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MEMA NTINE BENEFITS FUNCTIONA L A BILITIES IN MODERA TE TO SEV ERE A LZHEIMER’S DISEA SE

MEMANTINE BENEFITS FUNCTIONAL ABILITIES IN MODERATE

TO SEVERE ALZHEIMER’S DISEASE
B. WINBLAD1, S. GAUTHIER2, D. ÅSTRÖM3, K. STENDER3
1. Karolinska Institutet, Alzheimer Disease Research Center (KI-ADRC) NOVUM, Huddinge, Sweden; 2. McGill Center for Studies in Aging, Douglas Institute for Mental Health,
Montreal, Quebec, Canada; 3. H. Lundbeck A/S, Copenhagen, Denmark. Corresponding author: Bengt Winblad, Karolinska Institutet, Alzheimer Disease Research Center (KI-ADRC)
NOVUM, Floor 5, S-14157 Huddinge, Sweden, Phone: +46 8 585 85474, Fax: +46 8 585 83610, E-mail: bengt.winblad@ki.se

Abstract: Objective: Functional abilities are severely impacted in Alzheimer’s disease (AD). Loss of the ability to
perform complex (instrumental) and basic activities of daily living (ADL), leads to decreased independence and
increased caregiver burden. This post-hoc analysis investigated the effect of memantine (20 mg/day) on ADLs, as
measured by Alzheimer’s Disease Cooperative Study-Activities of Daily Living 19-item (ADCS-ADL19) and 23-
item (ADCS-ADL23) scales, in patients with moderate-to-severe AD. Design: Data were pooled from six
multicenter, randomized, placebo-controlled, double-blind, 6-month studies of memantine 20 mg/day.
Participants: Male and female patients aged ≥50 years at baseline with a Mini Mental State Examination (MMSE)
score <20. Measurements: ADCS-ADL19 and ADCS-ADL23 scales were pooled, and 14 shared items, with a
score range of 0-45, were identified and included in the analysis (ADL14). Basic ADLs (BADLs) were defined
as: eating, walking, toileting, bathing, and grooming. Instrumental ADLs (IADLs) were defined as: using a
telephone, watching television, conversing, clearing a table, finding belongings, obtaining a beverage, disposing
of household rubbish, travelling outside the house, and being left alone. Changes from baseline on single-item,
BADL (range: 0–15), IADL (range: 0–30), and total ADL14 scores were analysed for observed cases using
ANCOVA, with study, center and treatment as categorical explanatory variables and score at baseline as a
covariate. Results: 959 patients were treated with memantine and 867 patients received placebo. Memantine-
treated patients had less decline from baseline on the ADL14 total score, compared with placebo (p<0.001) at
study end. Memantine also showed lower reductions in BADLs (p<0.05) and IADLs (p<0.001), for observed
cases, compared with placebo. Memantine-treated patients showed less worsening than placebo recipients for the
ADL items: toileting (p<0.01), grooming (p<0.01), finding belongings (p<0.01), and travelling outside the house
(p<0.05). Conclusion: Compared with placebo, memantine shows benefits for both basic and instrumental ADLs
in patients with moderate-to-severe AD, suggesting that memantine treatment may lead to a more interactive and
dignified life for patients with moderate-to-severe AD.

Key words: Memantine, Alzheimer’s disease, functional ability.

Introduction towards the major burden for carers (6).

Alzheimer’s disease (AD) is a progressive neurodegenerative
condition characterized by memory impairment, deterioration of
language, other cognitive deficits, and behavioural problems
such as confusion, irritability, aggression, mood swings and
general withdrawal (1). In addition, functional impairments
include an inability to perform instrumental daily activities and
basic daily activities (2). It is the single most common cause of
dementia, and in Europe, accounts for approximately 55-80% of
all cases of dementia (3).
Progression of AD is defined by increasing functional and
behavioural impairments, which, in the moderate to severe
stages of the disease, can result in total dependence on a
caregiver and a high risk of institutionalisation (4, 5). Thus, a
patient’s functional performance gradually progresses from an
inability to perform instrumental daily activities, such as
telephoning and travelling alone, to an eventual decline in the
basic daily activities of eating, walking or grooming (2).
Deterioration in functional performance can be measured over
the space of 6-12 months (2). This loss of functional ability is
also one of the biggest problems for caregivers and contributes
Treatment interventions that enable a patient with AD to
retain some ability to perform activities of daily living and to
preserve their independence for longer, may prevent increases
in patient distress and caregiver burden that would ultimately
lead to patient institutionalisation. Memantine, a specific,
uncompetitive N-methyl-d-aspartate (NMDA) receptor
antagonist with moderate affinity and rapid voltage-dependent
kinetics, acts by targeting the neurotransmitter (glutamate)
system central to the pathology of AD (7, 8). Memantine has
been approved in Europe and the USA for the treatment of
patients with moderate-to-severe AD, and is the only treatment
in clinical use for AD that specifically targets the glutamatergic
system.
In clinical studies of outpatients with AD, memantine had
significant clinical effects on global status, cognitive
(including language, memory, orientation, praxis, and
visuospatial ability), functional, and behavioural (including
symptoms of delusions, agitation/aggression and
irritability/lability) outcomes, and was well tolerated with an
adverse event profile similar to placebo (9-12). Furthermore, in
nursing home patients with severe dementia (AD or vascular

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Received December 23, 2009
A ccepted for publication January 21, 2010
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dementia (VaD)), memantine improved activities of daily
living, care dependence and behavioural symptoms compared
with placebo (13). For these reasons, memantine has the
potential to improve the functional status of patients to a
greater extent than that seen with donepezil, for which there is
conflicting evidence in relation to its benefits on activities of
daily living in severe AD (14-16).
Six randomized, placebo controlled trials have assessed the
efficacy and safety of memantine 20 mg/day (17-22) and the
data on cognitive outcomes, behavioural symptoms and safety
and tolerability from these trials have been assessed in detail in
meta-analyses (9, 10, 12). The information on functional
performance from these studies has not been assessed in the
same way, and therefore, in this post hoc analysis, data from
these six studies were pooled to evaluate the effects of treatment
on functional performance in patients with moderate-to-severe
AD.
Methods
Study design and patient population
Data were pooled from six multicenter, randomized,
placebo-controlled, double-blind, 6-month studies of
memantine 20 mg/day (Table 1). All English-language
published double-blind, randomized, placebo-controlled, phase
III studies of memantine with a minimum duration of 24 weeks
were included in the analysis. All patients, or their legally
Table 1
Summary of the six memantine (20 mg/day) randomized, double-blind, placebo-controlled studies included in this analysis
authorized representatives, provided written informed consent
prior to participation.
Study design and patient populations have been described in
detail elsewhere (17-22). All patients were diagnosed with
probable AD according to the NINCDS-ADRDA criteria (23,
24). Briefly, study participants were male or female outpatients
aged ≥50 years at baseline. In all studies, patients received an
initial memantine dose of 5 mg/day (or placebo), which was
titrated in 5 mg/day increments at weekly intervals to 20
mg/day. Concomitant psychotropic medications were permitted
in five studies (17, 18, 20-22), but not in one study (19).
Efficacy outcome measures
Functional abilities were assessed in all six studies (17-22)
using the AD Cooperative Study-Activities of Daily Living 19-
item (ADCS-ADL19) or 23-item (ADCS-ADL23) structured
questionnaires at baseline, and after 4, 12 and 24 weeks. The
ADCS-ADL19 is used for patients with moderate to severe AD
and the ADCS-ADL23 for patients with mild to moderate AD
(11). Each item on these scales evaluates a patient’s ability to
perform an activity of daily living. Caregivers assess a patient’s
performance during the previous four weeks; increasing scores
indicate an improvement in functional ability, with a total score
of 54 (for ADCS-ADL19) or 78 (for ADCS-ADL23) indicating
optimal performance. In the present pooled analysis, mean
change in ADL score from baseline was assessed for 14

Study MMSE inclusion range (mean) Duration and other details Patients Efficacy measures

Peskind et al (2006) 10-22 (17.3) – mild to moderate 24 weeks 403 patients ADAS-cog,
Twice-daily memantine P: 202 ADCS-ADL23,
M: 201 CIBIC-Plus, NPI
Porsteinsson et al (2008) 10-22 (16.9) – mild to moderate 24 weeks, patients already 433 patients ADCS-ADL23,
receiving a cholinesterase P: 216 CIBIC-Plus,
inhibitor M: 217 MMSE, NPI
Once-daily memantine
Bakchine and Loft (2008) 11-23 (18.7) – mild to moderate 24 weeks 470 patients ADAS-cog,
Twice-daily memantine P: 152 ADCS-ADL23,
M: 318 CIBIC-Plus, NPI
Reisberg et al (2003) 3-14 (7.9) – moderate to severe 28 weeks 252 patients SIB,
Twice-daily memantine P: 126 ADCS-ADL19,
M:126 CIBIC-Plus, FAST,
GDS, MMSE, NPI
Van Dyck et al (2007) 5-14 (10.1) – moderate to severe 24 weeks 350 patients SIB,
Twice-daily memantine P: 172 ADCS-ADL19,
M: 178 BGP, CIBIC-Plus,
FAST, NPI
Tariot et al (2004) 5-14 (10.0) – moderate to severe 24 weeks, patients already 403 patients ADCS-ADL19,
receiving donepezil P: 201 BGP, CIBIC-Plus,
Twice-daily memantine M: 202 NPI,
SIB

P = placebo; M = memantine; ADAS-cog = Alzheimer’s Disease Assessment Scale Cognitive Subscale; SIB = Severe Impairment Battery; ADCS-ADL19 = 19-item AD Cooperative
Study-Activities of Daily Living Inventory; ADCS-ADL23 = 23-item AD Cooperative Study-Activities of Daily Living Inventory; BGP = Behavioural Rating Scale for Geriatric Patients;
CIBIC-plus = Clinician’s Interview-Based Impression of Change Plus Caregiver Input; FAST = Functional Assessment Staging; GDS = Global Deterioration Scale; NPI =
Neuropsychiatric Inventory. Cholinesterase inhibitors were donepezil , rivastigmine, or galantamine.

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overlapping items on the ADCS-ADL 19 and ADCS-ADL 23 with memantine. Significantly less worsening of individual
scales (for the purposes of this paper, referred to as ADL14), ADL scores (two BADL single-item scores [toileting and
because three studies recruited patients with mild-to-moderate grooming], and two IADL single-item scores [finding
AD and therefore used the ADCS-ADL23 (17, 18, 22) and three belongings and travelling outside the house]) were also recorded
studies recruited patients with moderate-to-severe AD and at week 24 in memantine recipients, compared with placebo
therefore used the ADCS-ADL19 (19-21). The score range for (Figure 3). The LOCF analysis showed similar significant
the ADL14 was 0-45. The basic ADLs (BADLs) comprised the differences, except the difference between groups for the
items eating (score range 0–3), walking (0–3), toileting (0–3), travelling outside the house item was not significant (p=0.14).
bathing (0–3), and grooming (0–3), and the instrumental ADLs Conversing worsened more in the placebo-group than in the
(IADLs) were the remaining non-basic items, which were using memantine-treated group, but the difference did not reach
a telephone (0–5), watching television (0–3), conversing (0–3), statistical significance (p=0.06 in OC analysis and p=0.08 in
clearing a table (0–3), finding belongings (0–3), obtaining a LOCF analysis).
beverage (0–3), disposing of household rubbish (0–3),
travelling outside the house (0–4), and being left alone (0–3). Table 2
For each item, scores ranged from 0 = ‘least able to perform Patient demographics and clinical characteristics at baseline
task’ to 3 or 4 = ‘most able to perform task’. (FAS; MMSE <20)
Statistical analyses
Placebo (n=867) Memantine
Efficacy analyses were conducted on the patients from the (n=959)
full analysis set (FAS; all patients who received at least one
dose of study medication and had at least one post-baseline Women, n (%) 550 (63.4) 644 (67.2)
efficacy assessment) with Mini Mental State Examination Mean (±SD) age, years 76.2 ± 8.3 76.2 ± 8.1
(MMSE) score <20 (moderate-to-severe AD), using an Caucasian ethnicity, n (%) 788 (90.9) 865 (90.2)
MMSE score, mean ± SD 12.2 ± 4.1 12.3 ± 4.2
observed-case (OC) approach and a last-observation-carried ADL19 total score, mean ± SD 33.1 ± 10.7 (n=499) 32.5 ± 10.7 (n=506)
forward (LOCF) approach to support the OC analyses. The ADL23 total score, mean ± SD 52.7 ± 13.2 (n=368) 51.3 ± 14.7 (n=453)
efficacy endpoints were the change from baseline in ADL14 ADL14 total score, mean ± SD 29.3 ± 8.5 (n=850) 29.0 ± 8.7 (n=938)
total score, BADL score and IADL score, and change in ADL14 Basic ADLs 12.4 ± 2.9 (n=850) 12.4 ± 3.0 (n=938)
single-item scores. Differences between memantine and Eating 2.7 ± 0.5 (n=850) 2.7 ± 0.5 (n=938)
placebo were analyzed within the OC and LOCF populations Walking 2.9 ± 0.5 (n=849) 2.8 ± 0.5 (n=938)
Toileting 2.6 ± 0.8 (n=850) 2.6 ± 0.8 (n=938)
using analysis of covariance (ANCOVA), with study, center, Bathing 2.0 ± 1.0 (n=850) 2.0 ± 1.0 (n=938)
and treatment as categorical explanatory variables and score at Grooming 2.3 ± 1.0 (n=849) 2.2 ± 1.0 (n=937)
baseline as a covariate. All efficacy analyses were tested at the Instrumental ADLs 16.8 ± 6.2 (n=850) 16.6 ± 6.3 (n=938)
two-sided 95% level of significance. Using a telephone 2.1 ± 1.3 (n=850) 2.1 ± 1.3 (n=938)
Watching television 1.0 ± 1.0 (n=835) 1.0 ± 1.0 (n=925)
Results Conversing
Clearing a table
2.1 ± 1.2 (n=850)
2.3 ± 1.1 (n=850)
2.1 ± 1.1 (n=937)
2.2 ± 1.2 (n=938)
Finding belongings 1.9 ± 1.1 (n=850) 1.9 ± 1.1 (n=938)
Baseline characteristics Obtaining a beverage 1.6 ± 1.2 (n=850) 1.6 ± 1.2 (n=937)
The FAS consisted of the 959 memantine-treated patients Disposing of litter 2.4 ± 1.0 (n=850) 2.4 ± 1.1 (n=938)
and 867 placebo recipients who had baseline MMSE scores of Travelling outside the house 2.4 ± 0.9 (n=850) 2.3 ± 0.9 (n=938)
Being left alone 1.5 ± 1.2 (n=540) 1.6 ± 1.2 (n=619)
less than 20. Baseline demographic and clinical characteristics,
including scores for the ADCS-ADL19, ADCS-ADL23, and ADL19 and ADL23 = Alzheimer’s Disease Cooperative Study-Activities of Daily Living 19
ADL14, were similar in the two treatment groups (Table 2). and 23 item scales; ADL14 = overlapping items on the ADL19 and ADL23 scales; MMSE =
Mini Mental State Examination.

Functional efficacy
Memantine-treated patients had smaller reductions (i.e., less
worsening) in scores on the ADL14 than placebo recipients.
Differences in functional decline between memantine-treated
and placebo-treated patients increased over time (Figure 1).
BADLs and IADLs decreased by less in the memantine-
treated patients than in placebo-treated patients (Figure 2). The
results from the LOCF analysis were consistent with those of
the OC analysis: at week 4 there were no significant differences
in the BADL or IADL scores in the two LOCF patient groups,
but by week 12 IADL scores were significantly less reduced in
memantine-treated patients than placebo-treated patients, and by
week 24 both BADL and IADL were significantly less reduced
Discussion
In this pooled post hoc analysis of six 6-month studies of
patients with moderate to severe AD (MMSE<20), memantine
(20 mg/day) treatment provided statistically significant benefits
in overall functional ability and activities of daily living
compared with placebo. These results confirm the initial, less
comprehensive, report of better functional ability with
memantine than placebo (11), and suggest that memantine
treatment may help patients maintain a more interactive life.
The ADCS-ADL19 and ADCS-ADL23 are reliable, sensitive
and validated instruments for assessing functional change in
patients with moderate to severe AD (2).

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Figure 1
Mean change from baseline in ADL14 total score, at Weeks 4, 12
and 24/28 (observed cases) and at Week 24/28 (last observation
carried forward) in the pooled population of patients with
moderate to severe AD. P-values from ANCOVA
Figure 2
Mean change from baseline in ADL14 BADL and IADL score
at Week 24/28 (observed cases) in the pooled population of
patients with moderate to severe AD. P-values from ANCOVA
Although the patients recruited in the clinical trials analysed
in this study were not selected for having functional
impairments, mean ADL14 total scores in both memantine and
placebo treatment groups at baseline were indicative of patients
with impaired functional ability. At study end, mean total score
significantly favoured memantine and a single-item analysis
revealed the significant benefits of memantine, compared to
placebo, in improving patients’ abilities to perform basic daily
activities, such as toileting and grooming, which are often
impaired in the moderate to severe stages of the disease (2).
Analyses according to OC and LOCF approaches did not
markedly influence the observed results in this analysis,
indicating the consistency of the functional benefits shown with
memantine. Furthermore, significant benefits of memantine
therapy were seen as early as week 12 (according to the ADL14
total scores and IADL scores).
The six trials included in this analysis all recruited
outpatients, but the findings were also congruent with results
from the subset analysis of nursing home patients with AD in
the 9M-BEST study (13).
773
Figure 3
Mean change from baseline in ADL single-item scores at Week
24/28 (observed cases)
a) BADL scores
b) IADL scores
An assessment of clinical effectiveness showed that
combination therapy with memantine plus cholinesterase
inhibitors slowed both cognitive and functional decline
(measured using the Weintraub ADL Scale) compared with
cholinesterase inhibitor monotherapy or no treatment (25). In
the current analysis, differences in functional decline between
memantine-treated and placebo-treated patients increased over
time, and Atri et al showed similar increases with time that
were sustained for at least four years (predicted frequency of
dependence rising from 37% to 74% in untreated patients and
from 32% to 57% in patients treated with memantine plus
cholinesterase inhibitors) (25).
AD is a complex disease, with a progressive course that
manifests as disturbances across functional, behavioural and
cognitive domains (1). As the only approved treatment for AD
that targets the glutamatergic system, memantine has been
shown to confer statistically significant advantages compared
with placebo on cognitive, behavioural, and global endpoints
throughout the course of AD (10-12, 26). In addition, the current
analysis provides evidence of benefits for memantine on
functional outcomes based on six 6-month studies in moderate
to severe AD. Furthermore, in efficacy and safety studies,
memantine treatment was consistently well tolerated (17-22).
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Indeed, the overall incidence of treatment-related adverse events
with memantine did not differ from placebo, in a published
pooled analysis of six randomized trials of memantine 20
mg/day in patients with AD (11).
It is well established that caregiver burden increases, as does
the risk of institutionalisation, in the more advanced stages of
AD (4, 5) – and functional decline plays a major part in the
burden and risk. The results from this post hoc analysis
demonstrate that memantine supports patient independence by
reducing the decline in basic and instrumental skills and their
ability to perform everyday tasks. This could potentially ease
the burden of caregiving and improve patient and carer quality
of life, and one study has shown that patients treated with
memantine required 52 hours less caregiver time per month
(1.5 h/day), than those receiving placebo (27). In addition,
patients with AD receiving memantine were three times more
likely to remain autonomous after 28 weeks of daily treatment
than patients receiving placebo (28), and recently it was shown
that nursing home admission for patients with AD was
significantly delayed during memantine treatment, in
combination with acetylcholinesterase inhibitors, compared
with patients receiving acetylcholinesterase inhibitors alone or
receiving no cognitive enhancers (29).
The investigation of single-items may lead to the
identification of specific areas of treatment effects; however, it
can also increase the risk of identifying random performance
fluctuations. The results of the single-item/sub-scale analyses
identified specific items for which memantine demonstrated a
significant beneficial effect, and these results were consistent at
the analysed time-points. The consistent results indicate that the
single-item/sub-scale scores are not random fluctuation but
significant effects of memantine on specific sub-domains.
There are, however, limitations to this study as it is a post-hoc
study with no correction for multiple testing.
These results suggest that memantine treatment may lead to
a more interactive and dignified life for patients with moderate-
to-severe AD, than placebo. The functional improvements
observed in this analysis add to the growing evidence
supporting the clinically meaningful benefits of memantine in
patients with moderate-to-severe AD.
A cknowledgements: The authors would like to thank all patients and caregivers
participating in the studies, and thank all investigators for their contributions to the studies.
H. Lundbeck A/S, Merz Pharmaceuticals GmbH and Forest Research Institute Inc. funded
the studies used for this analysis. H. Lundbeck A/S conducted the pooled analysis and
editorial assistance for this manuscript was provided by ESP Ltd (Sandhurst, UK) with
funding from H. Lundbeck A/S.
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