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

Section of Old Age Psychiatry, The University of Nottingham, A Floor, South Block, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Trials (Impact Factor: 1.73). 08/2009; 10(1):57. DOI: 10.1186/1745-6215-10-57
Source: PubMed


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.
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.
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.
Current controlled trials ISRCTN49545035.

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    • "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. "
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    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.
    International journal of medical sciences 05/2012; 9(3):248-55. DOI:10.7150/ijms.4363 · 2.00 Impact Factor
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    • "several on-off titrations, site-level dropout, high likelihood of selection bias, underpowered) and excessive attrition (>97% at year 3) making interpretation problematic, and the study failed to provide level I grade evidence. In response, the ongoing DOMINO-AD study [18], a long-term RCT, was launched. An important gap in the data that is to be assessed by the DOMINO-AD study is the comparison of combination therapy versus memantine alone (as well as vs. ChEI alone and vs. placebo); results from this landmark UK study are highly anticipated. "
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    ABSTRACT: Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer's disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness. To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs). Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs. RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization. Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed.
    Neurodegenerative Diseases 02/2012; 10(1-4):170-4. DOI:10.1159/000335156 · 3.51 Impact Factor
  • Maturitas 09/2009; 64(2):59-60. DOI:10.1016/j.maturitas.2009.08.014 · 2.94 Impact Factor
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