Trial 9403: Baseline Characteristics

Trial 9403: Baseline CharacteristicsDemographic ParameterDemographic Parameter

PlaceboPlacebo(N = 84)(N = 84)

MemantineMemantine(N = 82)(N = 82)

MMSEMMSE

Mean Mean SD SD 6.1 6.1 2.8 2.8 6.5 6.5 2.6 2.6

Min, MaxMin, Max 0, 90, 9 0, 90, 9

HISHIS

Mean Mean SD SD 5.7 5.7 3.2 3.2 5.2 5.2 2.9 2.9

Min, MaxMin, Max 1, 121, 12 1, 121, 12

BGP care dependencyBGP care dependency

Mean Mean SD SD 21.8 21.8 7.7 7.7 21.3 21.3 7.6 7.6

BGP cognitiveBGP cognitive

Mean Mean SD SD 5.4 5.4 2.5 2.5 5.5 5.5 2.6 2.6

Trial 9403: Baseline Characteristics by HIS Score

Demographic Demographic ParameterParameter

HIS HIS ≤ 4 (AD)≤ 4 (AD) HIS > 4 (VaD)HIS > 4 (VaD)PlaceboPlacebo(N = 38)(N = 38)




MMSEMMSE

Mean Mean SD SD 6.8 6.8 2.4 2.4 6.7 6.7 2.6 2.6 5.5 5.5 3.0 3.0 6.4 6.4 2.8 2.8

Min, MaxMin, Max 1, 91, 9 0, 90, 9 0, 90, 9 0, 90, 9

HISHIS

Mean Mean SD SD 2.7 2.7 1.1 1.1 2.9 2.9 1.0 1.0 8.1 8.1 2.2 2.2 7.6 7.6 2.1 2.1

Min, MaxMin, Max 1, 41, 4 1, 41, 4 5, 125, 12 5, 125, 12

BGP care dependencyBGP care dependency

Mean Mean SD SD 19.0 19.0 7.63 7.63 20.8 20.8 6.75 6.75 23.1 23.1 7.21 7.21 20.8 20.8 8.32 8.32

BGP cognitiveBGP cognitive

Mean Mean SD SD 4.6 4.6 2.72 2.72 5.1 5.1 2.62 2.62 5.6 5.6 2.23 2.23 5.3 5.3 2.62 2.62

Trial 9403: FDA Defined AD Subpopulation (LOCF)

PlaceboPlaceboN = 25N = 25

MemantineMemantineN = 38N = 38 M-PM-P

MeanMean SDSD MeanMean SDSD p-valuep-value

BGP-CareBGP-CareDependencyDependency -1.92-1.92 4.004.00 -6.39-6.39 5.725.72 0.0020.002

BGP-CogBGP-Cog -0.64-0.64 1.321.32 -2.16-2.16 2.012.01 0.0020.002

CGI-CCGI-C 3.723.72 0.680.68 3.053.05 0.770.77 < 0.001< 0.001

Trial 9403: Change from Baseline in BGP Care Dependency: VaD Subpopulation (HIS > 4)HIS > 4)

PlaceboPlacebo MemantineMemantine

p-value*p-value*NN MeanMean SDSD NN MeanMean SDSD

Endpoint Endpoint (LOCF)(LOCF) 4646 -3.7-3.7 5.635.63 4141 -4.8-4.8 4.744.74 0.3650.365

Week 12 Week 12 (OC)(OC) 4343 -4.0-4.0 5.595.59 3939 -5.1-5.1 4.734.73 0.3340.334

* Wilcoxon rank sum test (stratified by center)

ADCS-ADL19 Item Analyses Item Points Item Points

Eating 0-4 Find personal belongings 0-3

Walking 0-3 Obtain a beverage 0-3

Toileting 0-3 Dispose of garbage appropriately

0-3*

Bathing 0-3 Travel beyond home 0-4

Grooming 0-3 Left on own 0-3

Dressing 0-4 Run water for washing without help

0-1

Using a telephone 0-5 Turn off water after using without help 0-1

Watching television 0-3 Turn on a light when entering a dark area 0-1

Attend to conversation 0-3 Turn off light when leaving or going to sleep 0-1*

Clear dishes after meal/snack 0-3

*p< .10

Trial 9605: ADCS-ADL19: Cumulative Percentage of Patients Completing 28 Weeks of Treatment

0

10

20

30

40

50

60

70

80

90

100

-10 -5 0 5 10 15 20 25

ADCS-ADL Change from Baseline

Cum

ulat

ive

Perc

enta

ge

Placebo

Memantine

Trial 9605: Severe Impairment Battery: Cumulative Percentage of Patients Completing 28 Weeks of Treatment

0

10

20

30

40

50

60

70

80

90

100

-15 -10 -5 0 5 10 15 20 25 30

SIB Change from Baseline

Cum

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ive

Perc

enta

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Placebo

Memantine

Trial 9605: RUD

Residential StatusResidential StatusPlacebo Placebo

N = 76 (%)N = 76 (%)MemantineMemantineN = 90 (%)N = 90 (%) p-value*p-value*

BaselineBaseline

InstitutionInstitution 1313 77 .16.16

End pointEnd point

InstitutionInstitution 1818 88 .04.04

* Chi-square testBased on the TTP subset at week 28.Community = patient’s own home or friend’s/relative’s home. Institution = intermediate care facility, home oriented towards dementia care, or other long-term care facility.

Institutionalization

ADCS-ADL19 Item Analyses Item Points Item Points

Eating 0-4 Find personal belongings 0-3*

Walking 0-3 Obtain a beverage 0-3

Toileting 0-3 Dispose of garbage appropriately

0-3

Bathing 0-3 Travel beyond home 0-4

Grooming 0-3** Left on own 0-3

Dressing 0-4 Run water for washing without help

0-1

Using a telephone 0-5 Turn off water after using without help 0-1

Watching television 0-3* Turn on a light when entering a dark area 0-1

Attend to conversation 0-3* Turn off light when leaving or going to sleep 0-1

Clear dishes after meal/snack 0-3

*p < .10; **p < 0.01

Trial MD-02: NPIp = 0.002

p < 0.001

p = 0.010

Impr

ovem

ent

Wor

seni

ng

Treatment Week

-4.0

-3.0

-2.0

-1.0

0.0

1.0

2.0

3.0

4.0

0 12 24 End Point

Mea

n (S

EM) C

hang

e Fr

om B

asel

ine

Memantine/donepezilPlacebo/donepezil

Trial MD-02: CIBIC+ Subgroup Analyses

SubgroupPlaceboPlacebo MemantineMemantine

p-valuep-valueNN MeanMean MedianMedian SDSD NN MeanMean MedianMedian SDSD

MMSE ≤ 9 72 4.90 5 1.10 89 4.67 5 1.03 0.035

MMSE > 9 124 4.52 4 0.99 109 4.19 4 1.01 0.121

MMSE ≤ 10 93 4.91 5 1.05 104 4.63 5 1.03 0.004

MMSE > 10 103 4.43 4 1.00 94 4.17 4 1.02 0.403

Van Elteren test.

PCS Vital Sign Values – Criteria

Vital Sign ParameterVital Sign Parameter Observed ValueObserved ValueChange Relative to Change Relative to BaselineBaseline

Systolic Blood PressureSystolic Blood Pressure 180 mm Hg180 mm Hg Increase of Increase of 20 20 90 mm Hg90 mm Hg Decrease of Decrease of 20 20

Diastolic Blood PressureDiastolic Blood Pressure 105 mm Hg105 mm Hg Increase of Increase of 15 15 50 mm Hg50 mm Hg Decrease of Decrease of 15 15

PulsePulse 120 bpm120 bpm Increase of Increase of 15 15 50 bpm50 bpm Decrease of Decrease of 15 15

WeightWeightAnyAny Increase of Increase of 7% 7%AnyAny Decrease of Decrease of 7% 7%

Mean Change in Blood Pressure


n (%)n (%)


n (%)n (%)Diastolic Blood Pressure (mm Hg)Diastolic Blood Pressure (mm Hg)

Baseline, mean (SD)Baseline, mean (SD) 78.0 (9.9)78.0 (9.9) 78.1 (10.2)78.1 (10.2)Change From Baseline, mean (SD)Change From Baseline, mean (SD) -0.7 (9.2)-0.7 (9.2) -0.4 (10.2)-0.4 (10.2)Systolic Blood Pressure (mm Hg)Systolic Blood Pressure (mm Hg)Baseline, mean (SD)Baseline, mean (SD) 136.6 (16.6)136.6 (16.6) 138.0 (16.5)138.0 (16.5)Change From Baseline, mean (SD)Change From Baseline, mean (SD) -0.8 (17.0)-0.8 (17.0) -1.0 (16.6)-1.0 (16.6)

Double-Blind, Placebo-Controlled Dementia TrialsDouble-Blind, Placebo-Controlled Dementia Trials

NMDA Receptor Antagonist-Related Neuropathology Membrane bound cytoplasmic vacuoles within the

first day of dosing Vacuoles are dilated endoplasmic reticulum

and Golgi in neurons of cingulate, retrosplenial cortex

Visualization requires aldehyde perfusion Not observed in frozen or immersion fixed

brain tissue Neuronal vacuolization progresses to necrosis

in proportion of neurons, 2+ days after NMDA antagonist exposure

NMDA Antagonist Neuropathology Rodent specific Class effect of NMDA antagonists Not observed in primates at doses inducing

significant clinical signs Clinical relevance unknown

Memantine Neuropathologyis Rodent Specific Neuropathology only observed in rats and at

doses 12 or more times the MRHD(on a mg/m2 basis)

Neuropathology observed at doses 2-4x’s higher than ataxia

Neuropathology not observed in non-rodent species In dogs at dose which causes seizure and death In baboons at doses which cause significant

clinical signs

MRHD = maximum recommended human dose, 20 mg/day.MRHD = maximum recommended human dose, 20 mg/day.

Efficacy in MMSE Subpopulation:< 10, 5-9 and ≥ 10 – CIBIC+

-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0∆ < 10 ∆ 5-9 ∆ ≥ 10

Trial 9605Trial MD-02

p = 0.462

p = 0.180

p = 0.093

p = 0.035

p = 0.030

p = 0.121

Functional Activities Staging (FAST)1. No difficulties, either subjectively or objectively2. Complains of forgetting locations of objects; subjective work

difficulties3. Decreased job functioning evident to coworkers; difficulty in

traveling to new locations; decreased organizational capacity4. Decreased ability to perform complex tasks5. Requires assistance in choosing proper clothing6. (a) Difficulty putting clothing on properly

(b) Unable to bathe properly; may develop fear of bathing(c) Inability to handle mechanics of toileting(d) Urinary incontinence(e) Fecal incontinence

7. (a ) Ability to speak limited (1 to 5 words a day)(b) All intelligible vocabulary lost (c) Nonambulatory(d) Unable to sit up independently (e) Unable to smile(f) Unable to hold up head up

9605

ADCS-ADL19 Items Item Item PointsPoints ItemItem PointsPoints

EatingEating 0-40-4 Find personal belongingsFind personal belongings 0-30-3

Walking Walking 0-30-3 Obtain a beverageObtain a beverage 0-30-3

ToiletingToileting 0-30-3 Dispose of garbage Dispose of garbage appropriatelyappropriately 0-30-3

BathingBathing 0-30-3 Travel beyond homeTravel beyond home 0-40-4

GroomingGrooming 0-30-3 Left on ownLeft on own 0-30-3

DressingDressing 0-40-4 Run water for washing Run water for washing without helpwithout help 0-10-1

Using a telephoneUsing a telephone 0-50-5 Turn off water after using Turn off water after using without helpwithout help 0-10-1

Watching televisionWatching television 0-30-3 Turn on a light when entering Turn on a light when entering a dark areaa dark area 0-10-1

Attend to Attend to conversationconversation 0-30-3 Turn off light when leaving or Turn off light when leaving or

going to sleepgoing to sleep 0-10-1

Clear dishes after Clear dishes after meal/snackmeal/snack 0-30-3

ADCS-ADL19 Item Selection Criteria Used ADCS subjects with MMSE 0-15 50% of sample was able to do item (score > 0) Item Kappa ≥ 0.4 for test-retest reliability Item showed sufficient stepwise scaling

Compared performance/nonperformance ratios across MMSE scores

Decline ≥ 0.2 points at 12-months Cronbach’s alpha > 0.80 for total score

Galasko et al submitted

ADCS-ADL19 Item Formats Items 1-6

Regarding grooming, in the past 4 weeks, which best describes {S} optimal performance?

3 = cleaned and cut fingernails without physical help 2 = brushed and combed hair without physical help 1 = kept face and hands clean without physical help 0 = needed help for grooming of hair, face, hands, and fingernails

Items 7-15 In the past 4 weeks, did {S} dispose of garbage or litter in an appropriate place or

container at home? 0 = No 0 = Don’t know

If Yes; which best describes how {S} usually performed: 3 = without supervision or help 2 = with supervision 1 = with physical help

Items 16-19 In the past 4 weeks, did {S} usually turn off the faucet after finishing running water

without help? 1 = Yes 0 = No

ADCS-ADL19 Reliability Test-retest reliability

ADCS data, N = 145 MMSE 0-15, M = 7.3 ± 4.7 (Galasko et al submitted) 1-month: Kappa = 0.93 2-month: Kappa = 0.89

9605 (placebo group) 1-month: ICC = 0.92

MD-02 (placebo group) 1-month: ICC = 0.92 2-month: ICC = 0.92

Internal Consistency (Cronbach’s alpha) 9605 baseline placebo data = 0.92 MD-02 baseline placebo data = 0.92

SIB Concurrent Validity Correlations 100 pt version

Baseline correlations (ADCS; Schmitt et al 1997) MMSE = 0.83 CDR = -0.65; Sum of boxes = -0.75;

GDS = -0.68, FAST = -0.59 12-month change score correlations (ADCS; Schmitt et al 1997)

CDR = -0.25; Sum of boxes = -0.38;GDS = -0.19, FAST = -0.25

Baseline correlations (9605 placebo subjects) ADCS-ADL19 = 0.63; CIBIC (K-Tau) = -0.18;

NPI = 0.10; FAST = -0.40 Baseline correlations (MD-02 placebo subjects)

ADCS-ADL19 = 0.58; CIBIC (K-Tau) = -0.20;NPI = -0.29; FAST = -0.50

152 pt version; MMSE 0-13 (Saxton et al 1990) MMSE = 0.74

133 pt version; MMSE 0-13 (Saxton et al 1993) MMSE = 0.76; Mattis DRS = 0.88

BGP Scale Description

Comprehensive geriatric symptomatology rating scale Developed for nurses administration in geriatric settings

Beoordelingsschaal vor Oudere Patienten (BOP) Beurteilungsskala fur geriatrische Patienten (BGP) “Rating Scale for Geriatric Patients”

Based on Stockton Geriatric Rating Scale (Meer and Baker, 1966)

Lower scores = greater function (35 items, 0-2 points) Areas include

Aggressiveness, disability, disorientation, depression, inactivity, impaired communication, ADL impairment

Items primarily rated “never,” “sometimes,” or “often”

BGP Care Dependency3. Requires assistance with eating4. The patient is urinary or feces incontinent at

daytime10. The patient makes himself understood (by

speaking, writing, or gestures)11. The patient finds his way in the nursing home

(e.g., to his room, to the toilet, to his/her place at the table) [around the house]

12. The patient understands in what home or clinic he is [where he/she lives]

13. The patient knows the names of the staff [of family members and close friends]

14. The patient understands what you communicate to him (by speaking, writing, or gestures)

17. The patient reacts when being called by his name18. The patient keeps self occupied in useful

activities out of therapeutic activities (e.g., working, reading, playing games, hobbies, talking to others)

20. The patient socializes to one or several other patients [friends]

21. The patient urinates or defecates in inappropriate places

22. The patient helps other residents [family members/friends] on his own initiative (e.g., moving the wheelchair, passing items)

23. The patient is cooperative to do what is asked25. The patient always repeats the same movements of no

use (e.g., walking to and fro, toddling back and forth, wringing hands, and

26. The patient makes sounds which are directed to no one27. The patient enters into a conversation on his own

initiative28. The patient is allowed to go out30. The patient drowses during the daytime [takes naps

during the day]31. The patient requires assistance with dressing32. The patient is urinary or feces incontinent at night33. A special support is required to prevent the patient

from falling out of bed34. The patient disturbs other residents at night35. The patient is restless at night

Italic text= Cognitive subscaleBracketed text indicate changes for MD-02

Treatment Duration

Double-Blind Double-Blind Open-LabelOpen-LabelMemantineMemantine(N = 856)(N = 856)

TotalTotalMemantineMemantine(N = 1357)(N = 1357)

Placebo Placebo (N = 922)(N = 922)


Treatment Duration, n (%)Treatment Duration, n (%)

4 weeks (28 days) 4 weeks (28 days) 884 (95.9) 884 (95.9) 896 (95.4) 896 (95.4) 835 (97.5) 835 (97.5) 1306 (96.3) 1306 (96.3)



36 weeks (252 days) 36 weeks (252 days) 0 0 0 0 42 (4.9) 42 (4.9) 429 (31.6) 429 (31.6)

48 weeks (336 days) 48 weeks (336 days) 0 0 0 0 37 (4.3) 37 (4.3) 387 (28.5) 387 (28.5)

Core Dementia Trials

Dosing Scheme – Double-Blind Phase

Previous Previous TreatmentTreatment

Memantine Titration Memantine Titration GroupGroup Week 1Week 1 Week 2Week 2 Week 3Week 3

PlaceboPlacebo

Group AGroup AAMAM 00 5 mg/day5 mg/day 5 mg/day5 mg/day

PMPM 5 mg/day5 mg/day 5 mg/day5 mg/day 10 mg/day10 mg/day

Group BGroup BAMAM 00 00 00


Group CGroup CAMAM 5 mg/day5 mg/day 10 mg/day10 mg/day 10 mg/day10 mg/day


Group DGroup DAMAM 00 00 00


MemantineMemantineGroup EGroup E

AMAM 10 mg/day10 mg/day 10 mg/day10 mg/day 10 mg/day10 mg/day


Group FGroup FAMAM 00 00 00


Ongoing Trials – MD-03

Patient Populations

Trial GroupsTrial Groups

Treatment GroupsTreatment GroupsEstimated Memantine Estimated Memantine First Time ExposureFirst Time Exposure

Estimated Placebo/Estimated Placebo/Active ControlActive Control

Total Enrolled per Total Enrolled per TrialTrial

Trials in Dementia PopulationTrials in Dementia PopulationMEM-MD-01 155155 155155 310310MEM-MD-10 155155 155155 310310MEM-MD-12 216216 216216 432432MRZ-90001-9901 3939 1111 5050IE2101†† 8282 4141 12312399679 9494 4747 14114199817 55 55 1010MEM-MD-03 237237 00 475475MEM-MD-11 6565 00 129129MRZ-90001-9708 100100 00 100100IE2901 109109 00 109109MRZ-90001-9408/3 OLEX 00‡‡ 00 105105

Ongoing Trials

Agitation - MMSE <10

Agitation - MMSE >=10

Urinary Incontinence - MMSE <10

Urinary Incontinence - MMSE >=10

Fall - MMSE <10

Fall - MMSE >=10

Headache - MMSE <10

Headache - MMSE >= 10

Dizziness - MMSE <10

Dizziness - MMSE >= 10

Adverse Events (Reported by >5% Patients in the Memantine Group)Trials 9605 and MD-02 Combination (Moderate to Severe AD Patients) (1 of 2)

AE Preferred Term RR (95% CI’s) RR (95% CI)

Decrease Increase

.5 1 5 >10

0.66 (0.38, 1.16)

0.41 (0.21, 0.82)

1.20 (0.53, 2.74)

1.07 (0.45, 2.53)

0.93 (0.39, 2.21)

1.16 (0.51, 2.62)

2.55 (0.89, 7.33)

2.92 (0.76, 11.20)

1.66 (0.48, 5.79)

0.99 (0.46, 2.12)

Documents

Trial 9403: Baseline Characteristics