Trial of Memantine/Donepezil Paves the Way for Combination Therapy

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22 January 2004. Combining memantine with an older, widely used AD drug further improves measures of cognition, global well-being, activities of daily living, and behavior in people with moderate to severe AD, according to a study published in the January 21 JAMA. Pierre Tariot of the University of Rochester Medical Center, New York, with other clinicians of the Memantine Study Group, presented the first report to date of a prospective, double-blind, placebo-controlled trial addressing the question of whether combination therapy might become standard in AD treatment, much as it has for other diseases, such as AIDS.

The three established AD drugs are cholinesterase inhibitors (ChEIs; see ARF Live Discussion on cholinesterase inhibitors). By contrast, memantine—which won FDA approval last fall and is due in pharmacies next month (see ARF related news story)—is a low-affinity NMDA receptor antagonist that counteracts glutamine-mediated excitotoxicity. The fact that memantine and ChEIs work through separate neurotransmitter systems has raised hope that combination therapy might show either independent additive effects or synergistic effects, which could increase somewhat the modest benefit seen with one drug alone. Previously, a small open-label study had suggested this might be safe (Hartmann and Mobius, 2003), and further trials are ongoing.

The multicenter trial of 404 patients involved adding a six-month course of memantine to the drug regimen of people with moderate or severe AD who already were on stable doses of donepezil, as well as other drugs needed in these sick patients. Study participants were tested at baseline and every four weeks thereafter on cognitive, functional, and global outcomes. Tariot and colleagues report that adding memantine improved the patients’ performance on all primary and secondary outcome measures, which included several test batteries adapted for use in severely demented patients. More patients in the placebo-donepezil group than in the memantine-donepezil group dropped out due to side effects, indicating that the drug combination overall did not add further complications. There were differences on individual side effects, with more confusion and headaches, but less nausea, diarrhea, and incontinence, seen in the memantine than the placebo group.

The trial did not test different doses of memantine; all patients included in the analysis took 20 mg/d, the higher of two doses described in memantine’s FDA documents. It also did not include patients who were on rivastigmine or galantamine, the other two ChEIs. Therefore, this trial alone is insufficient to infer that memantine-ChEI combination therapy for AD is safe and effective in general, the authors note. An open-label extension of the current trial is gathering data on long-term consequences of this combination therapy; other trials are ongoing.—Gabrielle Strobel.

Reference:
Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I; Memantine Study Group. 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. Abstract


Comments on Related News
Related News: Memantine—Good for a Year, But Little Disease Modification

Comment by: Rachelle Doody
Submitted 16 January 2006 Posted 16 January 2006


The results of our study suggest that long-term (up to a year) use of memantine has sustained effects. We are encouraged that a high percentage of those completing the double-blind study enrolled in the open-label extension (97 percent), and that a high percentage of those who enrolled completed the open-label study (78 percent). This adds confidence to the observations that rates of change slowed down for subjects who switched from placebo to memantine, and remained slower than expected for subjects originally randomized to memantine.

Our study cannot answer the question of what happens after the first year on treatment. As in all open-label extension studies, there is gradual attrition during the open-label period, and the patients who remain in the study until the end are not formally followed after the extension period is over. In my clinical experience, moderate to severe patients maintained on a cholinesterase inhibitor and memantine seem to decline more slowly and retain more function for an extended period of time, often many years. Ethical issues related to long-term randomization of AD patients to placebo groups for longer than 6 months or so prohibit designing studies that would provide a definitive answer regarding how long the treatments should be maintained. In clinical practice, I would raise the issue of discontinuing treatment with a family if I did not see any cognitive or functional ability that we would like to retain. Practically, this is increasingly rare as AD patients who now live into very late stages of disease often succumb to another condition despite retained abilities and continued antidementia treatment.

Regarding your second point, memantine was used in Germany for many years before it began a formal development program in dementia, somewhat analogous to the use of hydergine in the U.S. and elsewhere in the world. The formal studies of memantine, performed according to draft regulatory guidelines which were not produced until the 1990s, resulted in the demonstration of efficacy in well-defined populations, and the approval of the drug here and in Europe.