DOMINO-AD
Donepezil and Memantine in Moderate to Severe Alzheimer's Disease
Clinical Question
In community-dwelling patients with moderate-to-severe Alzheimer's disease already on donepezil, does continuing donepezil, starting memantine, or combining both improve cognition and function over 52 weeks compared with stopping treatment?
Study Overview
Objective
To determine whether continuing donepezil, starting memantine, or combining both provides cognitive and functional benefit in patients with moderate-to-severe Alzheimer's disease already on donepezil
Study Summary
- Continuing donepezil vs discontinuing: SMMSE +1.9 points higher (95% CI 1.3-2.5; P<0.001); BADLS 3.0 points lower (95% CI 1.8-4.3; P<0.001)
- Memantine vs placebo memantine: SMMSE +1.2 points higher (95% CI 0.6-1.8; P<0.001); BADLS 1.5 points lower (95% CI 0.3-2.8; P=0.02)
- Combination donepezil + memantine vs donepezil alone: no significant additional benefit (interaction P=0.14 for SMMSE, P=0.09 for BADLS)
- Both SMMSE and BADLS benefits exceeded prespecified minimum clinically important differences
- Withdrawal from donepezil half as likely as from placebo (HR 0.51; P<0.001)
Intervention
2×2 factorial: continue donepezil 10 mg vs taper/discontinue; start memantine 20 mg vs placebo memantine; 52 weeks
Patients per Arm
Continue donepezil/placebo memantine: 73; Continue donepezil/active memantine: 73; Discontinue donepezil/placebo memantine: 73; Discontinue donepezil/active memantine: 76
Bottom Line
Continuing donepezil in moderate-to-severe Alzheimer's disease provided clinically meaningful cognitive and functional benefits compared with discontinuation (+1.9 points on SMMSE, -3.0 on BADLS; both P<0.001). Memantine also provided benefit (SMMSE +1.2, P<0.001; BADLS -1.5, P=0.02), but there was no significant additive benefit from combining donepezil and memantine. This trial provided the first robust evidence that cholinesterase inhibitors should be continued even as disease progresses beyond the mild-to-moderate stage.
Major Points
- DOMINO-AD was a UK multicenter, double-blind, placebo-controlled trial with a 2x2 factorial design (continue vs discontinue donepezil; start memantine vs placebo memantine) in 295 community-dwelling patients with moderate-to-severe AD (SMMSE 5-13).
- All participants had been on donepezil >=3 months (10 mg for >=6 weeks) and their prescribing clinician was considering a change in treatment. This pragmatic design reflected real-world clinical uncertainty.
- Continuing donepezil vs discontinuing showed significant benefits: SMMSE +1.9 points (95% CI 1.3-2.5; P<0.001) and BADLS -3.0 points (95% CI 1.8-4.3; P<0.001). Both exceeded prespecified minimum clinically important differences (SMMSE 1.4, BADLS 3.5).
- Starting memantine vs placebo memantine showed: SMMSE +1.2 points (95% CI 0.6-1.8; P<0.001) and BADLS -1.5 points (95% CI 0.3-2.8; P=0.02). BADLS benefit was below the minimum clinically important difference.
- The interaction between donepezil and memantine was not significant (P=0.14 for SMMSE, P=0.09 for BADLS), meaning no additional benefit was demonstrated from combination therapy beyond each agent alone.
- Patients assigned to continue donepezil were half as likely to withdraw from the study drug (HR 0.51; 95% CI 0.36-0.72; P<0.001). Memantine also reduced withdrawal probability (HR 0.66; P=0.02).
- NPI scores (neuropsychiatric symptoms) did not differ significantly between any treatment groups.
- The trial was underpowered for the planned 800 patients (only 295 enrolled), but a blinded interim analysis of reduced standard deviations confirmed adequate power at the smaller sample size.
Design
Study Type: Multicenter, randomized, double-blind, placebo-controlled trial with 2x2 factorial design
Randomization: 1
Blinding: Double-blind; patients, caregivers, clinicians, and outcome assessors blinded; randomization by UK MRC Clinical Trials Unit
Enrollment Period: February 2008 - March 2010
Follow-up Duration: 52 weeks
Centers: 15
Countries: United Kingdom
Sample Size: 295
Analysis: Intention-to-treat; multilevel modeling repeated-measures regression adjusted for baseline scores and minimization factors; no imputation of missing data
Inclusion Criteria
- Community-dwelling with caregiver
- Probable or possible moderate-to-severe Alzheimer's disease
- SMMSE score 5-13
- On donepezil >=3 months at dose of 10 mg for >=6 weeks
- Prescribing clinician considering change in drug treatment
Exclusion Criteria
- Severe or unstable medical conditions
- Already receiving memantine
- Considered unlikely to adhere to study regimens
Arms
| Field | Experimental | Control |
|---|---|---|
| Intervention | Continuation of donepezil 10 mg/day +/- memantine 20 mg/day (titrated from 5 mg over 4 weeks) | Discontinuation of donepezil (tapered over 4 weeks to placebo) +/- placebo memantine |
| Duration |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| SMMSE (continue vs discontinue donepezil): +1.9 points (95% CI 1.3-2.5), P<0.001 | BADLS (continue vs discontinue donepezil): -3.0 points (95% CI 1.8-4.3), P<0.001 | SMMSE (memantine vs placebo memantine): +1.2 points (95% CI 0.6-1.8), P<0.001 | BADLS (memantine vs placebo memantine): -1.5 points (95% CI 0.3-2.8), P=0.02 | Primary | P<0.001 | |||
| NPI (neuropsychiatric symptoms): no significant differences between any groups | Secondary | ||||
| DEMQOL-Proxy (quality of life): no significant differences | Secondary | ||||
| GHQ-12 (caregiver distress): no significant differences | Secondary | ||||
| Donepezil + memantine interaction: not significant (P=0.14 SMMSE, P=0.09 BADLS) | Secondary | P=0.14 | |||
| Time to treatment withdrawal: HR 0.51 for donepezil continuation (P<0.001); HR 0.66 for memantine (P=0.02) | Secondary | 0.51 | P<0.001 | ||
| Not reported | Adverse | No adverse event data extracted for this trial | |||
Funding
UK Medical Research Council and UK Alzheimer's Society
Based on: DOMINO-AD (New England Journal of Medicine, 2012)
Authors: R. Howard, R. McShane, J. Lindesay, ..., P. Phillips
Citation: N Engl J Med 2012;366:893-903
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