DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease – a multicentre RCT

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DOI: 10.1186/1745-6215-10-57 · Source: PubMed
Abstract
Background: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil. Method: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization. Discussion: There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point. Trial registration: Current controlled trials ISRCTN49545035.

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Trials
Open Access
Study protocol
DOMINO-AD protocol: donepezil and memantine in moderate to
severe Alzheimer's disease – a multicentre RCT
Rob Jones†1, Bart Sheehan†2, Patrick Phillips†3, Ed Juszczak†4,
Jessica Adams†5, Ashley Baldwin†6, Clive Ballard†7, Sube Banerjee8,
Bob Barber†9, Peter Bentham†10, Richard Brown†11, Alistair Burns†12,
Tom Dening†13, David Findlay†14, Richard Gray†15, Mary Griffin†16,
Clive Holmes†17, Alan Hughes†18, Robin Jacoby†19, Tony Johnson†20,
Roy Jones†21, Martin Knapp†22, James Lindesay†23, Ian McKeith†24,
Rupert McShane†25, Ajay Macharouthu†26, John O'Brien†27,
Caroline Onions†28, Peter Passmore†29, James Raftery†30, Craig Ritchie†31,
Rob Howard*32 for the DOMINO-AD team
Address: 1Section of Old Age Psychiatry, The University of Nottingham, A Floor, South Block, Queen's Medical Centre, Nottingham NG7 2UH,
UK, 2Health Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK, 3MRC Clinical Trials Unit, 22
Euston Road, London NW1 2DA, UK, 4Head of NHS Statistical Support Team, Centre for Statistics in Medicine, Wolfson College Annexe,
University of Oxford, Linton Road, Oxford OX2 6UD, UK, 5PO70, Institute of Psychiatry, De Crespigny Park, London SE5, UK, 6Knowlsey Resource
& Recover Centre, Whiston Hospital, Warrington Road, Prescot, Merseyside L35 5DR, UK, 7Wolfson Centre for Age Related Disease, Guy's Campus,
King's College, London SE1 1UL, UK, 8PO26, Section of Mental Health and Ageing, Health Services Research Department, The David Goldberg
Centre, The Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK, 9Institute for Ageing and Health, University of Newcastle, Wolfson
Research Centre, Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne, NE4 6BE, UK, 10Queen Elizabeth Psychiatric Hospital,
Mindelsohn Way, Edgbaston, Birmingham B15 2QZ, UK, 11Department of Psychiatry, Kings College London, Institute of Psychiatry, De Crespigny
Park, London SE5 8AF, UK, 12PBS 18, 2nd Floor, Education and Research Centre, School of Psychiatry and Behavioural Sciences, Wythenshawe
Hospital, Southmoor Road, Manchester M23 9LT, UK, 13Older People's Mental Health Service, Box 311, Fulbourn Hospital, Cambridge CB1 5EF,
UK, 14Dundee Community Health Partnership, Gowrie House, Royal Dundee Liff Hospital, Dundee DD2 5NF, UK, 15University of Birmingham,
Park Grange, 1 Somerset Road, Birmingham B15 2RR, UK, 16PO70 Institute of Psychiatry, De Crespigny Park, London SE5, UK, 17Department of
Old Age Psychiatry, Moorgreen Hospital, Botley Road, West End, Southampton, Hants SO30 3JB, UK, 18Department of Geriatric Psychiatry,
Inverclyde Royal Hospital, Larkfield Road, Inverclyde PA16 0NX, UK, 19University of Oxford, Department of Psychiatry, The Warneford Hospital,
Oxford OX3 7JX, UK, 20MRC Biostatistics Unit (& MRC Clinical Trials Unit, London), Institute of Public Health, University Forvie Site, Robinson
Way, Cambridge CB2 2SR, UK, 21Research Institute for Care of the Elderly, St Martin's Hospital, Bath BA2 5RP, UK, 22Department of Economics
of Mental Health, Kings College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK, 23Department of Health Sciences,
University of Leicester, Leicester General Hospital, Leicester LE5 4PW, UK, 24Old Age Psychiatry, University of Newcastle, Wolfson Research Centre,
Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne, NE4 6BE, UK, 25The Fulbrook Centre, The Churchill Hospital, Oxford OX3
7JU, UK, 26North West Kilmarnock Area centre, Western Road, Kilmarnock KA13 1NQ, UK, 27Wolfson Research Centre, Newcastle General
Hospital, Westgate Road, Newcastle-upon-Tyne NE4 6BE, UK, 28PO70 Institute of Psychiatry, De Crespigny Park, London SE5, UK, 29Whitla
Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK, 30School of Medicine, University of Southampton, Mail point 728, Bolrewood, Bassett
Crescent, East Southampton SO16 7PX, UK, 31Charing Cross Hospital, Claybrook Centre, 37 Claybrook Road, London W6 8LN, UK and 32PO70,
Institute of Psychiatry, De Crespigny, London SE5 8AF, UK
Email: Rob Jones - rob.jones@nottingham.ac.uk; Bart Sheehan - b.sheehan@warwick.ac.uk; Patrick Phillips - ppp@ctu.mrc.ac.uk;
Ed Juszczak - Ed.Juszczak@npeu.ox.ac.uk; Jessica Adams - jessica.adams@iop.kcl.ac.uk; Ashley Baldwin - ashley.baldwin@5bp.nhs.uk;
Clive Ballard - clive.ballard@kcl.ac.uk; Sube Banerjee - sube.banerjee@iop.kcl.ac.uk; Bob Barber - robert.barber@ntw.nhs.uk;
Peter Bentham - pwblmb@aol.com; Richard Brown - richard.brown@iop.kcl.ac.uk; Alistair Burns - alistair.burns@manchester.ac.uk;
Tom Dening - tom.dening@cpft.nhs.uk; David Findlay - david.findlay@nhs.net; Richard Gray - r.gray@bham.ac.uk;
Mary Griffin - mary.griffin@iop.kcl.ac.uk; Clive Holmes - ch4@soton.ac.uk; Alan Hughes - alan.m.hughes@gmail.com;
Robin Jacoby - robin.jacoby@psych.ox.ac.uk; Tony Johnson - tony.johnson@mrc-bsu.cam.ac.uk; Roy Jones - r.w.jones@bath.ac.uk;
Martin Knapp - martin.knapp@iop.kcl.ac.uk; James Lindesay - jebl1@leicester.ac.uk; Ian McKeith - i.g.mckeith@newcastle.ac.uk;
Rupert McShane - rupert.mcshane@obmh.nhs.uk; Ajay Macharouthu - vermaaz@rediffmail.com; John O'Brien - j.t.o'brien@newcastle.ac.uk;
Caroline Onions - caroline.onions@iop.kcl.ac.uk; Peter Passmore - p.passmore@qub.ac.uk; James Raftery - raftery@soton.ac.uk;
Craig Ritchie - c.ritchie@imperial.ac.uk; Rob Howard* - robert.howard@iop.kcl.ac.uk; the DOMINO-AD team - not@valid.com
* Corresponding author †Equal contributors
Published: 24 July 2009
Trials 2009, 10:57 doi:10.1186/1745-6215-10-57
Received: 19 April 2009
Accepted: 24 July 2009
Trials 2009, 10:57 http://www.trialsjournal.com/content/10/1/57
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Abstract
Background: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase
inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild
to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in
the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not
recommended by the England and Wales National Institute for Health and Clinical Excellence.
However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in
particular, what to do as the condition progresses from moderate to severe. Options include
continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase
inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to
establish the most effective drug option for people with AD who are progressing from moderate
to severe dementia despite treatment with donepezil.
Method: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled
trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with
Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited.
Each is randomized to one of four treatment options: continuation of donepezil with memantine
placebo added; switch to memantine with donepezil placebo added; donepezil and memantine
together; or donepezil placebo with memantine placebo. 800 participants are being recruited and
treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities
of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive
dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and
DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using
Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline,
6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone
interview to record institutionalization.
Discussion: There is considerable debate about the clinical and cost effectiveness of anti-dementia
drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those
managing patients at a particularly important clinical transition point.
Trial registration: Current controlled trials ISRCTN49545035
Background
Acetylcholinesterase inhibitors are widely prescribed to
patients with mild to moderate Alzheimer's disease (AD),
with studies showing they improve cognition and stabi-
lize cognition, function and behaviour for up to 6–12
months (see below). Although there is evidence that these
drugs are effective in the mild to moderate range of sever-
ity, there is at present little evidence to guide clinicians at
the critical decision point when patients deteriorate
beyond moderate to severe dementia. Memantine has sys-
tematic review level evidence to support efficacy in late
stage AD [1] and has been widely prescribed at this stage.
Again, however, there is not an adequate evidence base to
guide decisions about patients compliant with a
cholinesterase inhibitor but who have reached the moder-
ate to severe point where they might be considered for
memantine treatment.
There is therefore a pressing clinical need to provide an
evidence base for physicians on which to base decisions
about continued prescribing of cholinesterase inhibitors
in patients as they reach the moderate to severe stage of
AD but there have been no clinical trials that can provide
this evidence. There is also a need to evaluate the use of
memantine, which already has a licence for the treatment
of moderate to severe AD, alone and in combination with
a cholinesterase inhibitor at the point where patients
make the transition to moderate to severe disease. To
inform clinical practice and relevant decision-making
bodies (such as, for England and Wales, the National
This article is available from: http://www.trialsjournal.com/content/10/1/57
© 2009 Jones et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Trials 2009, 10:57 http://www.trialsjournal.com/content/10/1/57
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Institute for Health and Clinical Excellence, NICE) most
effectively, any trials that examine these issues should be
pragmatic and based on a representative patient popula-
tion in whom clinicians currently have genuine uncer-
tainty about how to proceed with treatment. Important
outcome measures for such a trial should include preser-
vation of activities of daily living and independence as
well as cost-utility data.
By recruiting patients who have reached the transition
point between moderate and severe dementia, and who
are already receiving anticholinesterase treatment, DOM-
INO-AD is designed to answer clinical questions about
efficacy and cost-effectiveness that have real relevance to
clinicians and policy making organisations.
Clinical Studies
A number of studies have demonstrated that acetylcho-
linesterase inhibitors modestly improve cognition in a
subgroup of patients with mild to moderate AD and stabi-
lize cognition, function and behaviour for 6 months [2-
11] and may continue to exert benefit for 12 months
[12,13]. Evidence has also been presented to suggest that
these drugs may continue to have a beneficial effect for up
to 2 years [14] although a recent influential systematic
review concluded that benefits of treatment are modest
and that the methodological quality of most published
trials could be questioned [15].
Acetylcholine and choline acetyltransferase levels do not
begin to fall significantly until dementia is advanced
[16,17]. Hence, there would be good theoretical reasons
to anticipate a therapeutic effect of cholinesterase inhibi-
tion at later stages of disease than the currently licensed
indication of mild to moderate severity. Trial evidence for
this comes from four particular sources.
Firstly, randomized double-blind placebo-controlled tri-
als of cholinesterase inhibitors that have included moder-
ate to severely affected patients [18] have shown
significant benefits over 24 weeks in cognitive, behav-
ioural and functional outcomes in a group of patients
whose SMMSE scores ranged from 5–17 (mean score for
patients receiving donepezil = 11.7).
Secondly, secondary analyses of trial data from mild to
moderate patients examining the subgroup of patients
with more severe illness have also shown benefits. Wilkin-
son [19] performed a post hoc analysis on pooled data
from 124 patients with SMMSE scores of 10–12 from the
4 pivotal galantamine studies. Cognitive and functional
abilities were significantly improved in galantamine
treated participants. Burns [20] retrospectively analyzed
pooled data from 117 patients selected from three RCTs of
rivastigmine on the basis of a SMMSE score of 10–12
points. Rivastigmine treatment over 6 months showed sig-
nificant benefits in cognitive and behavioural domains.
Further, Gauthier [21] and Feldman [22] reanalyzed ear-
lier Feldman [18] data focussing on 145 patients with a
SMMSE score of 5–12. At week 24, using the last observa-
tion carried forward principle for imputing missing data,
the mean differences in mean change from baseline scores
were 2.0 points for the SMMSE and 7.4 points for the
Severe Impairment Battery (SIB) in favour of the donepe-
zil treated participants and Clinician's Interview-Based
Impression of Change-Plus (CIBIC-plus) scores were sig-
nificantly improved compared with placebo with a 0.70
point mean treatment difference.
Thirdly, long term trial data within which participants
have progressed to more severe disease stages of illness
can also demonstrate apparent continued efficacy in mod-
erate to severe patients. In the AD2000 trial [14] 49% of
participants randomized to treatment with donepezil had
SMMSE scores of 10–18 points at study entry. Over the 2-
year study period, the donepezil group averaged SMMSE
scores 0.8 points higher than the placebo group. This ben-
efit was not restricted to any subgroup of patients in terms
of severity rating and was maintained over the trial period.
Raskind [23] demonstrated benefits of continuing galan-
tamine treatment for 36 months in a group of patients
whose mean SMMSE score at entry had been 19.7 points
and a proportion of whom would have entered the mod-
erate to severe category during the course of the study.
Fourthly, trials examining the effects of cholinesterase
inhibitor withdrawal provide some information. Typi-
cally, following a placebo washout period of 6 weeks at
the end of a trial, the benefits of 24 weeks of donepezil
treatment in terms of cognition and global function are
lost [24]. Most of such washouts have been at the end of
relatively short trials at which point patients have still
been only mildly to moderately affected. There are no
published randomized controlled trials examining the
effects of treatment withdrawal in patients at the moder-
ate to severe boundary that would help clinicians to make
decisions at the point where NICE guidance advises stop-
ping. Holmes [25] showed behavioural benefits of contin-
uing donepezil in a group of patients selected on the basis
of marked neuropsychiatric symptoms (NPI score>11) at
baseline and with a mean SMMSE score of 21.1 points.
Additionally, there is intriguing preliminary evidence that
a combination of a cholinesterase inhibitor and meman-
tine might be particularly beneficial in patients at this
severity point. For example, a study of 404 patients with
moderate to severe AD (SMMSE 5–14) who had been sta-
bilized on donepezil treatment for at least 6 months,
investigated the effect of adding memantine 10 mg b.d.
for 6 months [26]. The change in total mean (standard
Trials 2009, 10:57 http://www.trialsjournal.com/content/10/1/57
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error) scores favoured memantine over placebo for the
SIB; 1.0 (0.7) vs. -2.4 (0.74), Alzheimer's Disease Cooper-
ative Study Activities of Daily Living 19 (ADCS-ADL 19);
-1.7 (0.51) vs. -3.3 (0.55) and CIBIC-Plus; 4.38 (0.081)
vs. 4.64 (0.087). All other secondary measures showed
significant benefits of memantine treatment. Treatment
discontinuations because of adverse events were seen in
7.4% receiving memantine and 12.4% in those receiving
placebo. An unpublished Phase III study in mild to mod-
erate AD patients, however, has suggested that combina-
tions of a variety of cholinesterase inhibitors and
memantine may not provide additional benefits over
monotherapy in this less impaired group [27]. Overall,
the preliminary and post-hoc evidence of an effect on
behaviour has not yet been backed up by RCT evidence
which tests this question [28,29] and there is a clear need
for more data.
NICE Guidance
NICE recommended in 2001 [30] that cholinesterase
inhibitors (donepezil, rivastigmine and galantamine)
should be offered to patients with mild to moderate AD
whose MMSE score was above 12 points. NICE guidance
from 2001–2005 was that prescription should only be
continued while the MMSE score remained above 12
points and the patient's global, functional and behav-
ioural condition remained at a level where the drug was
considered to have a worthwhile effect. This recommen-
dation was made on the grounds of cost-containment,
rather than clinical efficacy, since many of the patients
who entered the trials that established efficacy had MMSE
scores of as low as 10 points.
Current NICE guidance for England and Wales [31],
which although amended in response to judicial review
since its original publication remains substantially the
same in its effect, recommends that the three acetylcho-
linesterase inhibitors donepezil, galantamine and rivastig-
mine are used as options in the management of people
with AD of moderate severity (MMSE score of between 10
and 20 points). Patients continuing on the drugs should
be reviewed six monthly by MMSE score and global, func-
tional and behavioural assessment, incorporating the
views of carers. Drug treatment should only be continued
while patients' MMSE score remains above 10 points and
their global, functional and behavioural condition
remains at a level where the drug is considered to be hav-
ing a worthwhile effect. Memantine is not recommended
as a treatment option for people with moderately severe to
severe AD except as part of a clinical study.
Aim of the study
The aim of the DOMINO-AD study is to determine, in a
factorial (2 × 2) design, whether there is worthwhile ben-
efit for patients, for whom there is uncertainty on whether
or not to continue cholinesterase inhibitors, from: 1) add-
ing memantine to donepezil, 2) switching to memantine
or 3) continuing donepezil compared to 4) placebo.
Objectives
Primary Objectives
The trial will test a number of hypotheses in memory
clinic patients who have declined in terms of cognitive
function to reach the transition point to moderate-to-
severe AD. These hypotheses are:-
a) patients with AD who continue donepezil beyond
the moderate to severe transition point will show a sig-
nificantly smaller decline on ratings of cognitive func-
tion and activities of daily living over the following 12
months than those discontinuing donepezil, with
analysis using all trial participants;
b) patients with AD who commence memantine ther-
apy at the moderate to severe transition point will
show a significantly smaller decline on ratings of cog-
nitive function and activities of daily living over the
following 12 months than those who do not, with
analysis using all trial participants;
c) patients given the combination of memantine and
donepezil at the moderate to severe transition point
will show additive or synergistic significant benefits
on measures of activities of daily living and cognitive
function after 12 months compared to those patients
continuing on either monotherapy.
Secondary Objectives
Secondary hypotheses to be tested are:-
a) patients with AD who continue donepezil beyond
the moderate to severe transition point will show a sig-
nificantly smaller deterioration on ratings of non-cog-
nitive symptoms and health related quality of life over
the following 12 months than those discontinuing
donepezil, with analysis using all trial participants;
b) patients with AD who commence memantine ther-
apy at the moderate to severe transition point will
show a significantly smaller deterioration on ratings of
non-cognitive symptoms and health related quality of
life over the following 12 months than those who do
not, with analysis using all trial participants;
c) patients given the combination of memantine and
donepezil at the moderate to severe transition point
will show additive or synergistic significant benefits
on measures of non-cognitive symptoms and health
related quality of life after 12 months compared to
those patients continuing on either monotherapy;
Trials 2009, 10:57 http://www.trialsjournal.com/content/10/1/57
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d) treatment of patients with donepezil beyond the
moderate to severe transition point will be more cost-
effective than discontinuing donepezil; memantine
therapy will be more cost-effective than placebo; the
combination of memantine and donepezil will be
more cost-effective than monotherapy;
e) patients who continue on donepezil beyond the
moderate to severe transition point will be institution-
alized later than those who do not; patients who com-
mence memantine therapy will be institutionalized
later than those taking placebo; patients who com-
mence the combination of memantine and donepezil
will be institutionalized later than those on mono-
therapy.
For carers, parallel secondary objectives concern changes
in psychological morbidity and health related quality of
life.
Methods
Design
This is a pragmatic, multicentre, double-blind (with
patient, carer, clinician, outcome assessor and investiga-
tors blinded), randomized, placebo controlled (double
dummy), parallel group, 2 × 2 factorial clinical trial. Fig-
ure 1 illustrates the trial design. All participants receive
trial interventions for 52 weeks. Participants are rand-
omized to one of four arms centrally by the Medical
Research Council (MRC) Clinical Trials Unit in London
via telephone. Randomization is by dynamic allocation
using minimization to ensure balanced allocation across
the following factors: centre, duration of donepezil treat-
ment prior to randomization, baseline SMMSE score and
age.
(Arm 1) Combination of donepezil plus memantine
Participants in this arm continue with their current
donepezil 10 mg/day regimen and immediately com-
mence active memantine at a dose of 5 mg per day,
increasing in 5 mg increments weekly until 20 mg per day
is achieved from week 4 onwards.
(Arm 2) Withdrawal of donepezil and prescription of memantine
Participants in this arm immediately commence active
memantine at a dose of 5 mg per day, increasing in 5 mg
increments weekly until 20 mg per day is achieved from
week 4 onwards. The donepezil dose is reduced to 5 mg
daily in weeks 1 to 4 and replaced with placebo donepezil
in week 5.
(Arm 3) Continued prescription of donepezil monotherapy
Participants in this arm continue with their current
donepezil 10 mg/day regimen and immediately com-
mence placebo memantine.
(Arm 4) Withdrawal of donepezil
Participants in this arm immediately commence placebo
memantine dose escalation and switch to donepezil 5 mg
daily in weeks 1 to 4, which is replaced with placebo
donepezil in week 5.
Planned inclusion/exclusion criteria
Inclusion criteria
People are eligible to participate if they are patients who
meet standardized clinical McKhann criteria [32] for
probable or possible AD, have been continuously pre-
scribed donepezil for at least 3 months and continuously
prescribed 10 mg donepezil for the previous 6 weeks.
They must have had no changes in prescription of any psy-
chotropic drugs (antipsychotic, antidepressant, benzodi-
azepine) in the previous 6 weeks, the prescribing clinician
must consider (based on NICE guidance, discussions with
patient and carer and clinical judgement) that change of
drug treatment (i.e. stop donepezil or introduce meman-
tine) may be appropriate and on testing with the SMMSE,
the standardized assessment of cognitive function, the
score is between 5 and 13. Also, to be eligible, the partici-
pant must be community resident with a family or profes-
sional carer or be visited on at least a daily basis by a carer.
Participants must have agreed to take part if considered
capable and the main carer (informal or professional)
must also have given consent to his/her own involvement
and to the participant's involvement.
Exclusion criteria
These include severe, unstable or poorly controlled medi-
cal conditions apparent from physical examination or
clinical history, current prescription of memantine, con-
tra-indications or previous adverse or allergic reactions to
trial drugs, involvement in another clinical trial or that the
clinician considers the patient would not be compliant.
Recruitment/consent procedures
Participants are identified from patients with AD meeting
study eligibility criteria who are being followed up in
memory clinics, out patient clinics or other components
of specialist mental health, geriatric medicine or neurol-
ogy services. Once a potential participant has been identi-
fied, the clinician obtains verbal consent to pass his/her
details to the research worker who then recruits the
patient in line with the trial standard operating proce-
dures.
Where possible, fully informed consent is obtained from
the patient. However, the majority of patients with mod-
erate to severe dementia lack the necessary mental capac-
ity to give fully informed consent. In this situation,
agreement to participate in the study is still obtained to
the patient's best level of understanding and the patient is
not enrolled if they refuse or show significant distress. For
Trials 2009, 10:57 http://www.trialsjournal.com/content/10/1/57
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Trial Flow ChartFigure 1
Trial Flow Chart.
ELIGIBILITY
Donepezil for 3 months, on 10mg 6weeks, SMMSE
5-13, uncertainty re continued benefit of donepezil,
community dwelling, carer available
S
C
R
E
E
N
I
N
G
EXCLUSIONS
On memantine
Contraindication
to trial drugs or
concerns over
compliance
Severe or unstable
illness
Patient already in
a trial
CONSENT
Patient or Personal Legal Representative
RANDOMIZATION
MRC CTU
Donepezil 10mg
Memantine 20mg
Donepezil Placebo
Memantine 20mg
Donepezil 10mg
Memantine Placebo
Donepezil Placebo
Memantine Placebo
BASELINE ASSESSMENT
6 week assessment
18 week assessment
30 week assessment
52 week assessment
Follow up 6 monthly for subsequen
t
3 years
POPULATION
Patients under care of 15 older adult services
with a dia
g
nosis of Alzheimer’s disease
Trials 2009, 10:57 http://www.trialsjournal.com/content/10/1/57
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sites in England and Northern Ireland, in line with The
Medicines for Human Use (Clinical Trials) Regulations
2004, consent is also obtained from the patient's personal
legal representative. For sites in Scotland, in line with the
Adults with Incapacity (Scotland) Act 2000, consent is
obtained from the adult's proxy. If neither is available to
consent, the patient is ineligible for the study.
Assessments
Study assessment measures will be applied at baseline
prior to randomization, at week 6 to assess the acute
effects of donepezil withdrawal, at week 18, week 30 and
at week 52. Participants will then be followed up every 26
weeks for 3 years by telephone interview to establish
whether and on what date they entered a care institution.
Trial completion is defined as completion of 52 weeks on
the trial medication or discontinuation of follow-up for
any cause. Participants who discontinue taking the trial
medication are encouraged to remain in follow-up. Partic-
ipants may not formally discontinue their follow-up and
remain on the trial medication. Arrangements for contin-
ued provision of the trial medication at the end of the trial
will be made on an individual basis by the clinician
responsible for the participant's care.
Primary Outcomes Measures
Standardized Mini-Mental State Examination (SMMSE)
The Mini-Mental State Examination is a well-established
measure of cognitive function in elderly people. It shows
good test-retest and inter-rater reliability and performs
satisfactorily against more detailed measures of cognitive
function [33]. The Standardized Mini-Mental State Exam-
ination (SMMSE) has been developed to improve the reli-
ability of the original instrument [34] and will be used to
assess decline in cognitive function during the trial. Scores
range from 30 (unimpaired) to 0 (impaired).
Bristol Activities of Daily Living Scale (BADLS)
The BADLS was specifically designed for use with demen-
tia patients living in the community and participating in
clinical trials [35]. The BADLS is sensitive to change, cor-
relates well with economic outcomes and, despite being a
carer rated instrument, appears to have good test-retest
reliability, on a stringent measure, and, additionally, the
levels of disability between which the scale aims to dis-
criminate were also carer generated, giving some perspec-
tive on the value of change. The BADLS will be used to
assess activities of daily living during the trial. Scores
range from 0 (unimpaired) to 60 (impaired).
Secondary Outcome Measures
Client Service Receipt Inventory (CSRI)
The CSRI describes service use, informal care and other
aspects of accommodation and care pertinent to the cost-
ing of interventions and their implications [36]. Parallel
sections of the CSRI will be used for those in: residential
care, at home with co-resident carer, and at home without
co-resident carer.
EuroQol EQ-5D (EQ-5D)
The EQ-5D instrument is a generic, utility-based health
related quality of life (HRQoL) measure [37]. It can be
simply administered to patients or carers in the form of a
self-completed questionnaire and has been used in
patients with neurological disorders. In this trial, the carer
will be completing the questionnaire. There are two core
components to the instrument: a description of the
respondent's own health using a health state classification
system with five dimensions, and a rating on a visual ana-
logue thermometer scale.
DEMQOL-Proxy
DEMQOL-Proxy is a 31 item, disease specific instrument
for evaluating HRQoL in dementia, which shows compa-
rable psychometric properties to the best available instru-
ments and has been validated in a UK population [38],
and given doubts about how well the EQ-5D performs
with people with dementia this usefully complements it.
Neuropsychiatric Inventory (NPI)
The NPI assesses twelve domains of possible behavioural
disturbance in dementia – using a screening strategy to
save time [39]. The NPI will be used in DOMINO-AD to
measure the caregiver's assessment of nature, frequency
and severity of Behavioural Psychological Symptoms of
Dementia (BPSD). NPI scores range from 0 (no distur-
bance) to 144 (maximum disturbance).
General Health Questionnaire 12 (GHQ-12)
The GHQ-12 is a well validated, widely used, self-rated
instrument for detecting psychological morbidity and
psychiatric disorder [40]. In DOMINO-AD GHQ-12 will
be used to measure levels of psychological distress in the
carers of study patients. Scores range from 0 (not dis-
tressed) to 12 (distressed) using the GHQ scoring
method, with a cut off of 2/3 utilised to discriminate cases
from non-cases.
Institutionalization
This will be assessed via a simple question as to where the
patient is living.
Statistics
Sample Size Calculation
The trial aims to recruit 800 patients over a period of 2
years. Even allowing for a 25% loss to follow-up, this sam-
ple size will provide over 90% power to detect small (0.25
standard deviations) overall treatment effects on the pri-
mary outcome measures with 90% power at p < 0.01. It
will also be sufficient to detect small differences (0.25
Trials 2009, 10:57 http://www.trialsjournal.com/content/10/1/57
Page 8 of 11
(page number not for citation purposes)
standard deviations) in the primary outcome measures at
any one assessment point with 80% power at p < 0.05,
and small to moderate differences (0.3 standard devia-
tions) with 90% power at p < 0.05. These differences are
equivalent to 1–2 point improvements in the SMMSE and
BADLS, which are considered the minimal clinically rele-
vant differences. The sample size calculations assume a
correlation between serial measurements of the SMMSE/
BADLS of around 0.6 (multiplying factor of 0.34 based on
1 baseline and 4 post-randomization measurements, as
described by Machin et al [41]) anticipating an analysis of
covariance with repeated measures.
Analyses
The primary analyses of the effect of donepezil and
memantine on BADLS and SMMSE will be analyzed using
multilevel modelling repeated measures (MMRM) regres-
sion methods, adjusted for baseline scores. This approach
gives greater power to detect differences than simple t-
tests on differences and will allow investigations to be
made to determine how long any benefits of treatment
persist, and whether the mode of action is one of sympto-
matic relief or disease modification. By including all time
points, MMRM analyses minimise the effect of any miss-
ing data. Nevertheless, vigorous efforts will be made to
minimise missing data, and sensitivity analyses will be
undertaken to explore potential bias from missing data.
The secondary outcome of time to institutionalization
will be analyzed using standard stratified log-rank and
Mantel-Haenszel tests, as used by the Early Breast Cancer
Trialists' Collaborative Group study [42], and results pre-
sented as odds ratio plots. Any exploratory analyses here
will use multivariate logistic and proportional hazards
regression. Excessive subgroup analyses can give rise to
misleading results and therefore all subgroup investiga-
tions will be interpreted cautiously.
Health Economic Evaluation
Service utilisation patterns, carer inputs and all associated
costs will be calculated for each patient, based on data col-
lected using a modified version of the CSRI, completed by
a family carer or professional carer. Unit costs to reflect
long-run marginal opportunity costs will be attached
using national figures where available. Each cost-effective-
ness analysis will be conducted from the perspective of (a)
the NHS and social services, and (b) society. The BADLS,
DEMQOL and a utility measure generated from the EQ-
5D will be used in turn in a series of cost-effectiveness
analyses, the last of these to generate Quality Adjusted Life
Year (QALY) measures (with societal weights). The associ-
ations between EQ-5D, DEMQOL, SMMSE and BADLS
scores, and changes therein, will also be examined, given
uncertainty about the validity of EQ-5D measures as
QALY generators within this population. Cost-effective-
ness acceptability curves will be plotted using bootstrap
analyses to locate the findings of the economic evaluation
in their wider decision-making context. Sensitivity analy-
ses will also examine the consequences of key assump-
tions in the cost-effectiveness analysis. In addition, a
mathematical model, developed from the AD2000 data-
base and using BADLS and NPI data, will be used to esti-
mate risks of institutionalization in treatment groups over
four years.
Ethical considerations
The protocol has been approved by the Scotland A
Research Ethics Committee, the MHRA and received local
site R&D approval. The trial will be conducted in compli-
ance with the European Union Clinical Trials Directive
(2001/20/EC), the associated UK Medicines for Human
Use (Clinical Trials) Regulations (2004) and Medicines
for Human Use (Clinical Trials) Amendment Regulations
2006, the Data Protection Act (1998), the principles of
ICH GCP guidelines (CPMP/ICH/135/95), the principles
of the Declaration of Helsinki (1996) and other require-
ments as appropriate.
An Independent Data Monitoring Committee (IDMC)
will monitor the progress of the trial including: recruit-
ment, protocol adherence, serious adverse events and side
effects of treatment as well as the difference between the
trial treatments on the primary outcome measures. The
IDMC will produce a report to the Trial Steering Commit-
tee (TSC) after every meeting and can recommend prema-
ture closure of the trial following clear evidence of benefit
or harm in accordance with the IDMC charter.
The main ethical issue here is that the severity of cognitive
impairment may significantly interfere with the individ-
ual patient's ability to give fully informed consent. With
patients entering this study having SMMSE scores of
between five and thirteen, the majority with this degree of
dementia will lack the necessary mental capacity to give
fully informed consent.
However, the aims of the study mean it is vital that a rep-
resentative patient group is randomized including those
that lack capacity. The DOMINO-AD study involves min-
imal risk to the patient and offers the potential of signifi-
cant clinical benefit, so it is ethically permissible to
randomize patients whose capacity is impaired.
Approaches to and legislation relating to obtaining
patients' agreement to participate in the study in this situ-
ation were described earlier.
Discussion
There is considerable debate about the clinical and cost
effectiveness of anti-dementia drugs. DOMINO-AD seeks
to provide clear evidence on the best treatment strategies
Trials 2009, 10:57 http://www.trialsjournal.com/content/10/1/57
Page 9 of 11
(page number not for citation purposes)
at a particularly important clinical transition point from
moderate to severe AD. The design of the study, with mul-
tiple centres, a double-blind placebo controlled design,
and central randomization, maximises recruitment
opportunities and minimises the risk of selection or allo-
cation bias. The results of existing trials have been influen-
tial in determining policy on prescribing for AD, but
evidence for those people deteriorating to this transition
point is lacking. This condition is certain to become more
prevalent in ageing populations and therefore the deci-
sion on continuing treatment in people showing deterio-
ration will be faced far more frequently in the future. The
results of this study will make a substantial contribution
to clinical decision-making in a situation currently charac-
terised by uncertainty.
Competing interests
Many of the investigators have received support from
pharmaceutical companies, for example, to attend confer-
ences, for giving lectures, for the provision of consultancy,
for the conduct of research, or for the development of
research infrastructure. Many investigators had no com-
peting interests and the list of investigators with compet-
ing interests, and the details which they declared, is as
follows:-
Professor Clive Ballard, King's College:
• Received honoraria from Novartis, Pfizer, Shire, Lun-
dbeck, Myriad, Janssen-Cilag, Astra Zeneca and Servier
pharmaceutical companies and research grants from
Novartis, Lundbeck, Astra-Zeneca and Janssen-Cilag
pharmaceuticals;
Professor Sube Banerjee, London, Maudsley:
• Development of the DEMQOL system;
• Received speaker and consultancy fees from all com-
panies involved in making anti-dementia medication
and has had an educational grant from Pfizer;
• Has worked for Department of Health;
Dr Peter Bentham, Birmingham:
• Is a paid consultant to Tau Therapeutics Pte Ltd;
Professor Alistair Burns, Manchester:
• Received research funding and honoraria and
expenses for consultancy work from companies
involved in the manufacturing and marketing of drugs
for dementia – Eisai, Pfizer, Shire, Baxter, Janssen-
Cilag. Does occasional lectures for companies hosting
meetings on behalf of these industries – Pharam-Ed
and Phase-V;
• Gets paid expenses from the Alzheimer's Society in
the UK and Alzheimer's Australia (for lectures in
2008);
• Received an honorarium from John Wiley for role as
editor of the International Journal of Geriatric Psychi-
atry and receive honoraria from a number of publish-
ers for books written and edited;
Assoc. Professor Rob Jones, Nottingham:
• Has received educational travel and expenses sup-
port for a conference attendance from Pfizer and on
another occasion from Boots;
• Has spoken at and/or organised educational events
which have received educational funding support
from companies with products in the field of Alzhe-
imer's disease and related conditions;
Professor Roy Jones, Bath:
• His research institute has received grant support,
consulting fees and honoraria from companies with
products in the field of Alzheimer's disease and related
conditions;
• The Research Institute for Care of the Elderly has
recently completed the development of a new research
building which has been funded as a result of dona-
tions to a major capital appeal. A number of pharma-
ceutical companies including Lundbeck, Merz, Eisai
and Pfizer working in the field of Alzheimer's disease
and dementia have contributed to this appeal;
Professor James Lindsay, Leicester:
• Has received speaker and consultancy fees from
companies involved in the manufacturing and mar-
keting of drugs for dementia – Eisai, Pfizer, Shire, Jans-
sen-Cilag;
Professor John O'Brien, Newcastle:
• Received honoraria from Pfizer, Shire, Lundbeck,
Janssen-Cilag and GE Healthcare, and provided con-
sultancy to GE Healthcare, Servier and Bayer.
Dr Peter Passmore, Belfast:
• Has been a member of speaker bureaus in interna-
tional meetings and conferences for Eisai, Janssen-
Trials 2009, 10:57 http://www.trialsjournal.com/content/10/1/57
Page 10 of 11
(page number not for citation purposes)
Cilag, Lundbeck, Novartis, Pfizer and national meet-
ings in UK for Bayer, Bristol-Myers Squibb, Astra
Zeneca, Sanofi-Synthelabo, Merck Sharp & Dohme,
Eisai, Shire, Novartis, Pfizer;
• Has been an advisor internationally for Bayer, Bris-
tol-Myers Squibb, Eisai, Janssen-Cilag, Novartis,
Pfizer, Sanofi-Synthelabo, and nationally in the UK
for Bayer, Bristol-Myers Squibb, Astra Zeneca, Sanofi-
Synthelabo, Merck Sharp & Dohme, Eisai, Shire, Lun-
dbeck, Novartis, Pfizer;
Dr Bart Sheehan, Warwick:
• Has received an educational travel grant and confer-
ence expenses from Janssen-Cilag.
Authors' contributions
RH conceived the study, assembled the group of investiga-
tors and co-investigators and, with them, developed and
finalised the protocol. All of the above have set up the trial
sites and made them ready to perform the trial. EJ, PP, RG
and TJ provided statistical advice in the design of the study
and its on-going evolution. RB assisted with psychometric
aspects of the trial's development and MK and JR assisted
with health economic aspects of the trial's development.
JA, CO and MG managed the trial data management and
co-ordinated development of the trial. RGJ, BS, PP and EJ
particularly developed this publication describing the trial
protocol. All the authors read and approved the final
manuscript.
Acknowledgements
The funding support of the MRC and the Alzheimer's Society to enable this
trial to take place is gratefully acknowledged. Additionally the help with ran-
domization from the MRC Clinical Trials Unit is gratefully acknowledged.
We are grateful for the assistance of Eisai Ltd and Lundbeck Pharmaceuti-
cals in supplying the medication and matching placebo, and also for the help
of Catalent Pharma Solutions with its central packaging, labelling and distri-
bution to local pharmacies.
We are particularly grateful for the help of our local collaborators, including
Dr Paul Koranteng (Northamptonshire), Dr Heinrich Lamprecht (Newcas-
tle), Jill Mann (Bath co-investigator) and Dr Stephen Pearson (Plymouth co-
investigator).
We especially wish to acknowledge the important help of the members of
the Trial Steering Committee, Cornelius Katona (Chair), Ken Wilson (Inde-
pendent Old Age Psychiatrist), Robert Hills (Independent Statistician), its
observer representative from the major funder, the MRC (Morven Rob-
erts), its observer representative from the sponsor, King's College London
(Caroline Murphy), and its observer patient/carer representative from the
Alzheimer's Society (Victoria Morgan). Similarly, we especially wish to
acknowledge the important help of the members of the Independent Data
Monitoring Committee, Brian Lawlor (Chair), Tony Bayer (Independent
Physician) and Deborah Ashby (Independent Statistician)
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    • "Recently, a fixed-dose combination (FDC) of MM hydrochloride extended release and DPZ hydrochloride has been approved by FDA under the trade * Corresponding author at: Pharmacokinetics & Metabolism name NAMZARIC TM for the treatment of moderate to severe AD in patients stabilized on MM and DPZ [2]. Clinically, adding MM to an Alzheimer Dementia Treatment Regimen which already includes DPZ showed an additive effect and proved to be the most effective therapy for AD patients who are progressing from moderate to severe dementia [3][4][5][6] . The FDC of MM and DPZ has been developed as a replacement indication for the patients who are often co-prescribed the individual drugs. "
    [Show abstract] [Hide abstract] ABSTRACT: Recently, a fixed dose combination (FDC) of memantine (MM) and donepezil (DPZ) has been approved for the treatment of Alzheimer's disease (AD). In the present work, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of MM and DPZ was developed and validated in rat plasma over the linearity range of 0.2-400ng/mL using amantadine (AM) as an internal standard. Both the analytes and IS were extracted using one step liquid-liquid extraction procedure. The analytes were separated on C18 reversed phase column with mobile phase consisting of a mixture of methanol and 10mM ammonium acetate, pH 5 (92:8 v/v) at a flow rate of 0.7mL/min. The detection of the analytes was done on triple quadrupole mass spectrometer operated in positive electrospray ionization mode (ESI) and quantified using multiple reaction monitoring (MRM). The method was fully validated in terms of linearity, accuracy, precision, recovery, matrix effect, dilution integrity, carry-over effect and stability. The within- and between-run precisions were <10% and accuracy was all within ±10%. The mean recovery of MM and DPZ was found to be greater than 80%. The % RSD value at higher as well as lower concentration was well within the acceptable range (±15%) in all the stability experiments. The method was successfully applied to the oral pharmacokinetics and drug-drug interaction study of MM and DPZ in male Sprague Dawley (SD) rats. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jul 2015
    • "Chen et al. [25] employed docking studies for beta breaker peptides to design molecules that can successfully inhibit Aβ-protein aggregation. However, although Aβ-protein fibrillogenesis has been studied extensively by many groups26272829303132333435, the exact mechanism of misfolding and aggregation of Aβprotein is still not clear. The present investigation is also one of the few drug discovery efforts to inhibit the aggregation of Aβ-protein, and we present here a combined study of ONIOM and molecular dynamics (MD) aimed at understanding the mechanism of misfolding and aggregation of Aβ-protein. "
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer’s disease (AD) is a neurodegenerative disorder that occurs due to progressive deposition of amyloid β-protein (Aβ) in the brain. Stable conformations of solvated Aβ1-42 protein were predicted by molecular dynamics (MD) simulation using the OPLSAA force field. The seven residue peptide (Lys-Leu-Val-Phe-Phe-Ala-Glu) Aβ16-22 associated with AD was studied and reported in this paper. Since effective therapeutic agents have not yet been studied in detail, attention has focused on the use of natural products as effective anti-aggregation compounds, targeting the Aβ1-42 protein directly. Experimental and theoretical investigation suggests that some compounds extracted from natural products might be useful, but detailed insights into the mechanism by which they might act remains elusive. The molecules nicotine and morin are found in cigarettes and beverages. Here, we report the results of interaction studies of these compounds at each hydrophobic residue of Aβ16-22 peptide using the hybrid ONIOM (B3LYP/6-31G**:UFF) method. It was found that interaction with nicotine produced higher deformation in the Aβ16-22 peptide than interaction with morin. MD simulation studies revealed that interaction of the nicotine molecule with the β-sheet of Aβ16-22 peptide transforms the β-sheet to an α-helical structure, which helps prohibit the aggregation of Aβ-protein. Figure Conformational structural changes of Aß1-42 protein in water environment using 50ns MD simulation
    Full-text · Article · Mar 2014
    • "Available treatments mainly offer symptomatic benefit such as improving or stabilizing the declined cognition and functional and/or behavioral symptoms. The cholinesterase inhibitor donepezil has been used to treat the patients with mild to moderately severe AD in many countries 1. The studies using the randomized double-blind placebo-controlled trials indicate that donepezil probably potentially benefits the patients with mild to moderate AD in cognition 2, global function, and activities of daily living 3. Now the combination of donapezil and other therapeutic strategies like medicamentum alliance is being generally studied in order to get the best treatment outcomes. "
    [Show abstract] [Hide abstract] ABSTRACT: To evaluate the efficacy and safety of donepezil plus natural hirudin in patients with mild-to-moderate Alzheimer's Disease. In the 20-week, randomized, open-label and controlled study, 84 patients received either donepezil (5 mg/day for the first 4 weeks and 10 mg/day thereafter) or donepezil plus natural hirudin (3 g/day) treatment. Efficacy was reflected by the change of the total scores of Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog), Activities of Daily Life (ADL) and Neuropsychiatric Inventory (NPI). The patients with the donepezil plus natural hirudin treatment showed more significant improvement in the daily activities and the decline of the cognition than those with donepezil treatment. Significant difference was present in the groups since the 8th week. No group difference was found in the NPI change. However, within the hirudin treatment group, more powerful efficacy including NPI assessment was found in the patients with vascular risk factors (VRF) as comparing to with those without VRF. The combination of donepezil and natural hirudin was well tolerated. The dropout rate was greater in the donepezil and natural hirudin (50%) treatment group than in the donepezil (39%) treatment group. Similar result was found in the incidence of adverse events (23.8% vs 19.0%), but there was no statistical difference between the two groups. Adverse events were the most common reason for the dropout. Although hemorrhage and hypersensitiveness were more common in donepezil plus Maixuekang treatment (11.9% and 7.1%) group than in donepezil treatment (2.4% and 2.4%) group, no significant difference was present between the two groups. Economic problem was another important reason for the patients' withdrawal. Compared with the donepezil treatment in the patients with mild-to-moderate AD, our results suggest that donepezil combined with natural hirudin may improve the treatment effects in the ADL, BPSD and cognition of the patients. Furthermore, this joint treatment is safe.
    Article · May 2012
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