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ARTICLES: M. J. Brodie, E. Perucca, P. Ryvlin, E. Ben-Menachem, H.-J Meencke for the Levetiracetam Monotherapy Study Group Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy Neurology 2007; 68: 402-408 [Abstract] [Full text] [PDF]

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Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy

Nitin K Sethi, Josh Torgovnick and Edward Arsura   (24 May 2007)

Reply from the authors

Martin J. Brodie, Emilio Perucca, Philippe Ryvlin, Elinor Ben-Menachem, Heinz-Joachim Meenche   (24 May 2007)

Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy 24 May 2007
Nitin K Sethi, NYP-Weill Cornell Medical Center, New York, NY Comprehensive Epilepsy Center 520 East 70th Street, New York, NY 10021, Josh Torgovnick and Edward Arsura Send Correspondence to journal: Re: Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy sethinitinmd{at}hotmail.com Nitin K Sethi, et al.	We read the Brodie et al article with interest. [1] The title and abstract suggest that the authors may provide physicians with new information in the treatment of newly diagnosed epilepsy. However, it seems likely that the study was designed to obtain approval for levetiracetam (Keppra) as initial monotherapy for epilepsy of focal onset. In the results, the proportion of patients reaching the primary end points was 73% in the levetiracetam group, much higher than the other reported groups cited in the methods section. This suggests that non-inferiority of levetiracetam as compared to carbamazepine was more easily demonstrated in the population studied by Brodie et al. Keppra was compared to carbamazepine CR (Tegretol CR) but no information is provided about therapeutic drug monitoring levels. The mechanism by which blinded encapsulation of the drugs under study was also undertaken by an interested party. In the New York area, Keppra has been aggressively marketed by industry-supported physician speakers touting the benefits of Keppra. Keppra has--in this area--gained widespread acceptance as a useful agent. The rapid change in physician prescribing habits has caused us to pause and reflect on the effect of marketing on this change. The fate of Felbatol, Tysabri, Vioxx and Ketek among other medications that have come to market and been promptly used causes us to be circumspect. We do not consider that disclosure implies the absence of bias, but rather should alert the reader to the potential for bias. Here this potential is considerable as it appears that UCB had a major role in the work. We are not convinced that these data demonstrate Keppra to be non-inferior to carbamazepine CR because the group studied was much easier to treat than previously reported groups and more importantly because we are not presented with all the data. We use Keppra and in certain circumstances off label as monotherapy. However, we do not believe that the current labeling should be changed based on the results presented in this article. References 1. Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy Neurology 2007;68:402-408. Disclosure: The authors report no conflicts of interest.
Reply from the authors 24 May 2007
Martin J. Brodie, Western Infirmary Glasgow, Scotland, G11 6NT, Emilio Perucca, Philippe Ryvlin, Elinor Ben-Menachem, Heinz-Joachim Meenche Send Correspondence to journal: Re: Reply from the authors Martin.J.Brodie{at}clinmed.gla.ac.uk Martin J. Brodie, et al.	Unlike previous regulatory trials, our study mimicked clinical practice in comparing levetiracetam with the standard of care (branded controlled-release carbamazepine, e.g. Tegretol CR, Novartis, not a generic) by matching the dose to individual needs and assessing seizure freedom over a relevant timescale. There is agreement between the American Academy of Neurology and American Epilepsy Society [2], the International League against Epilepsy (ILAE)[3] and the European Medicines Agency (EMEA) regarding the suitability of adequately powered active-control studies in assessing treatments for newly diagnosed epilepsy. Our inclusion criteria were similar to those of most monotherapy trials in newly diagnosed epilepsy. [3] Ours may have been more rigorous than others because we excluded patients with features suggestive of idiopathic generalized epilepsies. The results are consistent with studies using individualized doses in this population. [4]. Pre-treatment seizure frequency is a powerful predictor of recurrence. [4] Topiramate was approved as monotherapy in the U.S. based, in part, on a study in patients reporting 1 or 2 seizures only, resulting in 6-month seizure freedom rates of 83% at 400 mg/day and 71% at 50 mg/day. [5] The 6-month seizure freedom rate for carbamazepine in our study (67% in the ITT population) is consistent with that of 63% in a trial versus remacemide. [6] Plasma levels of both drugs were measured as an external measure of compliance, but results were not made available to investigators until unblinding. As most patients responded to the lowest dose, it is unlikely that making plasma levels available would have altered the outcome. All authors were involved in the design and conduct of the study whose protocol was based on extensive discussions with EMEA. The first author had access to the data and wrote the first draft of the manuscript, which was then finalized based on critical feedback by all co-authors. The sponsor was allowed to comment on the manuscript before submission, but the manuscript only reflects the intellectual contribution of its academic authors. All relevant data are disclosed. The study meets ILAE criteria for Class 1 evidence of efficacy and effectiveness [3] and resulted in EMEA granting a monotherapy license for levetiracetam in newly diagnosed epilepsy. References 2. French JA, Kanner AM, Bautista J et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004; 62:1252-1260. 3. Glauser T, Ben-Menachem E, Bourgeois B et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47:1094-1120. 4. Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol. 2006;13:277-282. 5. Arroyo S, Dodson WE, Privitera MD et al. Randomized dose-controlled study of topiramate as first line therapy in epilepsy. Acta Neurol Scand 2005;112:214-222. 6. Brodie MJ, Wroe SJ, Dean ADP et al. Efficacy and safety of remacemide versus carbamazepine in newly diagnosed epilepsy: comparison by sequential analysis. Epil Behav 2002;3:140-146. Disclosure: The study referred to in this correspondence was sponsored by UCB SA, who were involved in the design and conduct of the study; collection, management, and analysis of the data; and preparation and review of the manuscript. Drs. Brodie and Perucca have received grants from UCB Pharma exceeding $10,000. All authors have received honoraria from UCB SA.