PDF: DOMINO-AD
(2012)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
• 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
Inclusion Criteria
Community-dwelling; probable or possible moderate-to-severe Alzheimer's disease; SMMSE 5-13; on donepezil >=3 months at 10 mg for >=6 weeks; caregiver available; clinician considering changing treatment
Study Design
Arms: Array
Patients per Arm: Continue donepezil/placebo memantine: 73; Continue donepezil/active memantine: 73; Discontinue donepezil/placebo memantine: 73; Discontinue donepezil/active memantine: 76
Outcome
• BADLS (continue vs discontinue donepezil): –3.0 (95% CI 1.8-4.3), P<0.001
• SMMSE (memantine vs placebo): +1.2 (95% CI 0.6-1.8), P<0.001
• BADLS (memantine vs placebo): –1.5 (95% CI 0.3-2.8), P=0.02
• Combination vs monotherapy: no significant interaction
• NPI: no significant differences
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.
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled trial with 2x2 factorial design
- Randomization
- Yes
- Blinding
- Double-blind; patients, caregivers, clinicians, and outcome assessors blinded; randomization by UK MRC Clinical Trials Unit
- Sample Size
- 295
- Follow-up
- 52 weeks
- Centers
- 15
- Countries
- USA
Primary Outcome
Definition: 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
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - (1.3-2.5) | P<0.001 |
Citation
N Engl J Med 2012;366:893-903