Condition category
Nervous System Diseases
Date applied
28/03/2007
Date assigned
04/04/2007
Last edited
05/04/2012
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Contact information

Type

Scientific

Primary contact

Prof Robert Howard

ORCID ID

Contact details

Old Age Psychiatry
PO70
Institute of Psychiatry
De Crespigny Park
London
SE5 8AF
United Kingdom

Additional identifiers

EudraCT number

2007-001172-36

ClinicalTrials.gov number

NCT00866060

Protocol/serial number

2006/123

Study information

Scientific title

Acronym

DOMINO - AD

Study hypothesis

The trial will test a number of hypotheses in patients who have declined in terms of cognitive function to reach the transition point to moderate-to-severe Alzheimer's Disease (AD):
1. Patients with AD who continue donepezil beyond the moderate to severe transition point will show a significantly smaller decline on ratings of cognitive function and activities of daily living over the following 12 months than those discontinuing donepezil
2. Patients with AD who commence memantine therapy will show a significantly smaller decline on ratings of cognitive function and activities of daily living over the following 12 months than those who do not
3. Patients given the combination of memantine and donepezil 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
4. 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.

Ethics approval

Scotland A Research Ethics Committee on 28/05/2007 (ref: 07/MRE00/52).

Study design

Pragmatic multi-centre double-blind randomised placebo-controlled (double-dummy) parallel group 2 x 2 factorial clinical trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Treatment

Patient information sheet

Patient information can be found at: http://neuroscience.iop.kcl.ac.uk/domino/docs/patient.pdf

Condition

Alzheimer's Disease

Intervention

There will be four arms being assessed (all patients will be on donepezil when entering the trial):
Arm one: combination of donepezil 10 mg plus memantine 20 mg
Arm two: withdrawal of donepezil and prescription of memantine 20 mg
Arm three: continued prescription of donepezil 10 mg
Arm four: withdrawal of donepezil

The patients on each arm will receive the appropriate treatment once daily for 52 weeks.

Intervention type

Drug

Phase

Not Specified

Drug names

Donepezil, memantine

Primary outcome measures

1. Cognitive function measured by the Standardised Mini Mental State Exam (SMMSE)
2. Activities of daily living measured using the Bristol Activities of Daily Living Scale (BADLS)

All measures will be taken at zero, six, 18, 30 and 52 weeks.

Secondary outcome measures

1. Non-cognitive dementia symptoms measured using the neuropsychiatric inventory
2. Health related quality of life measured by Euro Quality of Life (EQ-5D) questionnaire and Demential Quality of Life (DEMQOL)-proxy
3. Care giver burden measured by the 12-item General Health Questionnaire (GHQ-12)
4. Cost effectiveness measured using the client service receipt inventory in conjunction with SMMSE and BADLS results

All measures will be taken at zero, six, 18, 30 and 52 weeks.

Overall trial start date

01/11/2007

Overall trial end date

31/08/2013

Reason abandoned

Eligibility

Participant inclusion criteria

Participants will be patients who meet National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for probable or possible AD and in addition will meet all of the following criteria:
1. Continuously prescribed donepezil for at least three months
2. No change in dosage of donepezil in previous six weeks
3. No changes in prescription of any psychotropic (antipsychotic, antidepressant, benzodiazepine) medication in previous four weeks
4. Prescribing clinician considers (based on National Institute of Clinical Excellence [NICE] guidance, discussions with patient and carer and clinical judgement) that change of drug treatment (i.e. stop donepezil or introduce memantine) may be appropriate and Standardised Mini Mental State Exam (SMMSE) = 5 to 13 (13 chosen as NICE threshold of 10 plus 1 SD on SMMSE score)
5. Patient is community resident and has family or professional carer or is visited on at least a daily basis by carer
6. Patient agrees to participate where possible
7. Main carer (informal or institutional) consents to their own involvement

Participant type

Patient

Age group

Not Specified

Gender

Not Specified

Target number of participants

800

Participant exclusion criteria

1. Patient has severe, unstable or poorly controlled medical conditions apparent from physical examination or clinical history
2. Patient is already prescribed memantine
3. Patient is unable to take trial medications
4. Patient is involved in another clinical trial
5. Patient has absolute contraindication to either donepezil or memantine
6. Clinician considers patient would not be compliant with medication

Recruitment start date

01/11/2007

Recruitment end date

31/08/2013

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Old Age Psychiatry, PO70
London
SE5 8AF
United Kingdom

Sponsor information

Organisation

Institute of Psychiatry (UK)

Sponsor details

c/o Gill Dale
Research and Development Office
Kings College London
De Crespigny Park
London
SE5 8AF
United Kingdom

Sponsor type

Research organisation

Website

http://www.iop.kcl.ac.uk/

Funders

Funder type

Research council

Funder name

Medical Research Council (UK) (grant ref: G0600989)

Alternative name(s)

MRC

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

1. 2009 protocol in http://www.ncbi.nlm.nih.gov/pubmed/19630974
2. 2012 results in http://www.ncbi.nlm.nih.gov/pubmed/22397651

Publication citations

  1. Protocol

    Jones R, Sheehan B, Phillips P, Juszczak E, Adams J, Baldwin A, Ballard C, Banerjee S, Barber B, Bentham P, Brown R, Burns A, Dening T, Findlay D, Gray R, Griffin M, Holmes C, Hughes A, Jacoby R, Johnson T, Jones R, Knapp M, Lindesay J, McKeith I, McShane R, Macharouthu A, O'Brien J, Onions C, Passmore P, Raftery J, Ritchie C, Howard R, , DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT., Trials, 2009, 10, 57, doi: 10.1186/1745-6215-10-57.

  2. Results

    Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, Burns A, Dening T, Findlay D, Holmes C, Hughes A, Jacoby R, Jones R, Jones R, McKeith I, Macharouthu A, O'Brien J, Passmore P, Sheehan B, Juszczak E, Katona C, Hills R, Knapp M, Ballard C, Brown R, Banerjee S, Onions C, Griffin M, Adams J, Gray R, Johnson T, Bentham P, Phillips P, Donepezil and memantine for moderate-to-severe Alzheimer's disease., N. Engl. J. Med., 2012, 366, 10, 893-903, doi: 10.1056/NEJMoa1106668.

Additional files

Editorial Notes