title: DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Current controlled trials ISRCTN49545035.
authors.affiliation: Section of Old Age Psychiatry, The University of Nottingham, A Floor, South Block, Queen's Medical Centre, Nottingham NG7 2UH, UK. rob.jones@nottingham.ac.uk
authors.forename: Rob
authors.initials: R
authors.lastname: Jones
authors.forename: Bart
authors.initials: B
authors.lastname: Sheehan
authors.forename: Patrick
authors.initials: P
authors.lastname: Phillips
authors.forename: Ed
authors.initials: E
authors.lastname: Juszczak
authors.forename: Jessica
authors.initials: J
authors.lastname: Adams
authors.forename: Ashley
authors.initials: A
authors.lastname: Baldwin
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
authors.forename: Sube
authors.initials: S
authors.lastname: Banerjee
authors.forename: Bob
authors.initials: B
authors.lastname: Barber
authors.forename: Peter
authors.initials: P
authors.lastname: Bentham
authors.forename: Richard
authors.initials: R
authors.lastname: Brown
authors.forename: Alistair
authors.initials: A
authors.lastname: Burns
authors.forename: Tom
authors.initials: T
authors.lastname: Dening
authors.forename: David
authors.initials: D
authors.lastname: Findlay
authors.forename: Richard
authors.initials: R
authors.lastname: Gray
authors.forename: Mary
authors.initials: M
authors.lastname: Griffin
authors.forename: Clive
authors.initials: C
authors.lastname: Holmes
authors.forename: Alan
authors.initials: A
authors.lastname: Hughes
authors.forename: Robin
authors.initials: R
authors.lastname: Jacoby
authors.forename: Tony
authors.initials: T
authors.lastname: Johnson
authors.forename: Roy
authors.initials: R
authors.lastname: Jones
authors.forename: Martin
authors.initials: M
authors.lastname: Knapp
authors.forename: James
authors.initials: J
authors.lastname: Lindesay
authors.forename: Ian
authors.initials: I
authors.lastname: McKeith
authors.forename: Rupert
authors.initials: R
authors.lastname: McShane
authors.forename: Ajay
authors.initials: A
authors.lastname: Macharouthu
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.forename: Caroline
authors.initials: C
authors.lastname: Onions
authors.forename: Peter
authors.initials: P
authors.lastname: Passmore
authors.forename: James
authors.initials: J
authors.lastname: Raftery
authors.forename: Craig
authors.initials: C
authors.lastname: Ritchie
authors.forename: Rob
authors.initials: R
authors.lastname: Howard
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000077265:Donepezil; D015259:Dopamine Agents / Q000627:therapeutic use*; D019317:Evidence-Based Medicine; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D008559:Memantine / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D012107:Research Design; D012720:Severity of Illness Index
chemical_list: D015259:Dopamine Agents; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil; D008559:Memantine