DOMINO AD Howard.

Study characteristics
Methods	Multicentre, double‐blind, placebo‐controlled, clinical trial with a two‐by‐two factorial design
Participants	Setting: UK, 15 centres between February 2008 and March 2010, with the last participant completing follow‐up in April 2014. Sample size: 295 patients in four treatment arms, of which two are relevant to this review (146 patients; 48 male and 98 female) Age: mean 77.1 years for all participants, 77.5 years for patients in two arms relevant to review Inclusion criteria: community‐dwelling patients probable or possible moderate or severe Alzheimer's disease, according to NINCDS‐ADRDA criteria, SMMSE range 5 to 13 prescribed donepezil continuously for at least 3 months and who had received a dose of 10 mg/day for at least the previous 6 weeks clinician considering a change in drug treatment (i.e. stopping donepezil or introducing memantine) on the basis of National Institute for Health and Clinical Excellence (NICE) guidelines, discussions with the patient and caregivers and the physician's clinical judgment Exclusion criteria: severe or unstable medical conditions receiving memantine considered unlikely to adhere to study regimens
Interventions	Patients were randomly assigned to one of four treatments, two of which are relevant to this review: continuation of donepezil, at a dose of 10 mg/day, with placebo memantine discontinuation of donepezil (administration of donepezil at a dose of 5 mg/day during weeks 1 through 4 and placebo donepezil starting in week 5), with placebo memantine
Outcomes	1. Cognitive function SMMSE 2. Activities of daily living Caregiver‐rated BADLS 3. Service use, informal care and other aspects of accommodation and care Client Service Receipt Inventory (CRSI) ‐ listed in protocol but was not in study report 4. Health‐related quality of life Patient: EuroQol EQ‐5D (EQ‐5D) ‐ listed in protocol but not reported in study report Patient: DEMQOL‐Proxy Caregiver: GHQ‐12 5. Neuropsychiatric symptoms NPI 6. Institutionalisation (defined as permanent transition to a care home, continuing care unit or hospital) Question as to where the patient is living 7. Safety and tolerability Adverse event monitoring Outcomes were measured at randomisation, 6, 18, 30 and 52 weeks, with the exception of GHQ‐12 which was not assessed at 18 weeks, and DEMQOL‐Proxy, which was not assessed at 6 weeks or 30 weeks.
Source of funding	UK Medical Research Council (MRC) and the Alzheimer's Society. Pfizer‐Eisai and Lundbeck donated supplies of the drugs.
Declaration of interest	Pfizer‐Eisai and Lundbeck had no involvement in the design or conduct of the study or the analysis or the reporting of the data
Notes	BADLS: Bristol Activities of Daily Living Scale DEMQOL‐Proxy: Dementia Quality of Life Proxy measure EuroQol EQ‐5D: EuroQol‐5 Dimension GHQ‐12: twelve‐item General Health Questionnaire NINCDS‐ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association NPI: Neuropsychiatric Inventory SMMSE: Standardised Mini‐Mental State Examination
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Treatment assignments were made (by telephone) by the UK Medical Research Council Clinical Trials Unit with the use of randomised minimisation". Full details were given in the Supplementary Appendix.
Allocation concealment (selection bias)	Low risk	"[To] maintain concealment of treatment assignments, the first 80 participants were assigned with the use of a prepared list of simple randomised assignments". Further details were provided in the Supplementary Appendix.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	To maintain blinding, identical placebos for both memantine and donepezil hydrochloride were co‐administered as indicated by randomisation. Donepezil and donepezil placebo, however, appeared different from memantine and memantine placebo. All trial staff, patients and carers were blinded, but statisticians and randomising staff were unblinded (details given in the Supplementary Appendix)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Figure 1 shows the number of patients who were enrolled, were assigned to a study group, and completed follow‐up". Figure 1 also included the number of patients in each of the study groups who were included in the primary intention‐to‐treat analysis. "Unless otherwise specified, we performed the analyses on data from all patients who underwent randomisation and who received at least one dose of study drug, applying the principle of intention to treat as much as was practically possible, given any missing data".
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data for the co‐primary outcomes (SMMSE scores and BADLS scores) were available for 99% of participants randomised. A modified intention‐to‐treat analysis (mITT) was performed on participants who were randomised and received at least one dose of the study drug (i.e. excluded eligible participants post‐randomisation who did not start assigned treatment). Total exclusion post‐randomisation was 1.4%, and is unlikely to affect the outcome.
Selective reporting (reporting bias)	Low risk	Three secondary outcome measures specified in the protocol ‐ the Client Service Receipt Inventory (CSRI, which describes service use, informal care and other aspects of accommodation and care pertinent to the costing of interventions and their implications), the EuroQol EQ‐D measure of health‐related quality of life and institutionalisation ‐ were not reported.
Other bias	Low risk	Appears to be free of other sources of bias