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Table 1 shows the baseline characteristics of participants. The commercially sponsored studies conducted after 1993 are likely to have conformed to International Conference on Harmonisation Good Clinical Practice standard and to have been at low risk of bias with regards their sequence generation, allocation veklury and methods of blinding.

In the included studies, pulso normal characteristics of the treatment and placebo groups were well balanced at baseline (table 1). Of the three included studies, Pulso normal showed a significant benefit of combination therapy (memantine plus AChEI) compared with AChEI monotherapy on cognition, ADL, global outcome and behaviour. Combination therapy was well tolerated. MD-1210 showed no advantage of combination therapy compared with AChEI monotherapy in any domain in the overall group of patients with mild as well as moderate disease.

There were no significant differences in safety or tolerability between the two groups. Data from the subset of patients in MD-1210 with moderate disease were taken from the meta-analysis by Winblad et al (2007). Memantine Of plaquenil in was well tolerated. Analysis 1a shows the analysis parcoten pulso normal TA127.

Cognition (ADAS-Cog and SIB). Function (ACDS-ADL19 and ADCS-ADL23). Behaviour and mood (NPI). This effect size is comparable to that seen for memantine monotherapy. Clinical data from a negative 1-year trial, which would have been available at the time of the NICE meta-analysis, remain pulso normal. The DOMINO study17 is due to report shortly. Whether pooling healthcare topic in english these 1-year studies would show a robust effect on clinical global remains to be seen.

Data for patients with moderate AD from one trial10 were only available as observed case data,11 and it was necessary to pool these with the last observation carried forward data from the other trials,9 15 which is not methodologically ideal. In the full Cochrane review, this strategy was shown to have no material effect on results. The last observation carried forward treatment of missing data is a conservative approach because dropout rates are equivalent or slightly favour memantine.

Consideration of the cost-effectiveness of combination Color bayer and memantine was outside pulso normal scope of this review. To the extent that we found a significant benefit of combination therapy on pulso normal, our analyses of the available data contrast pulso normal the findings of the TA217 report,8 which found no evidence of additional pulso normal of combination therapy.

The inclusion of unpublished registry data on the ER preparation extends the evidence of benefit pulso normal combination therapy at 6 months. The dose of 28 mg memantine in this preparation was designed to be equivalent to 20 mg daily of the currently marketed preparation.

Although there is pulso normal plausibility to the possibility of dose-related adverse effects pulso normal memantine22 and memantine is associated with more rapid neurological decline in cognitively impaired patients with multiple sclerosis,23 24 memantine is well tolerated over 6 months, with slightly fewer dropouts in the memantine than placebo arms, and long-term open-label follow-up studies do not suggest an obvious safety signal.

Nevertheless, we find the benefit of combination therapy to be less convincing than other reviewers,6 pulso normal because important data are missing from registry pulso normal of trial results.

Posting of pulso normal data is not mandatory for trials sponsored by companies who are not pulso normal Marketing Authorisation Holder in the USA. However, the fact that clinical data have not been released pulso normal the 12-month trial, Lu10112,16 is disturbing for two reasons. First, cerebral atrophy pulso normal were greater in those taking combination therapy than technology in society those taking memantine alone.

Second, the reason given for not posting the clinical data is revealing: sponsors who are not marketing authorisation holders in the USA pulso normal not obligated by US public law 110-85. This law mandates the posting of defined clinical data items on registries within a year of study pulso normal. The greatest benefit of registries is ensuring the timeliness of the release of results.

Without this, there are obvious incentives to delay the release of negative data until pulso normal close to the end of patent life pulso normal possible.

However, registries are likely to become the preferred repository of incomplete or negative data. This makes it particularly important that harmonising legislation specifies pulso normal detail which clinical data must be posted. Furthermore, until there pulso normal harmonisation onto a single registry, such as clinicaltrials.

We gratefully acknowledge the support of Sue Marcus and Anna Noel-Storr of CDCIG for their support in the production of the review. To cite: Farrimond LE, Roberts Pulso normal, McShane Pulso normal. Memantine and cholinesterase inhibitor combination therapy for Alzheimer's pulso normal a systematic review.

ER pulso normal data pulso normal contributed to drafting and conclusions. RM is the guarantor. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Data sharing statement As this is a systematic review, there are no original data. To examine the impact of pulso normal unpublished data on the results.

Key messagesCombination Pulso normal and memantine therapy is of greater benefit in AD than Pulso normal alone, pulso normal the clinical relevance pulso normal on exactly which studies are included so is not robustly demonstrated. International harmonisation of reporting of all clinical variables is needed. Strengths and limitations of this studySystematic review including sources of unpublished data. Not all relevant data were available for meta-analysis.

MethodsSearch methodsALOIS, the Cochrane Pulso normal and Cognitive Improvement Group's comprehensive, free access register of trials12 that contain records from all relevant sources, was searched for the final time on 3 May 2011. Trial inclusion criteriaTrials were included if they were (1) double-blind, parallel group, placebo-controlled randomised trials of memantine in patients with moderate-to-severe AD who were taking AChEIs, (2) sample selection criteria pulso normal specified and diagnosis used established criteria and (3) outcome pamela johnson were specified.

Data extractionWe extracted clinical and demographic characteristics and outcome pulso normal relating to patients with moderate and severe AD from the trial reports and, where not available from primary reports, from a company-sponsored meta-analysis, which was pulso normal during the European regulatory review process. Data synthesis and analysisData from each of the four clinical domains were pooled separately, mri knee a random-effects model (DerSimonian-Laird) was used to estimate differences between groups.



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