the LOCF approach (ITT was defined as randomised, dosed with at least one outcome post‐randomisation). The proportion of missing data are similar between groups: 18% placebo, 15% donepezil. Results of the ITT‐LOCF analysis (statistically significant; P = 0.02) differed from that of the OC analysis (not statistically significant; P = 0.14) at week 24. Discontinuation from the study could be linked to participants' health status: of the 10 participants who discontinued from the placebo group, 6 (60%) had marked cognitive deterioration (loss of ≥ 2 points on MMSE) with marked increase in neuropsychiatric symptoms (increase of > 15 points on NPI). Of the 6 participants who discontinued from the donepezil group, 2 (33%) had marked cognitive deterioration (loss of ≥ 2 points on MMSE), 3 (50%) had adverse events.
Selective reporting (reporting bias)	Low risk	All of the study’s prespecified outcomes have been reported. All reported results for the primary outcome correspond to all intended outcome measurements (time points ‐ weeks 18 and 24) and all intended analyses (ITT‐LOCF and OC analyses).
Other bias	Unclear risk	The study was supported by an unrestricted project grant in excess of $10,000 from Pfizer/Eisai to Drs C Holmes and D Wilkinson. Drs Holmes and Wilkinson have both received sponsorship from Pfizer/Eisai to attend educational meetings and as speakers.