09 Mar 2012

As Alzheimer's disease (AD) progresses into the advanced stage, physicians and families often grapple with how to adjust a patient's treatment regimen. In the U.S., patients already on an acetylcholinesterase inhibitor such as donepezil may continue, discontinue, replace the drug, or add another such as the NMDA receptor antagonist memantine. In the U.K., however, the National Institute for Health and Clinical Excellence (NICE), which sets clinical guidelines for the National Health Service, does not recommend donepezil for advanced AD or approve memantine as an add-on. What is the best course of action? According to a paper in the March 8 New England Journal of Medicine, a trial designed to address this question, led by Robert Howard, Kings College London, U.K., found that continuing donepezil treatment into the advanced stage of AD is better for cognition than discontinuing it. The trial data also indicate that substituting memantine offers less benefit than donepezil, and that adding memantine may be no better than continuing donepezil alone, though that latter finding is being challenged. "What was most surprising was the size of the effect of donepezil on cognition," Howard told ARF. "The implication of our study is that far more patients should receive the drug for longer."

In this multicenter, double-blind, randomized, placebo-controlled withdrawal trial, dubbed DOMINO (Donepezil and Memantine in Moderate to Severe Alzheimer's Disease), Howard and colleagues enrolled 295 community-dwelling adults with moderate to severe Alzheimer's disease who scored between 5 and 13 on the Standardized Mini-Mental State Examination (SMMSE). All had been treated with donepezil for at least three months (though many had taken the drug longer, some upwards of five years), and their physicians were considering a change in their therapeutic regimen. Controlling for length of previous donepezil treatment, age, baseline SMMSE score, and center, the team randomly assigned volunteers to stay on the drug, discontinue it (first halving the dose and then starting placebo), swap it for memantine, or add memantine. Patients were tested at six, 18, 30, and finally at 52 weeks with the SMMSE, caregiver-rated Bristol Activities of Daily Living Scale (BADLS), and other tests including the Neuropsychiatric Inventory (NPI).

Patients who stayed on donepezil showed a 32 percent cognitive improvement over those who were taken off the drug at 52 weeks, with an average 1.9-point better score on the SMMSE. Scores on the BADLS were better by about three points (though they fell just short of the authors' pre-specified minimum clinically important difference of 3.5), which amounts to 23 percent behavioral improvement. Patients with higher baseline SMMSE scores benefited the most from continued donepezil.

This study confirms that doctors in the U.S. may be on the right track in terms of prescribing these drugs into advanced stages of the disease, Howard said. He hopes the National Health Service will look upon this as useful evidence in formulating its recommendations. The finding coincides with donepezil's patent expiration, Howard pointed out, so it will become cheaper to keep patients on generic forms for longer. Cost and health economics figure prominently in the NICE’s deliberations.

DOMINO confirms what Andrew Budson, Boston University Alzheimer's Disease Center in Massachusetts, has concluded from his own clinical experience—that donepezil seems to turn back the clock six to 12 months in AD patients, whereas removal is like turning the clock forward by the same amount. "The bottom line is that cholinesterase inhibitors should be started in the earliest stage of Alzheimer's disease and continued throughout the majority of [the patient’s] life," Budson told ARF. "If you can keep someone at a higher level of function, even for six to 12 months, that can be an enormous savings to society at all levels."

In the British study, patients who swapped donepezil for memantine showed some cognitive and functional improvement over the discontinuation group, though neither met the pre-specified clinically important difference. However, memantine appears to help the patient come off of donepezil, said Howard. Adding memantine to continued donepezil treatment showed no added cognitive or functional improvement, but all patients on memantine had better behavioral scores on the NPI than those not on the drug, regardless of donepezil treatment. "The hint of an effect on behavioral symptoms is interesting and could provide a rationale for carrying out further research regarding the combination in this patient population," Douglas Galasko, University of California, San Diego, told ARF in an e-mail.

In 2004, Pierre Tariot, then at the University of Rochester Medical Center, New York, and colleagues reported that, in a larger, six-month study of 404 patients with moderate to severe AD, memantine as adjunctive therapy to donepezil led to significant cognitive, functional, and behavioral improvements over donepezil alone (see ARF related news story). The new results may not contradict that previous study, said Lon Schneider, University of Southern California, Los Angeles, who authored an accompanying NEJM editorial. DOMINO data show an additive benefit at six months that fades by 12 months, he pointed out. Still, further research is needed on whether the two drugs together are better than one, he said in his editorial. At the same time, he cautioned that the dramatically lower SMMSE scores in patients who discontinued donepezil could result from withdrawal, even though the dose was cut in half first. "It might turn out that, if the taper were slower, there would be no difference in those scores," Schneider told ARF. "That needs to be tested."

Schneider cautioned that DOMINO does not provide evidence that indefinite treatment with donepezil is warranted. This was not an efficacy trial, but a withdrawal trial, he said, and hence supports only limited interpretation of drug effects. As previous trials have suggested, donepezil improves cognition and delays functional decline in severely demented, donepezil-naive AD patients (see ARF related news story). Donepezil treatment also improved cognition and global function, but not activities of daily living, for patients with severe AD who were not donepezil naive but had been untreated for at least three months (see ARF related news story).

Tariot, now at Banner Alzheimer's Institute in Phoenix, Arizona, pointed out that enrollment into the DOMINO study fell far short of the 800 volunteers originally sought. The resulting small sample sizes, as well as unequal dropout rates and baseline differences between the groups, may not allow the study to determine whether or not added memantine had benefits beyond donepezil. "The failure to demonstrate a 'statistically significant' effect in this study does not mean or even imply that there is no effect," he wrote in an e-mail to Alzforum. Tariot points to a multicenter trial that did confirm his 2004 study (ClinicalTrials.gov). He further raises the question of how the placebo-treated patients whose cognition dropped off steeply were monitored and protected by the study’s data safety monitoring board (see full comment below).

About half the patients assigned to continue on donepezil stopped taking it during the course of the trial, suggesting that patients experienced side effects or perceived the drug to be ineffective. Even so, said Howard, those who stayed on it had the advantage. "The advice I would give to doctors is, carry on with donepezil so long as the patient is tolerating it and the patients and their caregivers want to go on," said Howard.—Gwyneth Dickey Zakaib

Comments

- Pierre Tariot
  Banner Alzheimer's Institute
- Posted: 09 Mar 2012
- Paper: Donepezil and memantine for moderate-to-severe Alzheimer's disease.
I applaud Howard et al. for attempting a clinical trial that has great potential public health significance. I and surely others also appreciate the support provided by the Medical Research Council. As part of a team committed to caring for and studying people with Alzheimer's disease at all stages, I am particularly grateful that there is continued interest in trying to improve the welfare of our fellow citizens who are experiencing more advanced dementia.

Trying to comment within the rapid news cycle means I am doing so before having had a chance to track down the paper's supplement. That said, there are a number of initial points and a potential concern that I would like to raise. It seems the headline goes something like this: Patients in this trial with moderate to severe Alzheimer's disease who were previously treated with donepezil did better in terms of simple measures of cognition and daily functioning if they stayed on donepezil or started on memantine. In contrast, those individuals who had been on donepezil and were switched to placebo declined precipitously.

While the limited instruments used in the trial are not particularly good at informing clinical decision-making, the results were nonetheless fairly stark and, therefore, in my opinion, highly clinically relevant. Any active treatment was beneficial: continuing donepezil, switching to memantine, or adding memantine. I note, however, that despite statements in the article to the contrary, there is no actual evidence of lack of effect of adjunctive memantine therapy. There are several reasons for saying this. First, the sample sizes at the study's end were small, ranging from 20 to 38 participants per group. Further, dropout rates between the groups were markedly different. There were also important baseline differences between the groups. It is important to be aware that, under these circumstances, the failure to demonstrate a "statistically significant" effect does not mean or even imply that there is no effect. Furthermore, inspection of the data indicates that there were differential effects by treatment groups for a large part of the treatment period for both co-primary endpoints; in my view, this is a clinically relevant finding.

I further note that the decline in measures of cognition and daily functioning among individuals treated with placebo was precipitous in this trial. Individual, let alone group, declines of this magnitude would typically have prompted concern during the course of a blinded trial that harm may have been done to patients, with possible implications for trial continuation. This issue is important. It is not addressed in the paper. The reader is left to wonder how patients were monitored and what the data safety monitoring board’s specific charter and role were in this trial, noting that the ethics of withdrawing treatment and putting patients on placebo should be considered carefully in designing and conducting such a trial.

There are some other methodological and operational considerations that can be raised. First, despite a two-year enrollment period, only 295 of an intended sample size of 800 were enrolled. The reasons for the shortfall are not explained. Second, an interim analysis was performed for unclear reasons in a manner not specified in the manuscript, indicating that the sample size could be reduced from 800 to 430. Interestingly, the funding agency then requested that the study be stopped before being completed according to the revised plan. The details of this unusual decision are unclear, although it was stated that it was important to report results as quickly as possible. Such a decision comes at a cost: Several goals of the study could not be achieved, yet the paper suggests that they were.

Alzforum requested a comment specifically on the statement in the NEJM that, "The findings of the study showing that combination therapy with memantine and a cholinesterase inhibitor was more effective than treatment with a cholinesterase inhibitor alone (Tariot et al., 2004) have not been replicated (Porsteinsson et al., 2008)." First, neither the present study, nor the JAMA paper referred to, for which I was an author and investigator, address "combination" therapy, but adjunctive therapy. The two are quite distinct. Second, a multicenter trial of adjunctive memantine in patients with moderate to severe Alzheimer's disease has been completed, and it replicates the findings reported in the 2004 JAMA paper. Its results have been presented publicly at international scientific conferences and are available at ClinicalTrials.gov. The statement quoted here is thus incorrect. Third, the citation used to indicate lack of replication (Porsteinsson et al.) refers to a study in patients with milder, rather than moderate to severe AD, and hence is not comparable.

Finally, there are some other differences between these two studies: design, sample size and power, state of equipoise, duration (six vs. 12 months), outcome measures (MMSE vs. SIB), dropout rates, and interim analyses. Interestingly, despite these differences, both studies still showed a positive effect on emerging behavioral symptoms measured by the NPI.

Taken together, the studies are very different, and lead to different conclusions. The bottom line, in my view, is that this was a very important undertaking. It achieved some important results that are likely to affect clinical practice and may influence considerations by NICE. Hopefully, those results that are less clear can be reframed so as to minimize confusion and avoid incorrect impact on best medical practice.

References:

Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, . Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004 Jan 21;291(3):317-24. PubMed.

Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT, . Memantine treatment in patients with mild to moderate Alzheimer's disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res. 2008 Feb;5(1):83-9. PubMed.

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