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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-Plus, parameters Behavior: NPI and BGP (Care dependency subscale) Tariot et al., JAMA 2004

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

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

  5. 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 * N = 171 Improvement N = 198 N = 198 N = 180 N = 197 N = 194 N = 169 N = 164  Memantine + donepezil  Placebo + donepezil Deterioration N = 153 N = 196 0 4 8 12 18 24 End Point (LOCF) Week Sustained Improvement of Cognition (SIB) by Memantine SIB score difference *p  0.03 versus placebo/donepezil Tariot et al., JAMA 2004

  6. 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 N = 182 N = 170  Memantine + donepezil  Placebo + donepezil Deterioration N = 163 N = 152 N = 197 0 4 8 12 18 24 End Point (LOCF) Week Significant Benefit of Memantine on Function (ADCS-ADL19) ADCS-ADL19 score difference *p  0.03 versus placebo/donepezil Tariot et al., JAMA 2004

  7. 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 * * N = 198 N = 172 N = 194 N = 181 N = 170  Memantine + donepezil  Placebo + donepezil Deterioration N = 196 N = 164 N = 152 0 4 8 12 18 24 End Point (LOCF) Week Significant Benefit of Memantine on Clinical Global Impression (CIBIC-Plus) CIBIC-Plus global score *p < 0.03 versus placebo/donepezil Tariot et al., JAMA 2004

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

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

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

  11. 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%) Good Safety and Tolerability of Memantine 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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