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George T. Grossberg, MD, St. Louis University School of Medicine, St
Louis, Missouri, USA
Yvonne Wirth, MD, PhD, Wirth Consulting, Stuttgart, Germany
Suzanne Hendrix, PhD, Pentara Corporation, Salt Lake City, Utah, USA
Michael Tocco, PhD, Forest Research Institute, Jersey City, New
Stephen M. Graham, PhD, Forest Research Institute, Jersey City, New
Dear Dr Groves:
After careful review of the article titled "Memantine and
cholinesterase inhibitor combination therapy for Alzheimer's disease: a
systematic review" (Farrimond et al, BMJ Open, 2012), we have
identified significant inaccuracies that we believe should be addressed.
Several important errors and inconsistencies occur in Figure 3, some
of which are also repeated in Table 2 (Analysis 3, Function). First, the
figure shows a numerical advantage for placebo over memantine extended-
release (ER) in trial MD-50, which is incorrect: in that trial , as
well as in trial MD-02  and in the subset of patients from MD-12 with
moderate AD , the memantine group demonstrated a smaller mean decline
on the measure of function than the placebo group. The corrected Figure 3,
which properly summarizes the data from these 3 trials, along with the
authors' original version, can be found at the following site:
As shown in the figure, for the outcome of function, Farrimond et al
calculated a standard mean difference (SMD) [95%CI] of -0.04 [-0.21, 0.13]
(P = 0.65), whereas, according to our calculations, the correct overall
SMD [95%CI] is -0.11 [-0.21, 0.00] (P = 0.05). Therefore, there is a large
discrepancy between their analysis and ours in terms of both the observed
effect (-0.04 vs -0.11) and the accompanying P-value (0.65 vs 0.05).
In addition, our analysis of Cognition (Table 2, Analysis 1b),
performed by applying the methodology outlined by the authors to the same
published data that they used, resulted in an SMD [95%CI] of -0.23 [-0.47,
0.00] (P= 0.05, significantly in favor of memantine), rather than their
published SMD of -0.16 [-0.54, 0.23] (P = 0.43). These corrected values
reveal that the TA127 analysis would have indeed demonstrated significant
cognitive benefits in favor of memantine/donepezil combination therapy had
the data been pooled, contrary to the authors' assertion.
We also bring to your attention several statements pertaining to
published literature or previously reported data. In the introduction, the
authors refer to the Patel and Grossberg manuscript  as a "company-
sponsored" review, which in fact was produced independently of industry
support, as stated in the acknowledgments ("no sources of funding were
used to assist in the preparation of this review"). Moreover, Table 1,
which correctly cites the Forest Clinical Trial Registry website as the
reference for the MD-50 study, incorrectly states that "the baseline
characteristics of patients in this unpublished study are not given."
These data are in fact reported in the summary clinical study report
posted on the website, with the exception of the mean NPI score (Placebo +
ChEI = 16.8; Memantine + ChEI = 17.2). In reference to the memantine ER
formulation (28 mg) used in the MEM-MD-50 study, the authors state in the
discussion section that "the dose of 28 mg memantine in this preparation
was designed to be equivalent to 20 mg daily of the currently marketed
preparation," which is incorrect: the new memantine formulation was
designed to provide a 40% increase in the maximum daily dose with a much
slower absorption rate (median Tmax of 12 h, compared with 3-7 h observed
with the immediate-release formulation).
The authors also speculate that "the trend for an adverse effect on
ADL may account for the fact that [the MD-50 trial] data have not been
published in peer review literature." This interpretation may have been
influenced by their misperception that placebo treatment was superior to
memantine for ADL in that trial (as exemplified by the error in Figure 3).
In fact, the manuscript describing this trial has been submitted for
publication. As reported previously , the trial demonstrated
significant benefits in favor of memantine ER on both primary efficacy
parameters (SIB and CIBIC-Plus) and two additional parameters (NPI and
Verbal Fluency Test), as well as a numerical advantage in favor of
memantine on the ADCS-ADL19.
Furthermore, the authors state that "the fact that clinical data have
not been released from the 12-month trial, Lu1011 , is disturbing";
however, the trial manuscript, which includes the clinical data, was
published --and indexed on PubMed and Embase-- in January, 2012 , two
months before the manuscript by Farrimond et al was accepted for
Finally, the authors state that "since the impact on clinical global
impression depends on exactly which studies are included, and there is no
benefit on function, the clinical relevance of combination therapy is not
robustly demonstrated." We believe that this statement is unfounded, for
the following reasons: (1) As demonstrated above (see the corrected Figure
3), there is a significant benefit on function when all three studies are
included in the meta-analysis. (2) In our opinion, the authors'
observation that study selection determines the overall effect on the
clinical global impression measure (CIBIC-Plus) contradicts the purpose of
conducting a meta-analysis. No relevant data set should be excluded from a
meta-analysis without a compelling reason - for example, significant
heterogeneity. Indeed, the authors' own analysis of global clinical
impression for all 3 datasets (Figure 1) demonstrates a significant
overall effect of memantine (p<0.001) without evidence of significant
heterogeneity, suggesting no reasons for excluding any of the trials.
Incidentally, if one data set were to be excluded, the most reasonable
choice would be the moderate subset from the MD-12 trial, due to its
higher baseline mean MMSE score (15, compared with a mean MMSE score of 10
for both MD-02 and MD-50). In that case, pooling of MD-02 and MD-50 data
would yield a significant overall treatment effect for cognition (SIB;
p<0.001), function (ADCS-ADL19; p=0.03), behavior (NPI; p<0.001),
and clinical global impression (CIBIC-plus; p<0.001).
In short, we believe that the conclusions in this manuscript are not
supported by the data, which, when pooled across all 3 trials, demonstrate
significant benefits of adding memantine to ChEIs on cognitive,
functional, behavioral, and global clinical outcome measures.
We strongly urge the authors to reassess and correct the analysis and
presentation of data in this manuscript (particularly Figure 3), and to
revise the discussion and conclusions so that they are consistent with the
corrected data. We respectfully suggest that an appropriate response would
be to withdraw the original publication and replace it with a corrected
version in BMJ Open.
George T. Grossberg, MD;
Co-author of manuscripts from trials MD-02 , MD-12 , and MD-50
(submitted) and the Patel and Grossberg 2011 review 
Yvonne Wirth, MD PhD;
Statistical consultant and co-author of meta-analysis  that was the
source for MD-12 data for patients with moderate AD
Suzanne Hendrix, PhD;
Michael Tocco, PhD;
Medical Affairs, Forest Research Institute
Stephen M. Graham, PhD;
Co-author of manuscripts from trials MD-02  and MD-50 (submitted)
 Farrimond LE, Roberts E, McShane R. Memantine and cholinesterase
inhibitor combination therapy for alzheimer's disease: A systematic
review. BMJ Open 2012;2(3).
 Grossberg G, Manes F, Allegri R, Miguel L, Robledo L, Gloger S,
et al. A multinational, randomized, double-blind, placebo-controlled,
parallel-group trial of memantine extended-release capsule (28 mg, once
daily) in patients with moderate to severe alzheimer's disease [abstract].
Alzheimers Dement 2008;4(4)(suppl 2):T793.
 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
 Winblad B, Jones RW, Wirth Y, Stoffler A, Mobius HJ. Memantine in
moderate to severe alzheimer's disease: A meta-analysis of randomised
clinical trials. Dement Geriatr Cogn Disord 2007;24(1):20-7.
 Patel L, Grossberg GT. Combination therapy for alzheimer's
disease. Drugs Aging 2011;28(7):539-46.
 Periclou A, Hu Y. Extended-release (er) memantine capsule (28 mg,
once daily): A multiple-dose, open-label study evaluating steady-state
pharmacokinetics in healthy volunteers [abstract]. Alzheimers Dement
2008;4(4 (suppl 2)):T792.
 Wilkinson D, Fox NC, Barkhof F, Phul R, Lemming O, Scheltens P.
Memantine and brain atrophy in alzheimer's disease: A 1-year randomized
controlled trial. J Alzheimers Dis 2012;29(2):459-69.
 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;5(1):83-9.
Dr. George T. Grossberg has received consulting fees from Avanir Pharmaceuticals, Baxter Bioscience, Forest Laboratories, Eli Lilly, Lundbeck, Novartis Pharmaceuticals, and Otsuka Pharmaceutical; his department also receives research funds from Abbott Laboratories, Baxter, Forest, Janssen Pharmaceuticals, Novartis, and Pfizer Pharmaceuticals, as well as data safety monitoring committee fees from Abbott, Merck, and Schering-Plough.
Dr. Yvonne Wirth is employed by Wirth Consulting, a statistical consultant of Merz, Inc.
Dr. Suzanne Hendrix is employed by Pentara Corporation, a statistical consultant of Forest Research Institute, Inc.
Drs. Michael Tocco and Stephen Graham are employed by Forest Research Institute.
Medical writing and editorial assistance was provided by Drs. Vojislav Pejovic and Michael L. Miller from Prescott Medical Communications Group, Chicago, IL