Efficacy, safety, and tolerability of adjunctive brivaracetam for secondarily generalized tonic-clonic seizures: Pooled results from three Phase III studies.
Secondarily generalized tonic-clonic seizures (SGTCS) are among the most devastating types of seizures, contributing to increased morbidity and mortality. Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle 2A (SV2A), has been shown to be useful for the adjunctive treatment of focal seizures. We sought to determine its specific efficacy in treating SGTCS.



Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 antiepileptic drugs (AEDs) who received placebo or BRV 50-200mg/day without titration over a 12-week treatment period. We report efficacy and safety/tolerability data for the BRV therapeutic dose range (50-200 mg/day) in patients with focal seizures including baseline SGTCS.



Patients (efficacy population, N=409) had been diagnosed with epilepsy for a mean±standard deviation duration of 22.2±13.1years. Baseline median SGTCS frequency was 3.0 per 28days. The majority (293, 71.6%) had failed ≥2 AEDs prior to study enrollment. The median percent reduction from baseline in SGTCS frequency/28days was: placebo, 33.3%; BRV 50mg/day, 66.6% (p<0.001); BRV 100mg/day, 61.2% (p=0.002); and BRV 200mg/day, 82.1% (p<0.001). The ≥50% responder rate for SGTCS was: placebo, 33.0%; BRV 50mg/day, 61.3% (p=0.003); BRV 100mg/day, 55.0% (p<0.001); and BRV 200mg/day, 64.0% (p<0.001). Freedom from SGTCS was achieved by: placebo, 14.8%; BRV 50mg/day, 22.6%; BRV 100mg/day, 31.0%; and BRV 200mg/day, 36.0% of patients. Time to first SGTCS during the treatment period was longer in patients receiving BRV than placebo (26days vs 8days, hazard ratio 0.55, p<0.001). In the SGTCS safety population (N=487), treatment-emergent adverse events (TEAEs) were reported by 60.6% of patients receiving placebo vs 65.0% of patients receiving BRV ≥50mg/day. Serious TEAEs were reported by 3.1% placebo vs 3.9% BRV ≥50mg/day. Discontinuations due to TEAEs were 3.9% placebo vs 6.3% BRV ≥50mg/day.



In patients with drug-resistant focal seizures, adjunctive BRV is effective in reducing the frequency of SGTCS. Almost one-third (30.4%) of patients were rendered completely free of SGTCS during the 12-week treatment period when taking BRV ≥50mg/day. BRV was well tolerated, with a TEAE profile consistent with that of the overall study population.
Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA. Electronic address: briandmoseley@gmail.com.
Brian D
BD
Moseley
Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: michael.sperling@jefferson.edu.
Michael R
MR
Sperling
Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA; Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: aliasadipooya@yahoo.com.
Ali A
AA
Asadi-Pooya
UCB Pharma, Smyrna, GA, USA. Electronic address: annie.diaz@ucb.com.
Anyzeila
A
Diaz
UCB Pharma, Raleigh, NC, USA. Electronic address: isami.elmoufti@ucb.com.
Sami
S
Elmouft
UCB Pharma, Raleigh, NC, USA. Electronic address: jasd54@gmail.com.
Jimmy
J
Schiemann
UCB Pharma, Raleigh, NC, USA. Electronic address: john.whitesides@ucb.com.
John
J
Whitesides
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D000069279:Drug Resistant Epilepsy / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011760:Pyrrolidinones / Q000009:adverse effects / Q000627:therapeutic use*; D012640:Seizures / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam
Brivaracetam; Drug-resistant epilepsy; Efficacy; Safety; Secondarily generalized tonic-clonic seizures; Tolerability