1. Journal of the American Medical Association (JAMA), 2004, 291: 317-324
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:

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: SIB parameters Function: ADCS-ADL19
Secondary efficacy Global: CIBIC-Plus, parameters Behavior: NPI and BGP (Care dependency subscale)
The severity of the disease was assessed by the Mini-Mental-State Examination (MMSE). The primary efficacy parameter of this study were the Severe Impairment Battery (SIB) and a modified 19-items Alzheimer‘s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). The SIB is a 40-items test to evaluate cognitive dysfunction in patients with more severe Alzheimer‘s disease. It assesses memory, orientation, language, attention, visuospatial ability and construction. The ADCS-ADL19 is a structured questionnaire to assess functional capacity. The modified ADCS-ADL19 consists of 19 items of daily living and is identical to the ADCS-ADL modified for severe dementia (ADCS-ADLsev) used in previous studies.
The secondary efficacy parameters included the Clinician’s Interview based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory (NPI) and the Behavioral Rating Scale for Geriatric Patients (BGP care dependency subscale). The CIBIC-Plus assesses the effect of medication on overall clinical status in patients with Alzheimer‘s Disease, incorporating caregiver observations as well as patients interviews. The NPI evaluates the frequency and severity of behavioral symptoms based on an interview of the caregiver and the BGP care dependency subscale reflects cognitive and functional characteristics associated with increased need for care.
The randomized, placebo-controlled, double-blind study was conducted in 37 centers in the United States. Assessments of the primary efficacy variables were conducted at baseline, after 4, 8, 12, 18 and 24 weeks (endpoint) of treatment. The overall objective of this study was to determine if memantine treatment is efficacious in patients with moderate to severe Alzheimer’s disease receiving a stable dose of donepezil.
Tariot et al., JAMA 2004

3. Disposition of Patients
Patients randomized N = 404
Patients treated N = 403
Completed N = 150 (75%)
Withdrew N = 51 (25%)
Placebo + donepezil N = 201
Memantine + donepezil N = 202
Completed N = 172 (85%)*
Withdrew N = 30 (15%)
This study was conducted with 403 outpatients. The baseline characteristics were not significantly different between the two treatment groups except for body weight which was 66.4 kg for the placebo treated patients and 70.7 kg for the memantine treated patients. All patients were treated with a stable individual dose of the cholinesterase inhibitor donepezil.
Generally one would expect a high dropout rate in moderate to severe Alzheimer’s disease patients. Surprisingly, the dropout rate in memantine treated patients was much lower than in the placebo group. While 25% of all patients in the placebo group withdrew from the study, in the memantine group 15% discontinued the treatment. This indicates already the favorable tolerability of memantine.
* p = 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 of donepezil treatment 126 weeks 129 weeks at baseline
Mean dose of donepezil treatment mg/d 9.49 mg/d at baseline
Patients included into the study had to be under treatment with the cholinesterase inhibitor donepezil for at least 6 months receiving a stable, individual dose ( mg/d) for at least 3 months. At baseline the mean duration of donepezil treatment was more than two years.
At baseline, the mean duration of donepezil treatment and mean dosage of donepezil was not significantly different between the placebo and memantine group.
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
Week
End Point
(LOCF)
N = 198
Improvement
Deterioration
N = 196
N = 171
N = 181
N = 185
N = 190
N = 197 4 3 2 1 -1 -2 -3 -4 12 8 18 24
 Memantine + donepezil
 Placebo + donepezil
N = 194
N = 180
N = 169
N = 164
N = 153 *
SIB score difference
The Severe Impairment Battery (SIB) is a 40-items test developed for the evaluation of cognitive dysfunction in patients with more severe Alzheimer‘s Disease. Six primary subscales assess memory, orientation, language, attention, visuospatial ability and construction. In addition, the scale assesses praxis, social interaction and orienting to name. The SIB scores range from 0 to 100, with higher scores reflecting higher levels of cognitive ability. Shown here is the mean ( SEM) change from baseline in the SIB score over 24 weeks of treatment with either memantine (20 mg/day) or placebo. The mean score at baseline was 79.8 for the placebo group and 77.8 for the memantine group (not significantly different). The data analysis is based on the observed cases (OC). Additionally the endpoint was also analyzed based on the intent-to-treat (ITT) population using the last observation carried forward (LOCF) method.
After 24 weeks a significant difference in the Severe Impairment Battery (SIB) of 3.4 points in favor of memantine was observed (p ≤ 0.001, ITT- LOCF). In particular, the mean SIB values of the patients receiving memantine remained above baseline throughout the trial.
* 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
Week 1 -1 -2 -3 -4
Improvement
Deterioration 4 12 8 18 24
 Memantine + donepezil
 Placebo + donepezil
N = 172
N = 197
N = 181
N = 185
N = 190
N = 198 *
N = 152
N = 163
N = 170
N = 182
N = 195
End Point
(LOCF)
ADCS-ADL19 score difference
The Alzheimer‘s Disease Cooperative Study Activities of Daily Living modified for patients with more severe dementia (ADCS-ADL19) is a structured questionnaire to assess functional capacity of patients with moderate to severe Alzheimer’s disease. This slide depicts the mean change in the ADCS-ADL19 ( SEM) score from baseline over 24 weeks of treatment with either memantine (20 mg/day) or placebo. The data analysis is based on the observed cases (OC). Additionally the endpoint was also analyzed based on the intent-to-treat (ITT) population using the last observation carried forward (LOCF) method.
The ability to carry out activities of daily living was significantly higher under memantine in comparison to placebo treatment in patients with moderate to severe Alzheimer’s disease receiving a stable individual donepezil therapy. A statistically significant treatment effect was shown as early as 4 weeks after the beginning of the trial. The mean change from baseline in the ADCS-ADL19 score after 24 weeks was – 2 points in the memantine group compared with – 3.4 points in the placebo group (p = 0.028, ITT- LOCF).
* p  0.03 versus placebo/donepezil
Tariot et al., JAMA 2004

7. CIBIC-Plus global score
Significant Benefit of Memantine on Clinical Global Impression (CIBIC-Plus)
OC / endpoint ITT (LOCF) 4.0 = no change
Week
Improvement
Deterioration
3.6
3.8
4.0
4.2
4.4
4.6
4.8 4 12 8 18 24
 Memantine + donepezil
 Placebo + donepezil
N = 172
N = 180
N = 182
N = 190
N = 197 *
N = 198
N = 194
N = 181
N = 170
N = 164
N = 152
N = 196
End Point
(LOCF)
CIBIC-Plus global score
The Clinician‘s Interview-Based Impression of Change plus Caregiver Input (CIBIC-Plus) is a systematical evaluation of change in the domains of cognition, function and behavior based on patient and caregiver interviews. The CIBIC-Plus is a change score on a 7-point scale, with 1 being marked improvement and 7 being marked worsening. By design, the baseline is set to “no change” (4.0). Shown is the mean CIBIC-Plus score ( SEM ) over 24 weeks of treatment with either memantine (20 mg/day) or placebo. The data analysis is based on the observed cases (OC). The endpoint was also analyzed based on the intent-to-treat (ITT) population using the last observation carried forward (LOCF) method.
At the study endpoint clinical global impression determined by the CIBIC-Plus score was statistically superior in the memantine group in comparison to the placebo group.
* p < 0.03 versus placebo/donepezil
Tariot et al., JAMA 2004

8. More Patients Improved under Memantine
ITT (LOCF) after 24 weeks = no change
Improvement
Worsening
Percentage of patients [%] 1 2 3 4 5 6 7 10 15 20 25 30 35 40
 Memantine + donepezil
 Placebo + donepezil 45
CIBIC-Plus global score
The Clinician‘s Interview-Based Impression of Change plus Caregiver Input (CIBIC-Plus) is a systematical evaluation of change in the domains of cognition, function and behavior based on patient and caregiver interviews. The CIBIC-Plus is a change score. Values < 4 indicate an improvement in comparison to baseline (1 = marked, 2 = moderate, 3 = minimal improvement). A rating of 4 indicates no change and values > 4 display worsening of clinical global impression versus baseline (5 = minimal, 6 = moderate, 7 = marked worsening). This slide shows the global change in patients treated with memantine or placebo at week 24. It shows the percentage of memantine or placebo treated patients with a certain CIBIC-Plus score at the study endpoint. Shown is the analysis of the intent-to-treat (ITT) population using the last observation carried forward (LOCF) method at the endpoint.
The benefit of memantine treatment on global outcome is shown. The distribution of values between memantine and placebo treated patients was significantly different (p = 0.03). The percentage of improved patients (CIBIC-Plus < 4) is higher in the memantine group than in the placebo group. Stabilization (CIBIC-Plus = 4) was more frequently seen in memantine patients. The percentage of patients showing impairment (CIBIC-Plus < 4) is higher in the placebo group. Overall at the endpoint 55% of the memantine patients were rated as improved or unchanged versus 45% of the placebo patients.
Tariot et al., JAMA 2004

9. Significant Benefit of Memantine on Behavior (NPI)
Improvement
Worsening * -1 1 2 3 4 5
Memantine + donepezil
Placebo + donepezil
ITT (LOCF) Mean change from baseline
NPI score difference
The Neuropsychiatric Inventory (NPI) assesses the frequency and severity of behavioral symptoms (including frequency and/or severity of agitation/aggression, irritability/lability, and appetite/eating changes) in patients with dementia based on an interview with the caregivers. Higher scores reflect more severe symptoms. The NPI was assessed at baseline and at the final visit. This slide depicts the mean change ( 95% confidence intervals) from baseline in the NPI score. Positive changes in score indicate clinical deterioration.
The LOCF NPI single-item analyses showed that memantine + donepezil treatment significantly reduced the frequency and/or severity of agitation/aggression (p < 0.001), irritability/lability (p = 0.005), and appetite/eating changes (p = 0.045) in comparison to the placebo + donepezil treatment.In the OC NPI single-item analyses the memantine + donepezil treatment significantly reduced the frequency and/or severity of agitation/aggression (p < ) and irritability/lability (p = 0.003) when compared to the placebo + donepezil treatment.
Memantine treatment resulted in a significantly better NPI score (p = 0.002) compared to the placebo group. After 24 weeks, a stabilization of the behavioral disturbances and psychiatric symptoms in patients treated with memantine was shown. In contrast, behavior and mood of the patients in the placebo/donepezil group deteriorated.
* p = versus placebo/donepezil
Tariot et al., JAMA 2004

10. Significant Benefit of Memantine on Care Dependency (BGP)-1 1 2 3 4 5 *
Memantine + donepezil
Placebo + donepezil
Improvement
Worsening
ITT (LOCF) Mean change from baseline
(Care dependency subscale)
BGP score difference
The Behavioral Rating Scale for Geriatric Patients (BGP), is an observer-rated scale for the assessment of functional and behavioral disturbances of geriatric patients. The “BGP care dependency subscale” reflects cognitive and functional characteristics associated with increased need for care. Higher values represent higher care-dependency. This slide shows the mean change from baseline ( 95% confidence intervals) of the “BGP care dependency subscale” over 24 weeks of treatment with either memantine (20 mg/day) or placebo. The data analysis is based on the last observation carried forward (LOCF) method.
Memantine treated patients performed significantly better than patients receiving placebo: care dependency deteriorated to a lower extent in the memantine group in comparison to the placebo group (p = 0.001).
* p = versus placebo/donepezil
Tariot et al., JAMA 2004

11. Good Safety and Tolerability of Memantine
Most frequently reported adverse events (incidence  5%)
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%)
Memantine + donepezil Placebo + donepezil
As expected in this population with moderate to severe Alzheimer’s disease (AD), the majority of patients experienced adverse events during the study (78% under memantine and 72% under placebo treatment). However, most adverse events were either mild to moderate in severity or not related or unlikely to be related to the study medication.
Although confusion was reported in many memantine-treated patients, it was rated as mild and transient and occurred at a median of 32 days and remitted within 2 weeks. In the placebo group, confusion was rated as severe and occurred at a median of 55 days and did not remit. Memantine/donepezil treatment also appears to reduce the incidence of agitation compared to placebo/donepezil treatment, which suggests that memantine may be able to reduce agitation in AD patients. The gastrointestinal adverse events (diarrhea, fecal incontinence) associated with donepezil were more commonly reported by patients taking placebo/donepezil compared with those taking memantine/donepezil. This may suggest that memantine positively influenced gastrointestinal adverse events.
Memantine is safe and well tolerated in patients with moderate to severe Alzheimer’s disease. It should be noted that more patients of the placebo-treated group (12.4%) discontinued the study due to adverse events than in the memantine group (7.4%).
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
This is the first prospective double-blind, placebo-controlled trial examining the benefits of memantine in patients under donepezil treatment suffering from moderate to severe Alzheimer’s Disease. This study shows that memantine is even efficacious in patients which are under treatment with a stable individual dose of the cholinesterase inhibitor donepezil.
Treatment with memantine was superior in efficacy to treatment with placebo in patients stabilized on donepezil as measured by cognition, function, global outcome, care dependency and behavior. This and other studies demonstrate that memantine treatment results in significantly better outcomes than placebo treatment in patients with moderate to severe AD.
Tariot et al., JAMA 2004