PDF: ESETT
(2020)Objective
To compare the efficacy and safety of levetiracetam, fosphenytoin, and valproate for established status epilepticus across three age groups (children, adults, and older adults)
Study Summary
• Treatment success approximately 50% across all three drugs in all age groups
• Any of the three drugs can be considered first-choice second-line therapy
Intervention
Levetiracetam 60 mg/kg IV (max 4500 mg), fosphenytoin 20 mg PE/kg IV (max 1500 mg PE), or valproate 40 mg/kg IV (max 3000 mg), all infused over 10 minutes
Inclusion Criteria
Age ≥2 years, treated for generalized convulsive seizure >5 min with adequate benzodiazepines, persistent/recurrent convulsions 5-30 min after last benzodiazepine dose
Study Design
Arms: Levetiracetam vs Fosphenytoin vs Valproate
Patients per Arm: 175 levetiracetam, 142 fosphenytoin, 145 valproate
Outcome
• Adults: levetiracetam 44%, fosphenytoin 46%, valproate 46%
• Older adults: levetiracetam 37%, fosphenytoin 35%, valproate 47%
Bottom Line
Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately 50% of patients across all age groups. No significant differences in efficacy were detected between drugs within any age group. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.
Major Points
- Response-adaptive randomization using Bayesian methods, stratified by age group (<18, 18-65, >65 years)
- Treatment success ~50% across all drugs and age groups; no drug met pre-specified criteria (0.975 posterior probability) for superiority or inferiority
- Children: LEV 52%, FOS 49%, VPA 52%; Adults: LEV 44%, FOS 46%, VPA 46%; Older adults: LEV 37%, FOS 35%, VPA 47%
- No interaction between age and treatment (P=0.93 for <18 vs >18; P=0.69 for continuous age)
- Trial terminated early at 478 enrollments after futility criterion met at planned 400-patient interim analysis (<1% chance of identifying superior drug)
- Higher intubation rate with fosphenytoin in children (33% vs 8% LEV and 11% VPA, P=0.0001) — isolated finding not seen in other age groups or trials
- Primary safety composite (life-threatening hypotension or arrhythmia) was rare and similar across all drugs
- 50% treatment success rate indicates better second-line therapies are still needed
Study Design
- Study Type
- Multicenter, double-blind, response-adaptive, randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; all patients, investigators, study staff, and pharmacists masked to treatment allocation
- Sample Size
- 478
- Follow-up
- Until hospital discharge or 30 days
- Centers
- 58
- Countries
- United States
Primary Outcome
Definition: Absence of clinically apparent seizures with improved consciousness and no additional antiseizure medication at 1 hour from start of infusion
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| N/A (three-arm comparison) | Children: LEV 52%, FOS 49%, VPA 52%; Adults: LEV 44%, FOS 46%, VPA 46%; Older adults: LEV 37%, FOS 35%, VPA 47% | - | No drug met 0.975 posterior probability threshold for superiority |
Limitations & Criticisms
- Trial terminated early after futility criterion met at 400 participants (vs planned 795); small sample limits power especially in older adults (n=51)
- Seizures not confirmed with EEG; some patients may have had sedation rather than subclinical seizures
- Isolated finding of increased intubation in children receiving fosphenytoin is inconsistent with other safety outcomes and other trials (EcLiPSE, ConSEPT)
- Few older adults enrolled (n=51), limiting meaningful inferences about this age group
- Type I error not corrected for multiple age subgroup comparisons
- Follow-up only until hospital discharge or 30 days; no long-term outcome data
- Conducted under exception from informed consent (FDA 21 CFR 50.24)
- 50% treatment success rate indicates better second-line therapies are still needed
Citation
Lancet 2020; 395: 1217-24