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ESETT

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial

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Year of Publication: 2020

Authors: James M Chamberlain, Jaideep Kapur, Shlomo Shinnar, ..., for the NETT and PECARN investigators

Journal: The Lancet

Citation: Lancet 2020; 395: 1217-24

Link: https://doi.org/10.1016/S0140-6736(20)30611-5

PDF: https://www.thelancet.com/action/showPdf...%2820%2930611-5

Clinical Question

Does treatment efficacy and safety of levetiracetam, fosphenytoin, and valproate for established (benzodiazepine-refractory) status epilepticus differ by age group (children, adults, and older adults)?

Study Overview

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

No significant differences in efficacy between levetiracetam, fosphenytoin, and valproate for benzodiazepine-refractory status epilepticus
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

Patients per Arm

175 levetiracetam, 142 fosphenytoin, 145 valproate

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

      

Design

Study Type: Multicenter, double-blind, response-adaptive, randomized controlled trial

Randomization: 1

Blinding: Double-blind; all patients, investigators, study staff, and pharmacists masked to treatment allocation

Enrollment Period: 2015-2018

Follow-up Duration: Until hospital discharge or 30 days

Centers: 58

Countries: United States

Sample Size: 478

Analysis: Bayesian adaptive analysis; response-adaptive randomization (1:1:1 for first 300, then updated every 100 patients); intention-to-treat

Inclusion Criteria

Age ≥2 years
Generalized convulsive seizure >5 min duration treated with adequate doses of benzodiazepines
Persistent or recurrent convulsions in ED for ≥5 min and ≤30 min after last dose of benzodiazepine
Adequate benzodiazepine doses: diazepam 10 mg IV, lorazepam 4 mg IV, or midazolam 10 mg IV/IM for adults/children ≥32 kg; weight-based dosing for children <32 kg

Exclusion Criteria

Known pregnancy
Prisoner status
Postanoxic seizures
Seizures precipitated by trauma
Seizures precipitated by hypoglycemia or hyperglycemia
Pre-emptively opted out of research
Already treated with non-benzodiazepine anticonvulsant for this episode
Known allergies or contraindications to any study drugs

Baseline Characteristics

Characteristic	Control	Active
Age (mean±SD)	N/A (three-arm comparison)	Children 6.1±4.3 yrs; Adults 42.6±14.1 yrs; Older adults 73.8±7.2 yrs
Female	~43% overall	Children 45%, Adults 42%, Older adults 41%

Arms

Field	Levetiracetam	Fosphenytoin	Valproate
Intervention	Levetiracetam 60 mg/kg IV (max 4500 mg) infused over 10 minutes	Fosphenytoin 20 mg PE/kg IV (max 1500 mg PE) infused over 10 minutes	Valproate 40 mg/kg IV (max 3000 mg) infused over 10 minutes
Duration	Single dose	Single dose	Single dose

Outcomes

Outcome	Type	Control	Intervention	P-value
Absence of clinically apparent seizures with improved consciousness and no additional antiseizure medication at 1 hour from start of infusion	Primary	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%	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
ICU admission (children)	Secondary		LEV 62%, FOS 63%, VPA 62%	NS
Median hospital stay (older adults)	Secondary		LEV 7 days, FOS 5 days, VPA 5 days
Life-threatening Hypotension or Arrhythmia (children)	Adverse		LEV 0%, FOS 3%, VPA 4%	NS
Endotracheal Intubation within 60 min (children)	Adverse		LEV 8%, FOS 33%, VPA 11%	0.0001
Acute Respiratory Depression (children)	Adverse		LEV 6%, FOS 18%, VPA 10%
Acute Seizure Recurrence 60 min-12 h (children)	Adverse		LEV 9%, FOS 15%, VPA 9%	NS
Mortality (older adults)	Adverse		LEV 20%, FOS 6%, VPA 0%

Subgroup Analysis

No interaction between age and treatment: p=0.93 for <18 vs >18 categorical comparison; p=0.69 for the main effect of continuous age; p=0.88 for interaction of continuous age (in years) by treatment. Post-hoc narrow age subgroups (0-5, 6-10, 11-17, 18-40, 41-65, >65) showed similar efficacy across all drugs.

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

Funding

National Institute of Neurological Disorders and Stroke (NINDS), NIH (awards U01NS088034, U01NS088023, U01NS056975, U01NS059041, U01NS073476)

Based on: ESETT (The Lancet, 2020)