Original article
Levetiracetam vs. sulthiame in benign epilepsy with centrotemporal spikes in childhood: A double-blinded, randomized, controlled trial (German HEAD Study)

https://doi.org/10.1016/j.ejpn.2013.03.014Get rights and content

Abstract

Objective

To show non-inferiority of levetiracetam to sulthiame with respect to efficacy, tolerability and safety in benign epilepsy with centrotemporal spikes in a prospective, double-blinded randomized controlled trial.

Methods

A sample size of 60 subjects (treatment group) was calculated to show reliable statistical results for non-inferiority. A total of 44 patients could be randomly allocated to either (LEV or STM) treatment group. Explorative data analysis was performed to investigate differences in the number of treatment failure events (occurrence of a seizure during the observation period of 6 months) and total dropouts. In addition, information of the occurrence of adverse events was collected.

Results

43 patients were analyzed. One patient had to be excluded due to protocol violation. Treatment failure events occurred in four patients (19.0%) in the LEV treatment group and in two patients (9.1%) in the STM treatment group, respectively, (p = 0.412). The number of dropouts due to adverse reactions was five in the LEV treatment group and one in STM treatment group (23.8% vs. 4.5%, respectively, p = 0.095). Severe adverse events occurred in patients treated with LEV (n = 2, 9.5%). The total number of dropouts due to either seizure recurrence or adverse events was significantly higher in the LEV group (n = 9, 42.9%) compared to the STM group (n = 3, 13.6%, p = 0.03).

Interpretation

The study results concerning non-inferiority were not conclusive, as the calculated sample size was not reached to support sufficient statistical power due to limited recruitment in a 26 months period. The rates of seizure free patients were [relatively] high in both groups. However, the results indicate that termination of drug treatment due to seizure recurrence or adverse events occurred more frequently in the LEV group compared to STM. Behavioral disturbances were the most common adverse event causing study termination.

Introduction

Benign epilepsy with centrotemporal spikes is the most common partial epilepsy in childhood accounting for 15–20% of all cases of epilepsy in this age group.1 It has been placed recently within epilepsy syndromes of unknown etiology of the latest ILAE classification of epileptic syndromes.2 The most characteristic seizure types are unilateral sensorimotor seizures of the oropharynx most commonly occurring during sleep. Generalized tonic-clonic seizures occur in up to 44% of cases.3 The typical EEG pattern consists of sharp waves occurring mainly over the centrotemporal region with marked increase in frequency during light sleep with genetic linkage to chromosome 15q14.4, 5 BECTS is commonly classified as a benign condition with complete remission of seizures in adolescents in the vast majority of cases. However, neuropsychological dysfunction and behavioral abnormalities are encountered in a considerable number of patients.6, 7 Controversy exists about whether or not and when to start antiepileptic drug therapy in patients with BECTS.1, 8 In addition, there are considerable geographic differences regarding which specific AED is used. While sulthiame appears to be the most commonly drug used in some Middle-European countries as Germany and Austria,9 valproic acid was defined more appropriate in others10 and carbamazepine/oxcarbazepine are the drugs of choice in the US followed by gabapentin, lamotrigine and levetiracetam.11

Sulthiame has been shown to reduce both seizure frequency and the number of interictal epileptic discharges in the EEG in a randomized placebo-controlled trial.12, 13 Recently, concerns have been raised about sulthiame impairing cognitive functions in patients with BECTS though the study population was low.14 Levetiracetam has not yet been investigated in randomized controlled trials on patients with BECTS, though data have shown efficacy and tolerability in both partial and generalized epilepsies in childhood.15, 16

The aim of the present study was to investigate efficacy, tolerability and safety of levetiracetam and sulthiame in a double-blinded, randomized head-to-head approach in patients with BECTS.

Section snippets

Study design and study population

This randomized, double-blinded, controlled trial was conducted over a period of 26 months between July 2006 (first patient in) and September 2008 (last patient out) involving 47 German centers (EudraCT No. 2005-004468-22). This study was initially planned as a non-inferiority trial of LEV compared to STM. The study was performed in accordance with the Declaration of Helsinki and its recent amendments. The ethical review boards of each study center approved the study design. All patients and/or

Patient recruitment

A total of 83 patients were screened for eligibility to enter the study. 44 patients were finally recruited within a recruitment period of 18 months between July 2006 and February 2008. The remaining subjects (n = 39) screened did not enter the study for the following reasons: parents refused consent to participate (n = 17, 43.6%), patients did not meet the inclusion criteria (n = 12, 30.8%), other reasons (n = 10, 25.6%, Fig. 2). There were no differences in the recruitment rates between

Discussion

In this randomized-controlled trial the efficacy of levetiracetam and sulthiame in patients with benign epilepsy with centrotemporal spikes was compared. The primary goal was analysis for non-inferiority of LEV treatment in BECTS compared to STM. However, the number of patients included in the study was too low to allow for such analysis. Given the small number of patients, efficacy of LEV and STM to avoid seizures within the observational period of 24 weeks did not differ significantly.

Disclosure related to contents of this article

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with these guidelines.

I.B. received speaker fees from UCB Pharma, Eisai, Novartis and Desitin.

M. B. received travel imbursement from UCB Pharma.

T. B. received fees for presentations and participations on advisory boards from UCB Pharma, Eisai and Desitin.

B.-A. N. received fees for presentations and advisory board meetings from UCB Pharma, Eisai and Desitin

K.-J.

Funding

UCB Pharma SA, Brussels, Belgium, funded partly this study.

Acknowledgments

We thank the members of the advisory board of the study CE Elger (Bonn, Germany), UH Mansmann (Munich, Germany) and BJ Steinhoff (Kehl-Kork, Germany). We thank Dr. Jan Rémi (Department of Neurology, University of Munich) for carefully reviewing the manuscript.

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    h

    The members of the German HEAD Study Group are listed in Appendix section.

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