memantine treatment in patients with moderate to severe alzheimer disease already receiving...

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

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)

Study Design

Tariot et al., JAMA 2004

Disposition of Patients

Patients randomized N = 404

Patients treatedN = 403

CompletedN = 150(75%)

WithdrewN = 51(25%)

Placebo + donepezilN = 201

Memantine + donepezilN = 202

CompletedN = 172

(85%)*

WithdrewN = 30(15%)


* p = 0.011 versus placebo/donepezil (completed)

Status of Donepezil Treatment at Baseline


Donepezil treatment history

Mean duration of donepezil treatment: > 2 years

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

Sustained Improvement of Cognition (SIB) by Memantine


SIB

sc

ore

dif

fere

nc

e

* p 0.03 versus placebo/donepezil

OC / endpoint ITT (LOCF) Mean change from baseline

Week

End Point(LOCF)

N = 198

Impr

ovem

ent

Det

erio

ratio

n

N = 196

N = 171N = 181

N = 185N = 190

N = 197

4

3

2

1

0

-1

-2

-3

-4

0 4 128 18 24

Memantine + donepezil

Placebo + donepezil

N = 198

N = 197 N = 194 N = 180

N = 169N = 164

N = 153

**

*

**

Significant Benefit of Memantine on Function (ADCS-ADL19)


AD

CS

-AD

L1

9 s

co

re d

iffe

ren

ce

* p 0.03 versus placebo/donepezil

OC / endpoint ITT (LOCF) Mean change from baseline

Week

1

0

-1

-2

-3

-4

Impr

ovem

ent

Det

erio

ratio

n

0 4 128 18 24


Placebo + donepezil

N = 172

N = 197

N = 181

N = 185N = 190N = 198N = 198

*

**

***

N = 198

N = 152N = 163

N = 170

N = 182N = 195

N = 197

End Point(LOCF)


Significant Benefit of Memantine on Clinical Global Impression (CIBIC-Plus)

CIB

IC-P

lus

glo

ba

l sc

ore

* p < 0.03 versus placebo/donepezil

OC / endpoint ITT (LOCF) 4.0 = no change

Week

Impr

ovem

ent

Det

erio

ratio

n

3.6

3.8

4.0

4.2

4.4

4.6

4.80 4 128 18 24


Placebo + donepezil

N = 172

N = 180

N = 182

N = 190

N = 197

*

*

*

*

N = 198N = 194N = 181 N = 170

N = 164

N = 152

N = 196

End Point(LOCF)

*


More Patients Improved under Memantine

CIB

IC-P

lus

glo

ba

l sc

ore

ITT (LOCF) after 24 weeks 4.0 = no change

Impr

ovem

ent

Wor

seni

ng

Percentage of patients [%]

1

2

3

4

5

6

7

0 5 10 15 20 25 30 35 40


Placebo + donepezil

45

Significant Benefit of Memantine on Behavior (NPI)

NP

I sc

ore

dif

fere

nc

e

Tariot et al., JAMA 2004 * p = 0.002 versus placebo/donepezil

Impr

ovem

ent

Wor

seni

ng

*-1

0

1

2

3

4

5Memantine +

donepezilPlacebo + donepezil

ITT (LOCF) Mean change from baseline

Significant Benefit of Memantine on Care Dependency (BGP)

BG

P s

co

re d

iffe

ren

ce

(Ca

re d

ep

en

de

ncy

su

bs

cal

e)

Tariot et al., JAMA 2004 * p = 0.001 versus placebo/donepezil

-1

0

1

2

3

4

5

*


Placebo + donepezil

Impr

ovem

ent

Wor

seni

ng

ITT (LOCF) Mean change from baseline

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

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

memantineTariot et al., JAMA 2004

memantine treatment in patients with moderate to severe alzheimer disease already receiving...

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