Francesco Brigo, Stanley C Igwe, Nicola Luigi Bragazzi

This is an updated version of the Cochrane review last published in 2015 (Issue 10). For nearly 30% of people with epilepsy, seizures are not controlled by current treatments. Stiripentol is a new 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, with promising effects. To evaluate the efficacy and tolerability of stiripentol as add-on treatment for people with focal refractory epilepsy who are taking AEDs. For the latest update, we searched the following databases on 21 August 2017: Cochrane Epilepsy Specialized Register, CENTRAL , MEDLINE, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). We contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials. Randomised, controlled, add-on trials of stiripentol in people with focal refractory epilepsy. Review authors independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life. On the basis of our selection criteria, we included no new studies in the present review. Only one study was included 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-quality evidence) nor evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43, low-quality 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-quality evidence). When specific adverse events were considered, confidence intervals were very wide and showed the possibility of substantial increases and small reductions in risks of neurological (RR 2.65, 95% CI 0.88 to 8.01, low-quality evidence) or gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36, low-quality evidence). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47, low-quality evidence), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group, low-quality 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. Since the last version of this review was published, we have found no new studies. 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 focal refractory epilepsy. Additional large, randomised, well-conducted trials are needed.