Open Access Highly Accessed Study protocol

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

Rob Jones1, Bart Sheehan2, Patrick Phillips3, Ed Juszczak4, Jessica Adams5, Ashley Baldwin6, Clive Ballard7, Sube Banerjee8, Bob Barber9, Peter Bentham10, Richard Brown11, Alistair Burns12, Tom Dening13, David Findlay14, Richard Gray15, Mary Griffin16, Clive Holmes17, Alan Hughes18, Robin Jacoby19, Tony Johnson20, Roy Jones21, Martin Knapp22, James Lindesay23, Ian McKeith24, Rupert McShane25, Ajay Macharouthu26, John O'Brien27, Caroline Onions28, Peter Passmore29, James Raftery30, Craig Ritchie31, Rob Howard32* and the DOMINO-AD team

Author Affiliations

1 Section of Old Age Psychiatry, The University of Nottingham, A Floor, South Block, Queen's Medical Centre, Nottingham NG7 2UH, UK

2 Health Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK

3 MRC Clinical Trials Unit, 22 Euston Road, London NW1 2DA, UK

4 Head of NHS Statistical Support Team, Centre for Statistics in Medicine, Wolfson College Annexe, University of Oxford, Linton Road, Oxford OX2 6UD, UK

5 PO70, Institute of Psychiatry, De Crespigny Park, London SE5, UK

6 Knowlsey Resource & Recover Centre, Whiston Hospital, Warrington Road, Prescot, Merseyside L35 5DR, UK

7 Wolfson Centre for Age Related Disease, Guy's Campus, King's College, London SE1 1UL, UK

8 PO26, 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

9 Institute for Ageing and Health, University of Newcastle, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne, NE4 6BE, UK

10 Queen Elizabeth Psychiatric Hospital, Mindelsohn Way, Edgbaston, Birmingham B15 2QZ, UK

11 Department of Psychiatry, Kings College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK

12 PBS 18, 2nd Floor, Education and Research Centre, School of Psychiatry and Behavioural Sciences, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK

13 Older People's Mental Health Service, Box 311, Fulbourn Hospital, Cambridge CB1 5EF, UK

14 Dundee Community Health Partnership, Gowrie House, Royal Dundee Liff Hospital, Dundee DD2 5NF, UK

15 University of Birmingham, Park Grange, 1 Somerset Road, Birmingham B15 2RR, UK

16 PO70 Institute of Psychiatry, De Crespigny Park, London SE5, UK

17 Department of Old Age Psychiatry, Moorgreen Hospital, Botley Road, West End, Southampton, Hants SO30 3JB, UK

18 Department of Geriatric Psychiatry, Inverclyde Royal Hospital, Larkfield Road, Inverclyde PA16 0NX, UK

19 University of Oxford, Department of Psychiatry, The Warneford Hospital, Oxford OX3 7JX, UK

20 MRC Biostatistics Unit (& MRC Clinical Trials Unit, London), Institute of Public Health, University Forvie Site, Robinson Way, Cambridge CB2 2SR, UK

21 Research Institute for Care of the Elderly, St Martin's Hospital, Bath BA2 5RP, UK

22 Department of Economics of Mental Health, Kings College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK

23 Department of Health Sciences, University of Leicester, Leicester General Hospital, Leicester LE5 4PW, UK

24 Old Age Psychiatry, University of Newcastle, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne, NE4 6BE, UK

25 The Fulbrook Centre, The Churchill Hospital, Oxford OX3 7JU, UK

26 North West Kilmarnock Area centre, Western Road, Kilmarnock KA13 1NQ, UK

27 Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne NE4 6BE, UK

28 PO70 Institute of Psychiatry, De Crespigny Park, London SE5, UK

29 Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK

30 School of Medicine, University of Southampton, Mail point 728, Bolrewood, Bassett Crescent, East Southampton SO16 7PX, UK

31 Charing Cross Hospital, Claybrook Centre, 37 Claybrook Road, London W6 8LN, UK

32 PO70, Institute of Psychiatry, De Crespigny, London SE5 8AF, UK

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Trials 2009, 10:57  doi:10.1186/1745-6215-10-57

Published: 24 July 2009

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