Additional Results from Two Randomized, Placebo-Controlled Trials of Stiripentol in Dravet Syndrome Highlight a Rapid Antiseizure Efficacy with Longer Seizure-Free Periods

STICLO studies were conducted with similar protocols and performed at multiple centers in France from October 1996 to August 1998, and in Italy from April 1999 to October 2000. Inclusion of patients diagnosed as DS was made according to the clinical criteria established by Dravet [17], i.e., onset of epilepsy in the first year of life with generalized clonic (or tonic–clonic) seizures, normal psychomotor development and normal electroencephalogram (EEG) before seizure onset, and, after 1 year of age, occurrence of atypical absences and myoclonia, generalized spikes and waves on EEG, and slowing of psychomotor development. Patients were aged between 3 and 18 years and had to have experienced at least four GTCS a month despite optimized therapy with valproate and clobazam. Patients receiving other drugs (except diazepam as a rescue medication and progabide), and those whose parents were unable to comply regularly with drug delivery and daily seizure diary, were excluded. According to local regulations, the design and conduct of the STICLO studies were approved by the Ethics Committee of the coordinating center in France, and by the Ethics Committees of each center in Italy. Written informed consent was obtained from the parents or guardian of all patients. Both studies were performed in accordance with the Helsinki Declaration of 1964 and its later amendments, Good Clinical Practices, and according to the local regulatory requirements.

After a 1-month baseline period, patients who continued to have at least 4 GTCS per month were randomly assigned to receive placebo or stiripentol at the dose of 50 mg/kg/day (maximum dose of 3000 mg/day) with no titration. Study treatment was given twice or three times daily, added on to valproate and clobazam during the 2-month double-blind period. To minimize adverse effects, the maximum dose of valproate was limited to 30 mg/kg/day and that of clobazam to 0.5 mg/kg/day. Doses could be decreased by 10 mg/kg/day for valproate in cases of loss of appetite and by 25% for clobazam in cases of drowsiness or hyperexcitability.

After the 2-month double-blind period, patients were allowed to enter an additional 1-month open-label extension period where they all received STP, with the blind maintained on treatment previously received (Figure S1). Patients who benefited from stiripentol treatment were then allowed to enter an open-label observational long-term follow-up study, followed by a temporary authorization for stiripentol use.

In both studies, response to treatment was defined by the reduction in the number of convulsive seizures compared to baseline. Response rate was calculated based on the decrease in monthly GTCS frequency, and it was considered as clinically meaningful (≥ 50% reduction), profound (≥ 75% reduction), or as seizure freedom (= 100% reduction).

Study investigators reported seizure frequency monthly by using the diary completed by parents and caregivers. In the present analysis, data from the diaries were entered for the first time and the seizure occurrence was captured daily, allowing the evaluation of additional parameters, such as the total number of seizure-free days and the longest period of consecutive days free of seizures. All types of seizures were reported in the diaries, but only GTCS were taken into account for the assessment of treatment efficacy, since these are the most disabling seizure types, are observed in all patients, and are easily identified. Conversely, counting other types of seizures, such as absence seizures or myoclonus, is less reliable and difficult to obtain.

At the end of the OLE period, investigators completed a specific follow-up form where they reported information regarding STP dosage, seizure frequency, and adverse events, if any. When available, data from the follow-up forms were captured for the present analysis.

Baseline characteristics and seizure frequency were reported by treatment groups with numbers and proportions for categorical variables, as well as mean standard deviation and the range of values for continuous variables. Seizure frequencies were adjusted for 30-day period to compare the corresponding frequencies. Percentage changes in seizure frequency was also represented on an individual basis by a waterfall chart, where patients were ordered by the magnitude of the change between baseline and 1st month under treatment, 2nd month under treatment, or OLE period.

Responder rates were reported by treatment group at 1-month, 2-month, and 3-month OLE. Considering the small sample sizes, confidence intervals at 95% (CI95%) were computed by the Wilson method with continuity correction [18]. In addition, the mean percentage change and CI95% from baseline in seizure frequency, and the cumulative proportion of responders as a function of the percentage reduction in the number of seizures, were shown graphically for each treatment group. A Sankey diagram was also used to describe and analyze longitudinal patient data during treatment period and OLE period.

Regarding patients’ diaries, the total number of seizure-free days was calculated and was adjusted for a 60-day period to make the 2-month double-blind period comparable between patients. Three patients with missing data from diaries during the 2-month treatment period were excluded. The longest period of consecutive seizure-free days during the double-blind period was also determined. A conservative approach was used as patients with missing diaries were not excluded and the interval was stopped if data were missing.

Moreover, a time-to-onset analysis was conducted using negative binomial regressions to model the cumulative number of seizures by treatment group during the follow-up from day 1 to day 30. Models were estimated to test the hypothesis that mean cumulative number of seizures is not different between the placebo and the STP group. At day n, the cumulative number of seizures from day 1 to day n during the treatment period were modeled by an intercept, the treatment group effect, and adjusted on the corresponding cumulative number of seizures from day 1 to day n during the baseline period. Logarithm of the period (n days) was added as an offset term. Least squares (LS) mean number of seizures count for STP and placebo groups were reported for each day n and ratios of LS means were tested to see if they were significantly different from 1. LS means and CI95% were reported graphically for each day and treatment group.

Detailed efficacy outcomes of the individual STICLO France and STICLO Italy studies are reported in Table 1. Both studies found similar results that clearly demonstrated STP efficacy. In STICLO France, the reduction in seizure frequency was greater on STP than on placebo (− 62% and + 12%, respectively; P < 0.0001), with significantly more patients having a clinically meaningful response (≥ 50% reduction in seizure frequency) (71% vs. 5%; P < 0.0001). Also, 9 patients were free of GTCS in the STP group but none in the placebo (P = 0.0013). The results of STICLO Italy were similar, with greater reduction in seizures (− 74% vs. − 13%; P = 0.0018) and more responders at 50% (67% vs. 9%; P = 0.0094). Three patients were free of GTCS in the STP group but none in the placebo.

In both studies, adverse events were more frequent in the STP group, and mainly involved the nervous system, such as drowsiness, hyperexcitability, and agitation, or the gastro-intestinal system, such as loss of appetite, weight loss, or weight gain.

Statistical tests performed on the demographic and primary endpoints of STICLO France (n = 41) and STICLO Italy (n = 23) studies confirmed data poolability. This resulted in a total of 64 patients with available data, and additional information from the open label period was available for 44 patients (69%).

At baseline, the placebo and STP groups were similar for demographic characteristics, medical history, and mean doses of concomitant antiseizure medications (Table 2). Mean number of generalized tonic–clonic or clonic seizures was high in both groups (21.7 ± 21.8 in the placebo group and 23.6 ± 22.8 in the STP group) despite optimized therapy with valproate and clobazam.

At the end of the first month of the double-blind treatment period, a marked and significant efficacy of STP was observed over placebo. Mean percent change in seizure frequency from baseline was − 85% in the STP group versus + 10% in the placebo group (P < 0.001) (Table 3). The proportions of patients who experienced a meaningful (≥ 50% reduction), profound (≥ 75% reduction), or seizure freedom (= 100% reduction) were 91%, 79%, and 48%, respectively in the STP group compared to 13%, 3%, and 0% in the placebo group (P < 0.001 in each case) (Table 3; Fig. 1). On an individual basis, during this first month, all patients from the STP group experienced a decrease in seizure frequency compared to baseline, while, in the placebo group, only 15 out of 31 patients had a lower frequency compared to baseline (Figure S2). Regarding time-to-onset of efficacy, a significant and maintained difference was demonstrated between the groups from day 4 onwards (P = 0.018) (Fig. 2).

At the end of the 2-month double-blind treatment period, mean percent change in seizure frequency from baseline was − 66% in the STP group versus + 4% in the placebo group (P < 0.001) (Table 3). In accordance with recommendations [19], the primary efficacy endpoint of the STICLO trials was the responder rate, defined as a ≥ 50% decrease in convulsive seizures. Stiripentol demonstrated a clear superiority over placebo as 72% of the patients were responder in the STP group versus 7% in the placebo group (P < 0.001) (Table 3; Fig. 1). When considering patients with a profound (≥ 75%) decrease in convulsive seizures, STP was again highly superior to placebo with 56% of the patients on STP responders versus 3% in the placebo group (p < 0.001). After 2 months of treatment, 38% of the patients on STP were free of GTCS, but none in the placebo group (P < 0.001) (Table 3; Fig. 1). On an individual basis, during the second month only 3 patients on STP had a higher seizure frequency compared to baseline, while, in the placebo group, similarly to the first month period, only 50% of the patients had a decreased seizure frequency compared to baseline (Figure S2).

Further to the switch to the OLE period, efficacy was maintained in patients from the STP group during the extra third month of treatment. Mean percent change in seizure frequency from baseline was − 62.3%, similar to the 66% decrease observed at the end of the double-blind treatment period (Table 3). Conversely, a dramatic decrease in seizure frequency was observed in patients previously receiving placebo (Fig. 3), with a mean percent change in seizure frequency from baseline of − 80.2% (Table 3). At the end of the OLE, no difference was found between the two treatment groups, neither regarding the mean percent change in seizure frequency from baseline (P = 0.5) nor in the responder rates (P = 0.45, P = 0.531, and P = 1 for ≥ 50%, ≥ 75%, and = 100% decrease in seizure frequency, respectively) (Table 3; Figs. 1,3). On an individual basis, all patients who switched from placebo to STP during the OLE had a decrease in seizure frequency, while only 3 patients who continued STP had a higher seizure frequency compared to baseline, similarly to the end of the second month treatment period (Figure S2).

The longitudinal individual treatment response over time visualized on a Sankey diagram confirmed STP efficacy and the maintenance of the effect over the 3-month period (Figure S3). In the STP group, 64% of the patients who were seizure-free at the end of the double-blind period remained so during the OLE. While some patients who were responders at month 1 and/or month 2 became non-responders during the OLE, 5 patients who were not responders at month 2 became responders during the OLE. Notably, 2 had a ≥ 50% decrease in seizure frequency compared to baseline, 1 had a ≥ 75% decrease, and 2 were seizure-free.

New data based on diaries were collected for 52 patients (81%), and the number of seizure-free days/60-day period and the longest period of consecutive days free of seizures during the double-blind treatment period were reported in the treatment group (Table 4; Fig. 4). There was a median number of 55.8 seizure-free days/60-day period in the STP group compared to 40.9 in the placebo group (P < 0.001) (Table 4). The median longest period of consecutive seizure-free days was 32 days in the STP group and 8.5 days in the placebo group (P < 0.001) (Fig. 4).

Adverse events were more frequent in the STP group (100% of patients presented at least one) than in the placebo group (45%). The most common adverse events across STICLO trials are presented in Table 5. Overall, the incidence of somnolence, anorexia, and weight decrease was significantly higher in STP than in the placebo group. Also, during the double-blind period, serious adverse events were reported in 2 patients in the STP group: one patient experienced an episode of SE, while an episode of giant urticaria (allergic dermatitis) was reported in a second patient, for whom treatment was suspended and then resumed uneventfully. In the placebo group serious adverse events were reported in 3 patients, consisting of somnolence and motor dysfunction involving the right half of the body, SE, and repeated seizures.