Effects of Memantine on behavioural symptoms in Alzheimer’s disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised,

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Effects of Memantine on behavioural symptoms in Alzheimer’s disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies Gauthier S., Wirth Y. and Möbius H.J. International Journal of Geriatric Psychiatry 2005, 20: 1-6

Baseline Characteristics Monotherapy Study Combination Study Patients completing 97 (77%)84 (67%)172 (85%)150 (75%) study, n (%) Gender, female 91 (72%)79 (63%)128 (63%)134 (67%) n (%) Mean age (years) Race, Caucasian 112 (89%)115 (91%)182 (90%)186 (93%) n (%) Mean MMSE score at baseline NPI total score, 21.4 (±15.8)19.5 (±15.6) 13.7 (±14.1) 13.9 (±12.8) Mean (± SD) MemantinePlaceboMemantine**Placebo** (N = 126)(N = 126)(N = 202)(N = 201) **stabilized on donepezil Gauthier et al., Int J Geriat Psychiatr 2005

Behavioral Outcome Monotherapy Study (Reisberg et al., 2003) Combination Therapy Study (Tariot et al., 2004) Analysis of behavioral symptoms by the 12-item version of the Neuropsychiatric Inventory (NPI) 9 of 12 items in favor of memantine 10 of 12 items in favor of memantine 252 Patients 403 Patients Gauthier et al., Int J Geriat Psychiatr 2005

Single Domain NPI Data Analysis from the Monotherapy Study (Reisberg et al., 2003) Gauthier S., Wirth Y. and Möbius H.J. International Journal of Geriatric Psychiatry 2005, 20: 1-6

No. of patients N = 252 (outpatients) DiagnosisProbable Alzheimer’s disease DesignDouble-blind, randomized, placebo- controlled, multicenter study Age  50 years (mean 76) SeverityMMSE 3 – 14 (mean 7.9) GDS 5 – 6 FAST  6a Dose; duration20 mg memantine/day; 28 weeks Primary efficacy Global: CIBIC-plus parameters Function: ADCS-ADL 19 Secondary efficacyCognition: SIB, Behavior: NPI parametersMMSE, FAST, GDS, Resource Utilisation in Dementia (RUD) Study Design Monotherapy Study Reisberg et al., N Engl J Med 2003

Baseline Characteristics Monotherapy Study Patients completing 97 (77%)84 (67%) study, n (%) Gender, female 91 (72%)79 (63%) n (%) Mean age (years) Race, Caucasian 112 (89%)115 (91%) n (%) Mean MMSE score at baseline NPI total score, 21.4 (±15.8)19.5 (±15.6) Mean (± SD) MemantinePlacebo(N = 126) Reisberg et al., N Engl J Med 2003

Benefits of Memantine on Behavioral Symptoms * p < 0.05 versus placebo Merz, data on file Mean change from baseline NPI score difference Week Improvement Decline 8 Memantine (20mg/day) Placebo * ITT, LOCF analysis

Benefits of Memantine on Individual NPI Domains (I) * p < 0.05, # p < 0.10 versus placebo Decline Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior Memantine Placebo 1.5 Improvement * * # NPI domain score difference Mean change from baseline ITT, LOCF analysis Gauthier et al., Int J Geriat Psychiatr 2005

Benefits of Memantine on Individual NPI Domains (II) Gauthier et al., Int J Geriat Psychiatr 2005 Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change Decline Improvement Memantine Placebo Mean change from baseline ITT, LOCF analysis NPI domain score difference

Benefits of Memantine on Individual NPI Domains * p < 0.05, # p < 0.10 versus placebo Decline Improvement Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change * * # Memantine Placebo NPI domain score difference Mean change from baseline ITT, LOCF analysis Gauthier et al., Int J Geriat Psychiatr 2005

Prevalence of Behavioral Symptoms at Baseline (I) Gauthier et al., Int J Geriat Psychiatr 2005 Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior Memantine Placebo 0100 [%] Prevalence of symptoms at baseline Patients showing symptom [%]

Prevalence of Behavioral Symptoms at Baseline (II) Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change Memantine Placebo 0 [%] Prevalence of symptoms at baseline Patients showing symptom [%] Gauthier et al., Int J Geriat Psychiatr 2005

Emergence of Behavioral Symptoms (I) * p < 0.05 versus placebo Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior Memantine Placebo 0 * 100 [%] Emergence of new behavioral symptoms post baseline Patients with new symptom [%] Gauthier et al., Int J Geriat Psychiatr 2005

Emergence of Behavioral Symptoms (II) Gauthier et al., Int J Geriat Psychiatr 2005 Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change Memantine Placebo 0 [%] Emergence of behavioral symptoms post baseline Patients with new symptom [%]

Improvement of Behavioral Symptoms (I) * p < 0.05 versus placebo Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior Memantine Placebo 0 * 100 [%] Improvement of behavioral symptoms at endpoint Patients with improved symptom [%] Gauthier et al., Int J Geriat Psychiatr 2005

Improvement of Behavioral Symptoms (II) Gauthier et al., Int J Geriat Psychiatr 2005 Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change Memantine Placebo 0 [%] Improvement of behavioral symptoms at endpoint Patients with improved symptom [%]

Benefits of Memantine Treatment on Agitation/Aggression Patients [%] * p < 0.05 versus placebo Emergence post baseline [%] * * Improvement post baseline Prevalence at baseline Prevalence, Emergence and Improvement of the symptom Agitation/Aggression Memantine Placebo

Good Safety and Tolerability of Memantine Most frequently reported adverse events (incidence >10%) MemantinePlacebo No. of patients126 (100%)126 (100%) No. of patients with AEs106 (84%)109 (87%) Agitation* 23 (18%)40 (32%) Urinary incontinence14 (11%)14 (11%) Urinary tract infection7 (6%)17 (13%) Insomnia13 (10%)10 (8%) Diarrhoea12 (10%)10 (8%) adapted from Reisberg et al., N Engl J Med 2003 * p < 0.05 versus placebo

Single Domain NPI Data Analysis from the Combination Study (Tariot et al., 2004) Gauthier S., Wirth Y. and Möbius H.J. International Journal of Geriatric Psychiatry 2005, 20: 1-6

No. of patients N = 403 (outpatients) DiagnosisProbable Alzheimer’s disease DesignDouble-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) SeverityMMSE 5 – 14 (mean 10) Dose; duration20 mg memantine/day; 24 weeks Primary efficacy Cognition: SIB parameters Function: ADCS-ADL 19 Secondary efficacyGlobal: CIBIC-Plus, parametersBehavior: NPI and BGP (Care dependence subscale) Study Design Combination Study Tariot et al., JAMA 2004

Baseline Characteristics Combination Study Patients completing 172 (85%)150 (75%) study, n (%) Gender, female128 (63%)134 (67%) n (%) Mean age (years) Race, Caucasian 182 (90%)186 (93%) n (%) Mean MMSE score at baseline NPI total score, 13.7 (±14.1)13.9 (±12.8) Mean (± SD) Memantine**Placebo** (N = 202)(N = 201) Tariot et al., JAMA 2004 * * stabilized on donepezil

Week * p < 0.05 versus placebo Benefits of Memantine on Behavioral Symptoms Tariot et al., JAMA 2004 * * stabilized on donepezil Mean change from baseline NPI score difference Improvement Decline 8 Memantine** Placebo** * LOCF analysis*

Benefits of Memantine on Individual NPI Domains (I) * p < 0.05 versus placebo * * stabilized on donepezil Gauthier et al., Int J Geriat Psychiatr 2005 Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior Decline Improvement Memantine** Placebo** NPI domain score difference Mean change from baseline ITT, LOCF analysis *

Benefits of Memantine on Individual NPI Domains (II) * p < 0.05 versus placebo Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change * * Decline Improvement Memantine** Placebo** NPI domain score difference Mean change from baseline ITT, LOCF analysis Gauthier et al., Int J Geriat Psychiatr 2005 * * stabilized on donepezil

Benefits of Memantine on Individual NPI Domains * p < 0.05 versus placebo Decline Improvement Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change Memantine** Placebo** * * * NPI domain score difference Mean change from baseline ITT, LOCF analysis Gauthier et al., Int J Geriat Psychiatr 2005 * * stabilized on donepezil

Good Safety and Tolerability of Memantine (I) Tariot et al., JAMA 2004 Most frequently reported adverse events (incidence  5%) No. of patients N = 202 (100%)N = 201 (100%) No. of patients with AEs 158 (78%) 145 (72%) Agitation19 (9.4%)24 (11.9%) Confusion16 (7.9%) 4 (2.0%) Dizziness14 (6.9%)16 (8.0%) Headache13 (6.4%) 5 (2.5%) Memantine** Placebo** Urinary tract infection12 (5.9%)10 (5.0%) Urinary incontinence11 (5.4%) 6 (3.0%) Diarrhea 9 (4.5%)17 (8.5%) Fecal incontinence 4 (2.0%)10 (5.0%) * * stabilized on donepezil

Good Safety and Tolerability of Memantine (II) Tariot et al., JAMA 2004 Most frequently reported adverse events (incidence  5%) No. of patients N = 202 (100%)N = 201 (100%) Fall15 (7.4%)14 (7.0%) Accidental injury10 (5.0%)16 (8.0%) Memantine** Placebo** Influenza-like symptoms15 (7.4%)13 (6.5%) Upper respiratory tract infection10 (5.0%)13 (6.5%) Peripheral edema10 (5.0%) 8 (4.0%) * * stabilized on donepezil

Summary Memantine: positively influenced behavioral symptoms of patients with moderate to severe AD. was significantly superior versus placebo on the domains Agitation/Aggression Delusions Irritability/Lability Appetite/Eating Change beneficial effects were most pronounced and consistent on Agitation/Aggression showing a reduction if present at onset of treatment a delay in emergence in asymptomatic patients.