STICLO
Stiripentol in Severe Myoclonic Epilepsy in Infancy: A Randomised Placebo-Controlled Syndrome-Dedicated Trial
Clinical Question
Does adding stiripentol to valproate and clobazam reduce seizure frequency in children with severe myoclonic epilepsy in infancy (Dravet syndrome)?
Study Overview
Objective
To evaluate stiripentol added to valproate and clobazam for seizures in children with severe myoclonic epilepsy in infancy (SMEI/Dravet syndrome).
Study Summary
- Responder rate (>50% reduction in clonic/tonic-clonic seizures) was 71% (15/21) with stiripentol vs 5% (1/20) with placebo (95% CI of the difference 42.2-85.7)
- Nine of 21 stiripentol patients (43%) became free of clonic/tonic-clonic seizures vs 0/20 on placebo
- Percentage change in seizure frequency from baseline: -69% (stiripentol) vs +7% (placebo), p<0.0001
- All 21 stiripentol patients had moderate side effects (drowsiness, loss of appetite) vs 8/20 on placebo; side effects resolved in 12/21 when co-medication doses were decreased
Intervention
Stiripentol (50 mg/kg/day, added without titration) vs placebo, added to existing valproate + clobazam; N=41 (21 stiripentol, 20 placebo)
Patients per Arm
21 stiripentol vs 20 placebo (total N=41)
Bottom Line
In 41 children with SMEI (Dravet syndrome) inadequately controlled on valproate + clobazam, adding stiripentol produced a 71% (15/21) responder rate vs 5% (1/20) on placebo, and 9/21 (43%) became free of clonic/tonic-clonic seizures vs 0/20 on placebo. All 21 stiripentol patients experienced moderate side effects (drowsiness, loss of appetite), which resolved in 12/21 with co-medication dose reduction. The effect may be partly attributable to stiripentol's CYP450 inhibition increasing clobazam/valproate levels.
Major Points
- In 41 children with SMEI/Dravet syndrome already on valproate + clobazam, adding stiripentol produced a 71% (15/21) responder rate (>50% reduction in clonic/tonic-clonic seizures) vs 5% (1/20) on placebo.
- Nine of 21 stiripentol patients (43%) became free of clonic/tonic-clonic seizures during month 2 vs 0/20 on placebo.
- Percentage change in seizure frequency from baseline: -69% (stiripentol) vs +7% (placebo), p<0.0001.
- 95% CI of the responder-rate difference: 42.2-85.7% (stiripentol arm 52.1-90.7%; placebo arm 0-14.6%).
- All 21 stiripentol patients had moderate side effects (drowsiness, loss of appetite) vs 8/20 on placebo; side effects resolved in 12/21 when co-medication doses were reduced.
- Design: 1-month baseline + 2-month double-blind add-on + open-label extension; STICLO Study Group; published Lancet 2000.
- Stiripentol is a CYP450 inhibitor; observed benefit may be partly mediated by increased clobazam/valproate plasma levels rather than a purely direct antiseizure action.
Design
Study Type: Multicenter, randomised, double-blind, placebo-controlled, add-on trial
Randomization: 1
Blinding: Double-blind
Follow-up Duration: 1-month baseline + 2-month double-blind treatment + open-label extension
Centers: Multiple French pediatric neurology centers
Countries: France
Sample Size: 41 (21 stiripentol, 20 placebo)
Analysis: Primary responder analysis during month 2 of the double-blind period vs baseline
Inclusion Criteria
- Children with severe myoclonic epilepsy in infancy (SMEI/Dravet syndrome)
- Currently receiving valproate and clobazam
- Inadequately controlled clonic or tonic-clonic seizures
Exclusion Criteria
- Receiving medications other than valproate, clobazam, diazepam (rescue), or progabide
- Inability to comply with drug delivery schedule and seizure diary completion
- Non-Dravet etiology
Arms
| Field | Stiripentol + VPA + CLB | Control |
|---|---|---|
| Intervention | Stiripentol 50 mg/kg/day (max 3000 mg/day), added without titration to existing valproate and clobazam | Matching placebo added to same VPA + CLB regimen |
| Duration | 2 months double-blind + open-label extension | 2 months double-blind |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Responder rate (>50% reduction in clonic/tonic-clonic seizure frequency during month 2 vs baseline) | Primary | 5% (1/20) | 71% (15/21) | 66.4% | p<0.0001 (for -69% vs +7% percentage change from baseline) |
| Seizure-free (clonic/tonic-clonic) during month 2 | Result: 9/21 (43%) stiripentol vs 0/20 (0%) placebo | Secondary | 0% (0/20) | 43% (9/21) | ||
| Percentage change in seizure frequency from baseline | Result: -69% (stiripentol) vs +7% (placebo) | Secondary | +7% | -69% | p<0.0001 | |
| Moderate side effects (drowsiness, loss of appetite) | Adverse | 40% (8/20) | 100% (21/21) | ||
| Resolved with co-medication dose reduction | Adverse | 57% (12/21) |
Subgroup Analysis
Not reported in the abstract
Criticisms
- Small sample size (N=41) limits detection of rare adverse events
- Short double-blind phase of only 2 months
- Pharmacokinetic confounding: stiripentol is a potent CYP450 inhibitor increasing clobazam/N-desmethylclobazam and valproate plasma levels; observed effect may be partly due to increased co-medication exposure rather than a purely direct antiseizure action
- Industry-funded by Biocodex (stiripentol manufacturer)
- Single fixed stiripentol dose of 50 mg/kg/day (no dose-response analysis)
- All 21 stiripentol patients experienced moderate side effects
- Highly selected population: only children already on VPA + CLB with SMEI and inadequately controlled seizures
Funding
Biocodex (manufacturer of stiripentol/Diacomit) -- industry-sponsored
Based on: STICLO (The Lancet, 2000)
Authors: Chiron C, Marchand MC, Tran A, ..., Pons G; STICLO Study Group
Citation: Chiron C et al. Lancet. 2000;356(9242):1638-1642. DOI: 10.1016/S0140-6736(00)03157-3
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