What were the key findings of the STICLO trial?

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STICLO

Stiripentol in Severe Myoclonic Epilepsy in Infancy: A Randomised Placebo-Controlled Syndrome-Dedicated Trial

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Year of Publication: 2000

Authors: Chiron C, Marchand MC, Tran A, ..., Pons G; STICLO Study Group

Journal: The Lancet

Citation: Chiron C et al. Lancet. 2000;356(9242):1638-1642. DOI: 10.1016/S0140-6736(00)03157-3

Link: https://pubmed.ncbi.nlm.nih.gov/11089822/

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.

      

Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled, add-on trial (STICLO France + STICLO Italy)

Randomization: 1

Blinding: Double-blind

Enrollment Period: STICLO France: October 1996 to August 1998; STICLO Italy: April 1999 to October 2000

Follow-up Duration: 1-month baseline + 2-month double-blind treatment (+ open-label extension)

Centers: Multiple French and Italian centers

Countries: France, Italy

Sample Size: STICLO France: 41; Pooled: 64

Analysis: Per-protocol; STICLO France primary; STICLO Italy confirmatory

Inclusion Criteria

Age 3 to less than 18 years
Diagnosis of Dravet syndrome (SMEI) per clinical criteria: seizure onset in first year of life, generalized clonic or tonic-clonic seizures, normal psychomotor development and EEG before onset
Currently receiving valproate and clobazam
At least 4 generalized clonic or tonic-clonic seizures per month despite optimized therapy
Inadequately controlled on current regimen

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 (up to 30 mg/kg/day) and clobazam (up to 0.5 mg/kg/day)	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	P-value
Responder rate (>50% reduction in clonic/tonic-clonic seizure frequency during month 2 vs baseline)	Primary	STICLO France: 5.0% (1/20); Pooled: ~6.9%	STICLO France: 71.4% (15/21); Pooled: ~71.9%	STICLO France: <0.0001; Pooled: <0.001
	Secondary
	Secondary
	Secondary
	Secondary
	Secondary
	Secondary
	Adverse	23%	67% (pooled)
	Adverse	10%	46%
	Adverse	16%	27%
	Adverse	23%	27%
	Adverse	6%	27%
	Adverse	13%	18%
	Adverse	3%	15%
	Adverse	10%	15%
	Adverse	0%	12%
	Adverse	7%	12%

Subgroup Analysis

Not reported separately; AEs resolved when co-medication doses reduced in 57% of stiripentol patients

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)

Funding

Biocodex (manufacturer of stiripentol/Diacomit) -- industry-sponsored

Based on: STICLO (The Lancet, 2000)