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Study Design

Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil. Tariot P.N., Farlow M.R., Grossberg G.T., Graham S.M., McDonald S. and Gergel I. for the Memantine Study Group Journal of the American Medical Association (JAMA), 2004, 291:317–324.

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Study Design

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  1. Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil Tariot P.N., Farlow M.R., Grossberg G.T., Graham S.M., McDonald S. and Gergel I.for the Memantine Study Group Journal of the American Medical Association (JAMA), 2004, 291:317–324

  2. Study Design No. of patients N = 403 (outpatients) Diagnosis Probable Alzheimer’s disease Design Double-blind, randomized, placebo-controlled, multicenter study Patients on donepezil for at least 6 months (stable dose for 3 months) Age ≥50 years (mean 75.5) Severity MMSE 5 – 14 (mean 10) Dose; duration 20 mg memantine/day; 24 weeks Primary efficacy Cognition: SIBparameters Function: ADCS-ADL19 Secondary efficacy Global: CIBIC-Plusparameters Behavior: NPI and BGP (Care dependency subscale) Tariot et al., JAMA 2004

  3. Disposition of Patients Patients randomizedN = 404 Patients treatedN = 403 Placebo + donepezilN = 201 Memantine + donepezilN = 202 CompletedN = 150(75%) WithdrewN = 51(25%) CompletedN = 172(85%)* WithdrewN = 30(15%) * p = 0.011 versus placebo/donepezil (completed) Tariot et al., JAMA 2004

  4. Status of Donepezil Treatment at Baseline Donepezil treatment history Memantine + donepezil Placebo + donepezil Mean duration ofdonepezil treatment at baseline 126 weeks 129 weeks Mean dose ofdonepezil treatment at baseline 9.25 mg/d 9.49 mg/d Mean duration of donepezil treatment: > 2 years Tariot et al., JAMA 2004

  5. Sustained Improvement of Cognition (SIB) by Memantine OC/endpoint ITT (LOCF) Mean change from baseline * 4 3 2 1 0 -1 -2 -3 -4 N = 185 * * N = 190 * N = 181 N = 197 * Improvement N = 171 N = 198 N = 198 SIB score difference N = 180 N = 197 N = 194 N = 169 N = 164 Decline Memantine + donepezil Placebo + donepezil N = 153 N = 196 0 4 8 12 18 24 End Point (LOCF) Week * p  0.03 versus placebo/donepezil Tariot et al., JAMA 2004

  6. Significant Benefit of Memantine on Function (ADCS-ADL19) OC/endpoint ITT (LOCF) Mean change from baseline 1 0 -1 -2 -3 -4 * * * N = 190 N = 198 N = 198 N = 185 * Improvement N = 181 N = 197 * N = 172 * N = 195 N = 198 ADCS-ADL19 score difference N = 182 N = 170 Decline Memantine + donepezil Placebo + donepezil N = 163 N = 152 N = 197 0 4 8 12 18 24 End Point (LOCF) Week * p  0.03 versus placebo/donepezil Tariot et al., JAMA 2004

  7. Significant Benefit of Memantine on Clinical Global Impression (CIBIC-Plus) OC/endpoint ITT (LOCF) 4.0 = no change 3.6 3.8 4.0 4.2 4.4 4.6 4.8 * N = 190 * N = 197 N = 182 Improvement * N = 180 * * CIBIC-Plus global score N = 198 N = 172 N = 194 N = 181 N = 170 Decline Memantine + donepezil Placebo + donepezil N = 196 N = 164 N = 152 0 4 8 12 18 24 End Point (LOCF) Week * p < 0.03 versus placebo/donepezil Tariot et al., JAMA 2004

  8. More Patients Improved under Memantine ITT (LOCF) after 24 weeks 4.0 = no change Memantine + donepezil Placebo + donepezil 1 2 3 4 5 6 7 Improvement CIBIC-Plus global score Decline 0 5 10 15 20 25 30 35 40 45 Percentage of patients (%) Tariot et al., JAMA 2004

  9. Significant Benefit of Memantine on Behavior (NPI) ITT (LOCF) Mean change from baseline * -1 0 1 2 3 4 5 Improvement NPI score difference Decline Memantine + donepezil Placebo + donepezil * p = 0.002 versus placebo/donepezil Tariot et al., JAMA 2004

  10. Significant Benefit of Memantine on Care Dependency (BGP) ITT (LOCF) Mean change from baseline -1 0 1 2 3 4 5 Improvement * BGP score difference (Care dependency subscale) Decline Memantine + donepezil Placebo + donepezil * p = 0.001 versus placebo/donepezil Tariot et al., JAMA 2004

  11. Good Safety and Tolerability of Memantine Most frequently reported adverse events (incidence ≥5%) Memantine + donepezil Placebo + donepezil No of patients N = 202 (100%) N = 201 (100%) Agitation 19 (9.4%) 24 (11.9%) Confusion 16 (7.9%) 4 (2.0%) Fall 15 (7.4%) 14 (7.0%) Influenza-like symptoms 15 (7.4%) 13 (6.5%) Dizziness 14 (6.9%) 16 (8.0%) Headache 13 (6.4%) 5 (2.5%) Urinary tract infection 12 (5.9%) 10 (5.0%) Urinary incontinence 11 (5.4%) 6 (3.0%) Accidental injury 10 (5.0%) 16 (8.0%) Upper respiratory tract infection 10 (5.0%) 13 (6.5%) Peripheral edema 10 (5.0%) 8 (4.0%) Diarrhea 9 (4.5%) 17 (8.5%) Fecal incontinence 4 (2.0%) 10 (5.0%) Tariot et al., JAMA 2004

  12. Summary • Patients with moderate to severe AD treated with memantine performed significantly better than placebo treated patients on five independent levels: • Cognition • Function • Global impression • Behavior • Care dependency • Sustained improvement compared to baseline in cognitive function was shown in memantine treated patients • The combination of memantine and donepezil was well tolerated and safe • These data emphasize the unique mechanism of action of memantine Tariot et al., JAMA 2004

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