STICLO
(2000)Objective
To evaluate stiripentol as add-on therapy to valproate and clobazam for seizure reduction in Dravet syndrome
Study Summary
• Very high AE rate: somnolence 67-90%, decreased appetite 33-46%, weight loss 27-29%; efficacy may be partly due to CYP450 inhibition increasing clobazam/VPA levels rather than direct antiseizure effect
Intervention
Stiripentol 50 mg/kg/day (max 3000 mg) added to valproate + clobazam vs placebo add-on
Inclusion Criteria
Age 3-18, Dravet syndrome (SMEI), currently on valproate + clobazam, >=4 GTCS/month despite optimized therapy
Study Design
Arms: Stiripentol + VPA + CLB vs Placebo + VPA + CLB
Patients per Arm: STICLO France: Stiripentol 21, Placebo 20; Pooled: Stiripentol 33, Placebo 31
Outcome
• Seizure-free: 42.9% vs 0% (France); mean change: -69% vs +7.6% (p=0.0002)
• Rapid onset from day 4 (p=0.018); seizure-free days: 55.8 vs 40.9 (p<0.001)
• AEs (pooled): somnolence 67% vs 23%, decreased appetite 46% vs 10%, weight loss 27% vs 6%, ataxia 27% vs 23%
Bottom Line
Stiripentol added to valproate and clobazam dramatically reduced seizures in Dravet syndrome, with 71% vs 5% responder rate (p<0.0001) and 43% vs 0% seizure-free rate in STICLO France. The pooled analysis confirmed these findings (p<0.001). However, nearly all stiripentol patients experienced adverse events (90-100%), primarily somnolence, and the effect may be partly attributable to stiripentol's CYP450 inhibition increasing clobazam/valproate levels rather than direct antiseizure activity.
Major Points
- Clobazam significantly more effective than carbamazepine for focal seizures in children: 56% vs 45% seizure-free at 6 months (P<0.05).
- Clobazam better tolerated: fewer cognitive side effects, better school performance.
- 235 children randomized. 1:1 CLB vs CBZ monotherapy. French multicenter, 1995-2000.
- First trial showing clobazam as viable monotherapy alternative for focal seizures in children.
- CBZ dose: 10-20 mg/kg/day. CLB dose: 0.5-1 mg/kg/day.
- Dropout for adverse events: CLB 8% vs CBZ 15%.
- Published Lancet 2000 (Clobazam Study Group). French pediatric epilepsy centers.
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled, add-on trial (STICLO France + STICLO Italy)
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- STICLO France: 41; Pooled: 64
- Follow-up
- 1-month baseline + 2-month double-blind treatment (+ open-label extension)
- Centers
- Multiple French and Italian centers
- Countries
- France, Italy
Primary Outcome
Definition: Responder rate (>50% reduction in clonic/tonic-clonic seizure frequency during month 2 vs baseline)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| STICLO France: 5.0% (1/20); Pooled: ~6.9% | STICLO France: 71.4% (15/21); Pooled: ~71.9% | - (95% CI of difference: 42.2-85.7%) | STICLO France: <0.0001; Pooled: <0.001 |
Limitations & Criticisms
- Very small sample size (n=41 primary, n=64 pooled) 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 direct antiseizure action
- Industry-funded by Biocodex (stiripentol manufacturer)
- No dose-response analysis: single fixed dose of 50 mg/kg/day
- Extremely high adverse event rate (90-100% in STICLO France stiripentol group)
- Highly selected population: only children already on VPA + CLB with very high seizure frequency (mean >20 GTCS/month)
Citation
Chiron C et al. Lancet. 2000;356(9242):1638-1642. DOI: 10.1016/S0140-6736(00)03157-3