A multicenter, outpatient, open-label study to evaluate the dosing, effectiveness, and safety of topiramate as monotherapy in the treatment of epilepsy in clinical practice

David Geffen School of Medicine, Mattel Children's Hospital at UCLA, University of California-Los Angeles, Los Angeles, CA 90095-1752, USA.
Epilepsy & Behavior (Impact Factor: 2.26). 08/2009; 15(4):506-12. DOI: 10.1016/j.yebeh.2009.06.021
Source: PubMed


This 24-week, multicenter, open-label trial was designed to evaluate the dosing, effectiveness, and safety of topiramate monotherapy for epilepsy and to identify patient and clinical characteristics predictive of optimally effective stabilized monotherapy doses. Of 406 randomized patients, 244 comprised the evaluable-for-efficacy population (12 weeks of treatment and stabilized topiramate dose during final 28 days); 213 were on topiramate monotherapy at the end of the trial. The mean stabilized daily dose of topiramate over the last 28 days of treatment (primary endpoint) was significantly lower for patients reporting one to three seizures (low seizure frequency, n=147) than for those reporting more than three seizures (high seizure frequency, n=66) during a 3-month retrospective baseline period (191 mg vs 239 mg, P=0.003). Patients in the low-seizure-frequency group reached a stable topiramate dose after a median of 36 days, compared with 53 days for patients in the high-seizure-frequency group. Linear and stepwise regression analyses showed baseline seizure frequency and lifetime seizure count to be significant (P<0.05) predictors of the stabilized dosage. Most treatment-emergent adverse events (TEAEs) were mild to moderate; those occurring with cumulative incidence rates >10% in either seizure frequency group were paresthesia, fatigue, anorexia, dizziness, somnolence, headache, and hypoesthesia; 18.2% of patients discontinued topiramate because of a TEAE, 5.1% reported serious TEAEs, and no deaths were reported during the study.

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    • "The most important reasons that the other 22 studies did not meet our inclusion criteria were that they did not report data on children separately (n = 11) (Chadwick et al., 1998; Schachter et al., 1999; Ingwersen et al., 2000; Beydoun et al., 2000; Sachdeo et al., 2001; Biton et al., 2001; Beydoun et al., 2003; Biton et al., 2003; Privitera et al., 2003; Gilliam et al., 2003; Arroyo et al., 2005) or they concerned add-on treatment instead of monotherapy (n = 6) (Duchowny et al., 1999; Siegel et al., 1999; Lindberger et al., 2000; Glauser et al., 2000; Sethi et al., 2002; Noachtar et al., 2008). The remaining studies were not included because the second-generation AED was not compared with another AED (n = 3) (Glauser et al., 2007; Verrotti et al., 2008; Sankar et al., 2009), it did not include children at all (n = 1) (Aikia et al., 2006), the primary endpoint was the effect on cognitive function (n = 1) (Kang et al., 2007), it was written in Chinese (n = 1) (Huang et al., 2009), or it concerned a review (n = 1) (Jensen, 1993). One additional study was included that was only published as an abstract (Bourgeois et al., 1998). "
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    ABSTRACT: Few randomised controlled trials (RCTs) have been performed in which a second-generation antiepileptic drug (AED) used as monotherapy was compared with placebo or another AED in children (<18 years of age) with epilepsy. We describe the results of the available studies, assess the validity of these results, and give recommendations for optimal study design for AED monotherapy studies in children with epilepsy. Studies were identified using PubMed (Medline), Embase and the Cochrane Library (January 1990-January 2010). All reports were assessed for methodological quality and results were summarised descriptively. Nine RCTs were included. No difference in efficacy and safety between second-generation AEDs and first-generation AEDs in children was detected. Considerable heterogeneity in study design, inclusion criteria and primary endpoints impaired formal meta-analysis and correct interpretation of results. Follow-up periods were between 2 and 104 weeks; the dosage of the tested AEDs varied between studies, with sometimes use of apparent subtherapeutic dosages; in only two studies the method of randomisation was well described, in only three the power calculations; several studies did not use an intention-to-treat analysis. Although from the available studies first- and second-generation AEDs appear to have similar efficacy and safety in children with epilepsy, these trials are inadequate to provide a sufficient evidence base for decision making. Better trials are needed: AEDs should be studied in optimal paediatric doses, power should be sufficient to detect small but clinically relevant differences, and the follow-up period should be long enough. Most important, primary endpoint to be evaluated should be time to treatment failure or retention rate, since these outcomes combine efficacy and safety.
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