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 Bayesian posterior probability of superiority or inferiority reached the 0.975 pre-specified criterion in any age group
- Children: LEV 52% (95% CrI 41-62), FOS 49% (38-61), VPA 52% (41-63); Adults: LEV 44% (33-55), FOS 46% (34-59), VPA 46% (34-58); Older adults: LEV 37% (19-59), FOS 35% (17-59), VPA 47% (25-70)
- No interaction between age and treatment (p=0.93 for <18 vs >18 categorical; p=0.69 for main effect of continuous age; p=0.88 for interaction of continuous age by treatment)
- Pre-planned 400-patient interim futility criterion met for the overall cohort and adults; DSMB allowed continued pediatric enrollment (adding 78 patients, 76 children) toward a pediatric stopping boundary planned at 500 enrollments but assessed early after an adverse event; final enrollment 478
- 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% | - (95% credible intervals — LEV: children 41-62, adults 33-55, older adults 19-59; FOS: children 38-61, adults 34-59, older adults 17-59; VPA: children 41-63, adults 34-58, older adults 25-70) | Bayesian posterior probabilities used rather than frequentist P values; none of the posterior probabilities of being most (or least) effective reached the pre-specified 0.975 threshold in any age group |
Limitations & Criticisms
- Trial terminated early: 400-patient futility criterion met for the overall cohort and adults, but DSMB allowed continued pediatric enrollment (adding 78 patients, mostly children); pediatric stopping boundary planned at 500 enrollments was assessed early in response to an adverse event, with final enrollment 478 (vs originally planned maximum 795)
- 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