The DOMINO-AD trial (Jones et al, 2009) was a pragmatic multi-centre randomised trial with the primary aim of identifying the best treatment options for those living at home with moderate to severe Alzheimer’s Disease dementia (AD).
Currently the most commonly prescribed cholinesterase inhibitor Donepezil (Aricept) is only licensed for treating those with mild to moderate AD. The evidence suggests its effectiveness is very slight in terms of cognitive and functional outcomes for those with more severe symptoms, so it is often discontinued as the disease progresses. Memantine is a glutamate agonist and works differently. It is widely prescribed as an alternative to cholinesterase inhibitors, and for more severe symptoms.
Underpowered for the primary outcomes
DOMINO-AD had a planned sample size of 800 with the power to show differences in two primary outcomes assessed over one year:
- Cognition: measured using the Standardised Mini-Mental State Examination (SMMSE)
- Activities of daily living: measured using the Bristol Activities of Daily Living Scale (BADLS)
Although the original planned sample size was 800, this was adjusted to 430 after an interim blinded analysis of accrued data. The final number randomised was 295 because of slower than expected recruitment. The reason given for accepting the 30% shortfall in participants in the primary report (Howard, 2012) was that:
…the public funder of the study (Medical Research Council) believed that the disadvantages of a delay in reporting results outweighed the benefits of increasing the power of the study.
Participants in the trial were all living at home, and were already taking Donepezil. They were eligible if they had moderate to severe dementia measured using the SMMSE.
The 295 participants were recruited and randomised to four groups between February 2008 and March 2010:
- No active treatment (Discontinue Donepezil and receive placebo + placebo Memantine)
- Memantine only (Discontinue Donepezil and receive placebo + active Memantine)
- Donepezil only (Continue Donepezil + placebo Memantine)
- Donepezil and Memantine (Continue Donepezil + active Memantine)
The results of the study in terms of the primary outcomes (Howard, 2012) showed that those who continued with Donepezil scored higher on the SMMSE by an average of 1.9 points. The minimum clinically important difference had been determined as 1.4 in a previous study (Howard, 2010).
The results also showed that those who continued with Donepezil had a lower score on BADLS (indicating less impairment) of 3.0 points. The minimum clinically important difference was determined as 3.5.
I don’t understand how you can make a judgement about the minimally important clinical difference based on this type of measurement. Surely the importance of the size of the difference depends on where you are on the scale to begin with.
Nursing home placement: a secondary outcome?
In October 2015 the DOMINO-AD team published an article in The Lancet Neurology (Howard, 2015) reporting the results of one of the secondary outcomes – the effect of discontinuation of drug treatment on nursing home placement over a year. They followed up participants over the next 3 years. The last participant completed follow up in April 2014.
The results of this secondary and post-hoc analysis showed that:
Withdrawal of Donepezil increased the risk of nursing home placement over 12 months, but not over the following three years.
The presence or absence of Memantine appeared to have no effect.
Pragmatic trials need pragmatic outcome measures
An accompanying commentary by Anders Wimo (Wimo, 2015) welcomes the results but questions, as I do, the fact that nursing home placement is a secondary outcome. DOMINO-AD describes itself as a pragmatic phase 4 trial. So why was the “real life” outcome of nursing home placement not a primary outcome? It is something that really matters to patients and carers, and has a big impact on service providers, resource use and on society. It can also be measured very easily.
As Wimo suggests:
Annual assessments, short case report forms and simple measurements of function can be a realistic option for pragmatic randomised trials.
Clinicians and carers can work together to change practice and improve future research
I hope that this paper will prompt clinicians to think about the risks of automatically withdrawing Donepezil when dementia symptoms become moderate to severe. I also hope carers will find the findings empowering and will facilitate well-informed shared decision making.
However, the increased burden faced by informal carers living in the community when dementia symptoms worsen is an important consideration, and should also be measured as a primary outcome in future trials looking at the effects of treatments for Alzheimer’s Disease.
Howard, R., McShane, R., Lindesay, J., Ritchie, C., Baldwin, A., Barber, R., Phillips, P. P. J. (2015). Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO-AD) trial: secondary and post-hoc analyses. The Lancet Neurology, 4422(15), 1–11. doi:10.1016/S1474-4422(15)00258-6 [Abstract]
Jones R, Sheehan B, Phillips P, et al. (2009) 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.
Howard R, McShane R, Lindesay J et al. (2012) Donepezil and Memantine for moderate-to-severe Alzheimer’s disease N Engl J Med, 366, pp. 893–903
Howard R, Phillips P, Johnson T, et al. (2010) Determining the minimum clinically important differences for outcomes in the DOMINO trial. Int J Geriatr Psychiatry 2010; 26:812-817
Wimo A. (2015) Long-term effects of Alzheimer’s disease treatment, The Lancet Neurology, Volume 14, Issue 12, December 2015, Pages 1145-1146, ISSN 1474-4422, http://dx.doi.org/10.1016/S1474-4422(15)00302-6.
Donepezil, nursing home placement and Alzheimer’s Disease https://t.co/bqzy3lpzI4 #MentalHealth https://t.co/Vl7kmUUR9H
RT iVivekMisra Donepezil, nursing home placement and Alzheimer’s Disease https://t.co/U0qCA2PwRU #MentalHealth https://t.co/poAr5IESb4
RT https://t.co/rECGrLpB1A Top story: Donepezil, nursing home placement and Alzheimer’s Disease https://t.co/QD76G2FWaE, see more …
Thanks for picking up our trial in the Blog. The clear message from the trial – that stopping cholinesterase inhibitor treatment at the moderate-to-severe point in AD is a bad thing – has already had impact on treatment guidelines and physician practice.
You ask why nursing home placement was a secondary outcome when it is of such obvious importance to patients, their families and the healthcare system. To be honest, we didn’t anticipate that the drugs would make a difference on this complex outcome. Donepezil is a symptomatic and not a disease-modifying treatment and the reasons for nursing home placement in an individual patient are very varied. We would also have needed to conduct a much larger trial to have been adequately powered from the outset to detect a small change in the rate of institutionalisation. Hence we went for cognition and function as co-primaries. Personally, I think that these are also pretty important outcomes to patients and their families too.
Thanks for the quick response Robert. I thought the trial results were pretty exciting and I am very pleased it has already had an impact on guidelines and practice. I guess with the primary versus secondary outcome thing, it gives readers without quite sophisticated understanding of statistics the impression that researchers think these outcomes are less important, which I know is not the case. I don’t understand why you say nursing home placement is a complex outcome though, although I agree the reasons for it are.
Every trialist hopes to get a clear result! I think nursing home placement was a complex outcome for lots of reasons. For example, there is a wide range of potential care placements and the choice of facility that a person with dementia will be admitted to when they can no longer live independently depends as much on what is available locally and immediately as on their specific care needs. Also, very few people with dementia go straight from their own homes to a nursing home. Frequently, a hospital admission will lead to an assessment that a return home is unsafe and so placement will be recommended. But this might be weeks or months after the breakdown of independent living at home.
Hi @ALOISCommunity Response from Robert Howard on your blog (re nursing home placement as secondary outcome) https://t.co/8QoQam1Nxs
Donepezil, nursing home placement and Alzheimer’s Disease https://t.co/OJa6K1xeUO
Nursing home placement in Donepezil & Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO-AD) trial https://t.co/JQQFcis4ot
@Mental_Elf: Nursing home placement on Donepezil in Moderate/ Severe Alzheimer’s Disease https://t.co/JQQFcis4o Rob Howard @UCLPsychiatry
Dementia carer burden should be a primary outcome in future trials, says @ALOISCommunity https://t.co/JQQFcis4ot
Don’t miss: Donepezil, nursing home placement and Alzheimer’s Disease https://t.co/JQQFcis4ot #EBP