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Memantine in Moderate to Severe Alzheimer’s Disease

Memantine in Moderate to Severe Alzheimer’s Disease. Reisberg B., Doody R., Stöffler A., Schmitt F., Ferris S. H., and Möbius H. J. New England Journal of Medicine 2003, 348: 1333-1341. Study Design. No. of patients N = 252 (outpatients) Diagnosis Probable Alzheimer’s disease

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Memantine in Moderate to Severe Alzheimer’s Disease

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  1. Memantine in Moderate to Severe Alzheimer’s Disease Reisberg B., Doody R., Stöffler A., Schmitt F., Ferris S. H., and Möbius H. J. New England Journal of Medicine 2003, 348: 1333-1341

  2. Study Design No. of patients N = 252 (outpatients) Diagnosis Probable Alzheimer’s disease Design Double-blind, randomized, placebo- controlled, multicenter study Age  50 years (mean 76) Severity MMSE 3 – 14 (mean 7.9) GDS 5 – 6 FAST  6a Dose; duration 20 mg memantine/day; 28 weeks Primary efficacy Global: CIBIC-plusparameters Function: ADCS-ADL19 Secondary efficacy Cognition: SIB, Behavior: NPI parameters MMSE, FAST, GDS, Resource Utilisation in Dementia (RUD) Reisberg et al., N Engl J Med 2003

  3. Disposition of Patients Patients screenedN = 345 Screen failuresN = 93 (27%) Patients randomizedN = 252 PlaceboN = 126 MemantineN = 126 CompletedN = 84(67%) WithdrewN = 42(33%) CompletedN = 97(77%) WithdrewN = 29(23%) Reisberg et al., N Engl J Med 2003

  4. 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 N = 126 both groups N = 107 * N = 97  Memantine (20 mg/day)  Placebo N = 105 N = 84 0 12 28 Significant Benefit of Memantine in Clinical Global Impression (CIBIC-Plus) OC analysis 4.0 = no change Improvement CIBIC-Plus global score Worsening Week *p = 0.025 versus placebo Reisberg et al., N Engl J Med 2003

  5.  Memantine (20 mg/day)  Placebo 0 5 10 15 20 25 30 35 40 Benefit of Memantine in Clinical Global Impression (CIBIC-Plus) after 28 Weeks OC analysis 4.0 = no change 1 2 3 4 5 6 7 Improvement CIBIC-Plus global score Worsening Relative frequency (%) Reisberg et al., N Engl J Med 2003

  6. N=119 1 0 -1 -2 -3 -4 -5 -6 -7 N = 107 N = 126 both groups * N = 97 N = 117 N = 106  Memantine (20 mg/day)  Placebo N = 84 0 4 12 28 Significant Benefit of Memantine in Activities of Daily Living OC analysis Mean change from baseline Improvement ADCS-ADL19 score difference Worsening Week *p = 0.003 versus placebo Reisberg et al., N Engl J Med 2003

  7. ‡ Travels outside home  Memantine (20 mg/day)  Placebo ‡ Uses a telephone * Disposes of litter * Clears a table * Makes conversation -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 Benefit of Memantine in Activities of Daily Living (ADCS-ADL19) OC analysis Mean change from baseline at week 28 ADCS-ADL19 score difference ‡ p < 0.1 versus placebo, *p < 0.05 versus placebo Reisberg et al., N Engl J Med 2003

  8. 4 2 0 -2 -4 -6 -8 -10 -12 N = 119 N = 107 N = 126 both groups * N = 117 N = 97  Memantine (20 mg/day)  Placebo N = 106 N = 83 0 4 12 28 Significant Benefit on Cognition (Severe Impairment Battery) OC analysis Mean change from baseline Improvement SIB score difference Worsening Week *p = 0.002 versus placebo Reisberg et al., N Engl J Med 2003

  9. Orienting to name  Memantine (20 mg/day)  Placebo Construction * Visuospatial ability Praxis Attention Language Orientation Memory * Social interaction 0 -1 -2 -3 -4 -5 Benefit of Memantine on Cognition (Severe Impairment Battery) OC analysis Mean change from baseline at week 28 SIB category subscore difference *p < 0.05 versus placebo Reisberg et al., N Engl J Med 2003

  10. -0.2 0 0.2 0.4 0.6 0.8 N = 107 * N = 126 both groups N = 97 N = 105  Memantine (20 mg/day)  Placebo N = 84 0 12 28 Significant Benefit of Memantine on Function (FAST) OC analysis Mean change from baseline Improvement FAST score difference Worsening Week *p = 0.007 versus placebo Reisberg et al., N Engl J Med 2003

  11. Significantly More Patients Respond to Memantine Treatment ITT population Missing value = non-responder Definition of Memantine Placebo p-valueresponse (N = 126) (N = 126) Improvement orstabilisation in: 29% 10% 0.0004 CIBIC-Plus and N = 36 N = 13 SIB or ADL p-value is based on Fisher’s exact test Reisberg et al., N Engl J Med 2003

  12. Significant Benefit of Memantine in the Main Efficacy Parameters OC analysis OC analysis Mean change from baseline Memantine Placebo Difference p-value (N = 97) (N = 84) CIBIC-Plus* 4.38 4.74 0.36 0.025 ADCS-ADL19 -2.49 -5.86 -3.37 0.003 SIB -4.46 -10.16 -5.70 0.002 * 4.0 = no change p-values are based on Wilcoxon-Mann-Whitney test for between treatment comparison Reisberg et al., N Engl J Med 2003

  13. Good Safety and Tolerability of Memantine Most frequently reported adverse events (incidence >10%) Memantine Placebo No. of patients 126 (100%) 126 (100%) No. of patients with AEs 106 (84%) 109 (87%) Agitation 23 (18%) 40 (32%) Urinary incontinence 14 (11%) 14 (11%) Urinary tract infection 7 (6%) 17 (13%) Insomnia 13 (10%) 10 (8%) Diarrhea 12 (10%) 10 (8%) Reisberg et al., N Engl J Med 2003

  14. Summary • Statistically significant benefit of memantine compared to placebo on three independent levels: • clinical global impression • functional capacity in activities of daily living • cognition in moderate to severe Alzheimer‘s disease • Good safety and tolerability of memantine Reisberg et al., N Engl J Med 2003

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