PDF: MEM-MD-02
(2003)Objective
To evaluate the efficacy and safety of memantine in outpatients with moderate-to-severe Alzheimer's disease
Study Summary
• ADCS-ADLsev at 28 weeks: –3.1 vs –5.2 change; difference 2.1 (P=0.02 LOCF; P=0.003 observed cases)
• SIB at 28 weeks: –4.0 vs –10.1 change; difference 5.7 (P<0.001 LOCF; P=0.002 observed cases)
• Responder analysis: 29% memantine vs 10% placebo (P<0.001)
• FAST: less functional deterioration with memantine (P=0.02)
• No significant difference in adverse events
Intervention
Memantine 20 mg/day (10 mg BID) vs placebo for 28 weeks
Inclusion Criteria
Age >=50; probable Alzheimer's disease (DSM-IV and NINCDS-ADRDA); MMSE 3-14; GDS stage 5 or 6; FAST stage >=6a; community-dwelling with reliable caregiver; stable antidepressant allowed; no AChEI, antiparkinsonian, or antipsychotic agents
Study Design
Arms: Array
Patients per Arm: Memantine: 126; Placebo: 126
Outcome
• ADCS-ADLsev (28 wk): –3.1 vs –5.2; difference 2.1, P=0.02
• SIB (28 wk): –4.0 vs –10.1; difference 5.7, P<0.001
• Responders: 29% vs 10%, P<0.001
• FAST: P=0.02 favoring memantine
• MMSE: no significant difference
• NPI: no significant difference
Bottom Line
Memantine 20 mg/day significantly reduced clinical deterioration across multiple domains in moderate-to-severe Alzheimer's disease. The CIBIC-Plus global assessment favored memantine (P=0.03, observed cases), as did the ADCS-ADLsev functional measure (mean difference 2.1, P=0.02) and the Severe Impairment Battery cognitive measure (difference 5.7, P<0.001). A predefined responder analysis showed 29% of memantine-treated patients improved vs 10% on placebo (P<0.001). This pivotal trial led to FDA approval of memantine for moderate-to-severe Alzheimer's disease, providing the first treatment for advanced stages of the disease.
Major Points
- This pivotal phase 3 trial enrolled 252 outpatients with moderate-to-severe Alzheimer's disease (MMSE 3-14, GDS stage 5-6, FAST >=6a) from 32 US centers, randomized 1:1 to memantine 20 mg/day or placebo for 28 weeks.
- The coprimary endpoints were the CIBIC-Plus (global clinical impression) and the ADCS-ADLsev (functional activities modified for severe dementia). Both showed significant benefit with memantine.
- The CIBIC-Plus at 28 weeks showed a mean difference of 0.3 points favoring memantine (P=0.06 with LOCF, P=0.03 for observed cases). This clinician-rated global change measure captured overall clinical improvement.
- The ADCS-ADLsev showed significantly less functional deterioration: -3.1 with memantine vs -5.2 with placebo (difference 2.1; P=0.02 LOCF, P=0.003 observed cases).
- The Severe Impairment Battery (SIB), a cognitive measure designed for advanced dementia, showed the most robust result: -4.0 memantine vs -10.1 placebo (difference 5.7; P<0.001).
- FAST (Functional Assessment Staging) also favored memantine (P=0.02), showing less functional deterioration. A composite responder analysis showed 29% vs 10% response (P<0.001).
- MMSE, GDS, and NPI did not show significant between-group differences, reflecting the limitations of these instruments in advanced dementia.
- The safety profile was favorable, with no significant differences in adverse events between groups. Seventy-one patients discontinued prematurely (42 placebo, 29 memantine). The mean age was 76 years, 67% female.
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind; identical-appearing tablets
- Sample Size
- 252
- Follow-up
- 28 weeks
- Centers
- 32
- Countries
- USA
Primary Outcome
Definition: CIBIC-Plus at 28 weeks: 4.5 (memantine) vs 4.8 (placebo); difference 0.3, P=0.06 (LOCF), P=0.03 (observed cases) | ADCS-ADLsev at 28 weeks: -3.1 (memantine) vs -5.2 (placebo); difference 2.1, P=0.02 (LOCF), P=0.003 (observed cases)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | P=0.06 |
Citation
N Engl J Med 2003;348:1333-41