Abstract
Background
There is a need to expand monotherapy options available to a clinician for the treatment of new partial-onset or generalized-onset seizures. A Cochrane systematic review for clobazam monotherapy is expected to define its place in the treatment of new-onset or untreated seizures and highlight gaps in evidence.
Objectives
To evaluate the efficacy, effectiveness, tolerability and safety of clobazam as monotherapy in people with new-onset partial or generalized seizures.
Search methods
We searched the following databases: Cochrane Epilepsy Group Specialized Register (5 March 2013), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, January 2013, Issue 1), MEDLINE (Ovid, 1946 to July 1, 2014), Database of Abstracts of Reviews of Effectiveness (DARE, January 2013, Issue 1), BIOSIS Previews (all years, searched on 5 March 2013). There were no language restrictions.
Selection criteria
Randomized or quasi-randomised controlled trials comparing clobazam monotherapy versus placebo or other anti-seizure medication in people with two or more unprovoked seizures or single acute symptomatic seizure requiring short-term continuous anti-seizure medication, were eligible for inclusion.
Data collection and analysis
Primary outcome measure was time on allocated treatment (retention time), reflecting both efficacy and tolerability. Secondary outcomes included short- and long-term effectiveness measures, tolerability, quality of life, and tolerance measures. Two authors independently extracted the data.
Main results
We identified two trials fulfilling the review criteria, which included 163 participants. None of the identified studies reported the preselected primary outcome measure. A meta-analysis was not possible. Lack of detail regarding concealment of allocation and a high risk of performance and detection bias in one study prompted us to downgrade the quality of evidence for some of our results due to risk of bias.
Regarding retention at 12 months, we detected no evidence of a statistically significant difference between clobazam and carbamazepine (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.61 to 1.12); low quality evidence. There was low quality evidence that clobazam led to better retention compared with phenytoin (RR 1.43, 95% CI 1.08 to 1.90). We could not determine whether participants receiving clobazam were found to be less likely to discontinue it due to adverse effects as compared to phenytoin (RR 0.10, 95% CI 0.01 to 1.65, low quality evidence).
Authors’ conclusions
We found no advantage for clobazam over carbamazepine for retention at 12 months in drug-naïve children and a slight advantage of clobazam over phenytoin for retention at six months in adolescents and adults with neurocysticercosis in a single clinical trial each. At present, the available evidence is insufficient to inform clinical practice.
Plain language summary
Clobazam monotherapy for partial onset and generalized onset seizures
Review question: This review appraises the evidence for clobazam monotherapy for the treatment of new-onset or untreated partial-onset or generalized-onset seizures.
Background: Epilepsy is one of the most common diseases of the brain. It is characterized by an abnormal propensity for the brain to have seizures, which are discrete episodes of abnormal neuronal electrical activity. This abnormal electrical activity may arise from a particular part (partial-onset seizures) or whole of the brain at once (generalized-onset seizures). In this review we assessed clobazam as monotherapy for new-onset or untreated seizures, partial or generalised onset seizures.
Study characteristics: Our searches (run on 1 July 2014) identified two studies (Canadian Study Group 1998 and Kaushal 2006) of moderate quality comparing clobazam with other anti-seizure medications (carbamazepine and phenytoin) for monotherapy of partial-onset or generalized-onset seizures. The Canadian Study Group 1998 is a multi-center study which compared the effectiveness of clobazam and carbamazepine monotherapy in 115 children with untreated epilepsy and Kaushal 2006 is a single-center study comparing clobazam with phenytoin in 48 adolescents and adults with solitary neurocysticercus granuloma. In clinical trials with anti-seizure medications, effectiveness is conventionally measured by the time a person remains on allocated treatment. This reflects the notion that the person will stop taking medicine either if it is not working or if there are unacceptable adverse effects.
Key results: We did not find any significant advantage for clobazam over carbamazepine in people with previously untreated partial-onset or generalized-onset seizure for retention at 12 months. Our analysis showed a slight advantage of clobazam over phenytoin for retention at six months for adolescents and adults in one study. It should be mentioned that this study was limited to participants with seizures due to a particular infection of the brain called neurocysticercosis.
Neither study measured the amount of time that participants remained on allocated treatment (retention time), quality of life or seizures. We did assess data from the studies regarding the number of participants who remained on treatment at specific timepoints. However, we were unable to determine whether people with previously untreated partial-onset or generalized-onset seizure receiving clobazam were more likely to remain on treatment at 12 months than those given carbamazepine due to low numbers of participants in the study. Our analysis showed a slight advantage of clobazam over phenytoin for retention at six months in adolescents and adults in one study limited to participants with seizures due to neurocysticercosis. Because of the low number of participants we could not be certain that people receiving clobazam were less likely to discontinue treatment due to adverse effects when compared with those given phenytoin.
Quality of evidence: At present, there is insufficient evidence to inform clinical practice regarding clobazam monotherapy in partial-onset or generalized-onset seizures. The quality of evidence for the outcomes we were able to include was affected by problems with the design of the included studies and the low number of participants overall. There is a definite need for well-designed, adequately powered, randomized controlled trials of clobazam for monotherapy of new-onset or untreated seizures.
