Johannsen 2006.

Study characteristics
Methods	3‐phase study comprising a 12‐week pre‐randomisation, open‐label donepezil treatment phase, a 12‐week randomised double‐blind placebo‐controlled phase and a 12‐week single‐blind donepezil treatment phase (continuation or rechallenge).
Participants	Setting: 57 investigational sites in Belgium, Denmark, Greece, Hungary, Iceland, the Netherlands, Poland, and the USA. All sites were outpatient dementia and/or memory clinics and patients were living at home or in an assisted home care facility prior to study entry. Sample size: 619 patients completed the open‐label phase, 202 were randomised to continued donepezil treatment (N = 99) or placebo (N = 103), and 171 entered the single‐blind phase (N = 88 continued treatment and N = 83 were rechallenged with donepezil). Age: mean 72.7 ± 8.6 years for patients randomised into double‐blind phase Inclusion criteria Mild to moderate probable or possible AD according to DSM‐IV and NINCDS‐ADRDA criteria MMSE 10‐26 ≥ 50 years Ambulatory or ambulatory when aided with a walker or cane Sufficient hearing and vision to comply with testing procedures Exclusion criteria Resident in a nursing home Current use of any investigational or approved drugs for AD
Interventions	During the open‐label phase, all patients received donepezil 5 mg/day for 4 weeks, increased to 10 mg/day thereafter. Patients who showed a clear clinical benefit after 24 weeks of open‐label donepezil treatment were considered to have completed the study and were not followed further. Patients who did not show a clear clinical benefit were randomised into the 12‐week double‐blind phase to continue with donepezil 10 mg/day or to receive placebo. After 12 weeks of double‐blind treatment, patients receiving placebo were rechallenged with donepezil in a single‐blind manner, beginning with 5 mg/day and increasing to 10mg/day after 4 weeks. The patients treated with donepezil during the double‐blind phase continued to receive donepezil at 10 mg/day for the remaining 12 weeks of the study. Only the double‐blind phase of this study is relevant to this review.
Outcomes	1. Cognitive function ADAS‐Cog/11 at 0, 6 and 12 weeks MMSE at 0, 6 and 12 weeks 2. Neuropsychiatric status NPI at 0, 6 and 12 weeks 3. Activities of daily living DAD at 0, 6 and 12 weeks 4. Safety Adverse effects
Source of funding	Pfizer Inc., New York, NY, USA and Eisai Inc., Teaneck, NJ, USA
Declaration of interest	Dr Johannsen has received honoraria from the study sponsors. Dr Hampel has received an investigator‐initiated research grant and honoraria from the study sponsors. Dr Salmon has received honoraria for participating in conferences organised by the study sponsors. Drs Xu and Schlndler are employees of Pfizer Inc., and also hold equity in the company. Dr Qvitzau was an employee of Pfizer Denmark when the study was being conducted. Dr Richardson is an employee of Eisai Inc. PPS International Communications (Worthing, UK) assisted in the development of the manuscript.
Notes	AD: Alzheimer's disease ADAS‐Cog/11: Alzheimer's Disease Assessment Scale–Cognitive Subscale DAD: Disability Assessment for Dementia DSM‐IV: The Diagnostic and Statistical Manual of Mental Disorders Fourth Edition MMSE: Mini‐Mental State Examination NINCDS‐ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association NPI: Neuropsychiatric Inventory
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed using a computer‐generated randomisation list provided by Pfizer Inc
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	Blinding was implemented with identical film‐coated tablets within a blister‐packaged card. The use of identical placebo would ensure that participants were blind to the assigned intervention. However, it is not known whether trial personnel were blinded as the randomisation list provided by the independent party was available to them. No further information on blinding was provided in the publication. The 12‐week double‐blind phase was followed by a single‐blind phase, and there was no information on how unblinding was done. Treatment‐related adverse events were similar between groups and so the risk of unblinding due to adverse events among participants is small.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was not clear who the assessors were, or whether they were blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Of the 202 patients randomised, 171 patients completed the trial, corresponding to a completion rate of 85%. Withdrawal rates were 11% for patients randomised to receive donepezil and 19% for patients randomised to receive placebo. Data for the primary outcome (ADAS‐Cog/11) were therefore available for 85% of randomised participants (89% donepezil, 81% placebo; Figure 2). The proportions of missing data were similar between groups: 11% donepezil, 19% placebo. In the OC analysis, outcome data were available for 83% of randomised participants (87% donepezil, 80% placebo; Table 4). ITT was defined as randomised, dosed, with at least one outcome post‐randomisation. Results of the ITT‐LOCF analyses differed qualitatively (change scores from baseline to week 12) from that of OC analysis, although both were not statistically significant (Table 4). Discontinuation from the study could be related to participants' health status: of the 11 participants who discontinued from the donepezil group, 2 (18%) had insufficient clinical response (decline/no change in MMSE) and 3 (27%) withdrew consent for undocumented reasons. Of the 20 participants who discontinued from the placebo group, 3 (15%) had adverse events related to the study drug and 9 (45%) withdrew consent for undocumented reasons.
Selective reporting (reporting bias)	High risk	The study's specified outcomes were reported. Both ITT‐LOCF and OC analyses were reported as planned. However, although ADAS‐Cog/11, MMSE, NPI and DAD were measured at weeks 6 and 12 (end of double‐blind phase), only results at week 12 were reported.
Other bias	Unclear risk	This study was funded by Pfizer Inc., New York, NY, USA and Eisai Inc., Teaneck, NJ, USA.