Meta-Analysis Finds Memantine Ineffective for Mild AD

Article excerpt

There is no evidence that memantine is effective for mild Alzheimer's disease in the very studies that two manufacturers used to seek approval of the drug for that indication, according to a report published on line in the journal.

In addition, the effect sizes of memantine's "benefit" for moderate Alzheimer's disease (AD) are so small in the same studies that the drug's usefulness is questionable in that patient group as well, wrote Dr. Lon S. Schneider of the University of Southern California, Los Angeles, and his associates.

Memantine is indicated for moderate to severe AD in the United States and Europe, but often is prescribed "off label" for mild AD or even mild cognitive impairment. Research indicates that up to 63% of patients with mild AD receive the drug, and one study showed that "nearly 40% of U.S. neurologists surveyed reported prescribing memantine at least sometimes to patients with mild cognitive impairment," Dr. Schneider and his colleagues noted.

An American manufacturer recently applied to the Food and Drug Administration and a European manufacturer applied to the European Medicines Agency to expand approval of memantine to mild AD. In support of their applications, both companies submitted meta analyses of the same three clinical trials assessing the drug in combined cohorts with mild to moderate AD.

Neither company supplied data separating mild from moderate AD. However, by subtracting data in one meta analysis from that in the other, Dr. Schneider and his associates were able to directly assess the effects of me mantine in mild AD and in moderate AD separately, in their own meta-analysis of these same three clinical trials.

"All three trials included random allocation to treatment, patients and investigators blinded to treatments, and outcome assessments performed while blinded to treatment assignment," they noted.

A total of 1,128 patients completed the studies, including 431 (38%) with mild AD (Arch. Neurol. 2011 April 11 [doi:10.100l/archneurol.2011.69]).

"There was no evidence for the efficacy of memantine in the subset of patients with mild AD on any of the outcomes in any trial or when statistically combined," the investigators wrote.

Memantine exerted "no significant effects" whether patients with mild AD were assessed using the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog), the Clinician's Interview-Based Impression of Change Plus Caregiver's Input (CIBlC-plus), the Alzheimer Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, or the Neuropsychiatric In ventory (NPI).

These instruments assess cognition, global change, functional activities, and behavior, respectively.

Moreover, once data on moderate AD was separated from that on mild AD, there also was no significant difference between memantine and placebo for moderate AD on any of these measures in any of the individual trials, except for a significant effect on the CIBIC-plus in one of the three trials. When the trials were combined, the difference between active drug and placebo was significant on two of the instruments (the ADAS-cog and the CIBIC-plus), albeit with very small effect sizes.

To put these effects sizes into perspective, Dr. Schneider and his colleagues wrote, they were about half of those found in many trials of cholinesterase inhibitors,. …

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