Meta-Analysis Questions Memantine Effectiveness for Mild Alzheimer’s

There is no evidence that memantine is effective for mild Alzheimer’s disease in the very studies that two manufacturers used to win approval of the drug for that indication, according to a report published online April 11 in the Archives of Neurology.

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 memantine 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:10.1001/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 (CIBIC-plus), the Alzheimer Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, or the Neuropsychiatric Inventory (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, they were about half of those found in many trials of cholinesterase inhibitors, Dr. Schneider and his colleagues wrote.

"Contrary to the conclusions of the U.S. meta-analysis, we found no effects for memantine on any of the four outcomes in mild AD and no significant effects for memantine on activities of daily living or behavior in the subset of patients with moderate AD," Dr. Schneider and his colleagues wrote.

"The authors of the U.S. meta-analysis incorrectly claimed that memantine ‘demonstrated consistent benefits compared with placebo for cognitive measures, global clinical impression, and functional outcomes across the overall spectrum of AD severity,’ and they further elaborated that their results ‘support the hypothesis that drugs indicated for AD are beneficial for all patients with clinically diagnosed disease, and that arbitrary divisions into severity groups might not be necessary for treatment or drug development in this field.’

"Our results ... do not support these assertions, and they provide insight into why the FDA did not approve the manufacturer’s application to market the drug for mild AD," the investigators wrote.

The investigators added that this lack of evidence for memantine’s efficacy "could come to light only because the European meta-analysis was a subset of the U.S. meta-analysis. If the European meta-analysis had not excluded patients with higher MMSE scores, then it would not have been possible to distinguish the particular lack of evidence for the efficacy of memantine in the mild AD group, which comprised nearly 40% of the patients overall," they wrote.

The findings of the authors’ meta-analysis also support the argument that "results of randomized clinical trials of marketed drugs should be made available soon after trials are completed. Timely release combined with the willingness to openly examine subsets of patients and individual patient outcomes would have allowed earlier recognition of some limitations in memantine’s broader efficacy."

In the United States, that in turn could have spared the half of patients with mild AD and the "substantial portion" of those with mild cognitive impairment from receiving memantine when there is no evidence that the drug is helpful to them and some evidence that it is not helpful, the researchers said.

The meta-analysis was supported by the U.K.’s Medical Research Council, the California Alzheimer Disease Center program, and the University of Southern California Alzheimer Disease Research Center. Dr. Schneider reported being an editor of the Cochrane Collaboration Dementia and Cognitive Improvement Group, which oversees the systematic review of drugs for cognitive impairment and dementia; he also reported having ties to numerous drug companies, including some that market memantine.

There is no evidence that memantine is effective for mild Alzheimer’s disease in the very studies that two manufacturers used to win approval of the drug for that indication, according to a report published online April 11 in the Archives of Neurology.

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 memantine 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:10.1001/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 (CIBIC-plus), the Alzheimer Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, or the Neuropsychiatric Inventory (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, they were about half of those found in many trials of cholinesterase inhibitors, Dr. Schneider and his colleagues wrote.

"Contrary to the conclusions of the U.S. meta-analysis, we found no effects for memantine on any of the four outcomes in mild AD and no significant effects for memantine on activities of daily living or behavior in the subset of patients with moderate AD," Dr. Schneider and his colleagues wrote.

"The authors of the U.S. meta-analysis incorrectly claimed that memantine ‘demonstrated consistent benefits compared with placebo for cognitive measures, global clinical impression, and functional outcomes across the overall spectrum of AD severity,’ and they further elaborated that their results ‘support the hypothesis that drugs indicated for AD are beneficial for all patients with clinically diagnosed disease, and that arbitrary divisions into severity groups might not be necessary for treatment or drug development in this field.’

"Our results ... do not support these assertions, and they provide insight into why the FDA did not approve the manufacturer’s application to market the drug for mild AD," the investigators wrote.

The investigators added that this lack of evidence for memantine’s efficacy "could come to light only because the European meta-analysis was a subset of the U.S. meta-analysis. If the European meta-analysis had not excluded patients with higher MMSE scores, then it would not have been possible to distinguish the particular lack of evidence for the efficacy of memantine in the mild AD group, which comprised nearly 40% of the patients overall," they wrote.

The findings of the authors’ meta-analysis also support the argument that "results of randomized clinical trials of marketed drugs should be made available soon after trials are completed. Timely release combined with the willingness to openly examine subsets of patients and individual patient outcomes would have allowed earlier recognition of some limitations in memantine’s broader efficacy."

In the United States, that in turn could have spared the half of patients with mild AD and the "substantial portion" of those with mild cognitive impairment from receiving memantine when there is no evidence that the drug is helpful to them and some evidence that it is not helpful, the researchers said.

The meta-analysis was supported by the U.K.’s Medical Research Council, the California Alzheimer Disease Center program, and the University of Southern California Alzheimer Disease Research Center. Dr. Schneider reported being an editor of the Cochrane Collaboration Dementia and Cognitive Improvement Group, which oversees the systematic review of drugs for cognitive impairment and dementia; he also reported having ties to numerous drug companies, including some that market memantine.

There is no evidence that memantine is effective for mild Alzheimer’s disease in the very studies that two manufacturers used to win approval of the drug for that indication, according to a report published online April 11 in the Archives of Neurology.

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 memantine 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:10.1001/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 (CIBIC-plus), the Alzheimer Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, or the Neuropsychiatric Inventory (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, they were about half of those found in many trials of cholinesterase inhibitors, Dr. Schneider and his colleagues wrote.

"Contrary to the conclusions of the U.S. meta-analysis, we found no effects for memantine on any of the four outcomes in mild AD and no significant effects for memantine on activities of daily living or behavior in the subset of patients with moderate AD," Dr. Schneider and his colleagues wrote.

"The authors of the U.S. meta-analysis incorrectly claimed that memantine ‘demonstrated consistent benefits compared with placebo for cognitive measures, global clinical impression, and functional outcomes across the overall spectrum of AD severity,’ and they further elaborated that their results ‘support the hypothesis that drugs indicated for AD are beneficial for all patients with clinically diagnosed disease, and that arbitrary divisions into severity groups might not be necessary for treatment or drug development in this field.’

"Our results ... do not support these assertions, and they provide insight into why the FDA did not approve the manufacturer’s application to market the drug for mild AD," the investigators wrote.

The investigators added that this lack of evidence for memantine’s efficacy "could come to light only because the European meta-analysis was a subset of the U.S. meta-analysis. If the European meta-analysis had not excluded patients with higher MMSE scores, then it would not have been possible to distinguish the particular lack of evidence for the efficacy of memantine in the mild AD group, which comprised nearly 40% of the patients overall," they wrote.

The findings of the authors’ meta-analysis also support the argument that "results of randomized clinical trials of marketed drugs should be made available soon after trials are completed. Timely release combined with the willingness to openly examine subsets of patients and individual patient outcomes would have allowed earlier recognition of some limitations in memantine’s broader efficacy."

In the United States, that in turn could have spared the half of patients with mild AD and the "substantial portion" of those with mild cognitive impairment from receiving memantine when there is no evidence that the drug is helpful to them and some evidence that it is not helpful, the researchers said.

The meta-analysis was supported by the U.K.’s Medical Research Council, the California Alzheimer Disease Center program, and the University of Southern California Alzheimer Disease Research Center. Dr. Schneider reported being an editor of the Cochrane Collaboration Dementia and Cognitive Improvement Group, which oversees the systematic review of drugs for cognitive impairment and dementia; he also reported having ties to numerous drug companies, including some that market memantine.