Stiripentol as an add-on treatment for drug-resistant focal epilepsy

Background

Epilepsy is one of the more common chronic neurological disorders; it affects 1% of the population worldwide. A large proportion of these people (up to 30%) continue to have seizures despite adequate therapy with antiepileptic drugs (AEDs), used singularly (as monotherapy) or in combination (polytherapy). These individuals are regarded as having drug-resistant epilepsy. Stiripentol is an AED that was developed in France and was approved in 2007 by the European Medicines Agency (EMA) as add-on therapy with valproate and clobazam for the treatment of Dravet syndrome (a rare, drug-resistant epilepsy that begins in the first year of life in an otherwise healthy infant). This review appraises evidence for the use of stiripentol as add-on treatment for drug-resistant focal epilepsy in individuals taking AEDs.

Results

On the basis of our review criteria, we included only one study in the review (32 children with focal epilepsy). This study adopted a responder-enriched design and found no clear evidence of seizure reduction (≥ 50%) nor of seizure freedom with add-on stiripentol compared with placebo. Add-on stiripentol led to greater risk of adverse effects considered as a whole (risk ratio (RR) 2.65, 95% confidence interval (CI) 1.08 to 6.47) compared with placebo. Generalisation of study results to a more widespread population is limited by the fact that only responders to stiripentol (i.e. patients experiencing a decrease in seizure frequency of at least 50% compared with baseline) were included in the randomised, add-on, placebo-controlled, double-blind portion of the study. Also, the very small sample size with the correspondingly high dropout rate prevents generalisation of study results. Finally, because of the adopted design, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency.

Certainty of the evidence

We judged the included study to be at low to unclear risk of bias. Using GRADE methodology, we rated the certainty of the evidence as low.

Currently, no available evidence supports the use of stiripentol as add-on treatment for drug-resistant focal epilepsy. Large, randomised, well-conducted trials on this topic are needed.

The evidence is current to February 2020.

Authors' conclusions: 

We have found no new studies since the last version of this review was published. Hence, we have made no changes to the conclusions of this update as presented in the initial review. We can draw no conclusions to support the use of stiripentol as add-on treatment for drug-resistant focal epilepsy. Additional large, randomised, well-conducted trials are needed.

Read the full abstract...
Background: 

This is an updated version of the Cochrane Review first published in 2014, and last updated in 2018.

For nearly 30% of people with epilepsy, seizures are not controlled by current treatments. Stiripentol is an antiepileptic drug (AED) that was developed in France and was approved by the European Medicines Agency (EMA) in 2007 for the treatment of Dravet syndrome as an adjunctive therapy with valproate and clobazam.

Objectives: 

To evaluate the efficacy and tolerability of stiripentol as add-on treatment for people with drug-resistant focal epilepsy who are taking AEDs.

Search strategy: 

For the latest update, we searched the following databases on 27 February 2020: Cochrane Register of Studies (CRS Web); and MEDLINE (Ovid, 1946 to 26 February 2020). CRS Web includes randomised or quasi-randomised controlled trials from the Specialized Registers of Cochrane Review Groups including Epilepsy, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials.

Selection criteria: 

Randomised, controlled, add-on trials of stiripentol in people with drug-resistant focal epilepsy.

Data collection and analysis: 

Review authors independently selected trials for inclusion and extracted data. We investigated outcomes including 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life.

Main results: 

On the basis of our selection criteria, we included no new studies in the present review update. We included only one study from the earlier review (32 children with focal epilepsy). This study adopted a responder-enriched design and found no clear evidence of a reduction in seizure frequency (≥ 50% seizure reduction) (risk ratio (RR) 1.51, 95% confidence interval (CI) 0.81 to 2.82; low-certainty evidence) or evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43; low-certainty evidence) when add-on stiripentol was compared with placebo.

Stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47; low-certainty evidence). When we considered specific adverse events, confidence intervals were very wide and showed the possibility of substantial increases and small reductions in risks of neurological adverse effects (RR 2.65, 95% CI 0.88 to 8.01; low-certainty evidence) and gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36; low-certainty evidence). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47; low-certainty evidence), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group; low-certainty evidence).

The external validity of this study was limited because only responders to stiripentol (i.e. patients experiencing a ≥ 50% decrease in seizure frequency compared with baseline) were included in the randomised, add-on, placebo-controlled, double-blind phase. Furthermore, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency. Very limited information derived from the only included study shows that adverse effects considered as a whole seemed to occur significantly more often with add-on stiripentol than with add-on placebo.

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