Brivaracetam 50mg/5ml solution for injection vials

SummaryPurposeBrivaracetam (BRV) is a novel high‐affinity synaptic vesicle protein 2A ligand currently being investigated for the treatment of epilepsy. The purpose of this phase III study was to evaluate the efficacy and safety/tolerability of adjunctive BRV in adults with uncontrolled partial‐onset (focal) seizures.MethodsThis was a prospective, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, fixed‐dose trial (N01253; NCT00464269). Adults aged 16–70 years with well‐characterized partial epilepsy not fully controlled despite treatment with one or two antiepileptic drugs (AEDs) were enrolled. Patients who experienced eight or more partial‐onset seizures, whether or not secondarily generalized, during the 8‐week prospective baseline period were randomized (1:1:1:1) to receive twice‐daily placebo (PBO) or BRV (5, 20, or 50 mg/day) without titration. The primary efficacy endpoint was percent reduction over PBO in baseline‐adjusted partial‐onset seizure frequency/week during the 12‐week treatment period. Comparison of BRV with PBO was sequential (50, 20 mg/day, then 5 mg/day). Secondary endpoints included ≥50% responder rate and median percent reduction from baseline in partial‐onset seizure frequency/week. Post hoc analyses included the primary efficacy endpoint evaluated over 28 days and exploratory subanalyses of efficacy by seizure subtype. Safety and tolerability assessments included treatment‐emergent adverse events (TEAEs), laboratory tests, electrocardiography, vital signs, and physical and neurologic examinations.Key FindingsOf 400 patients randomized, 396 were included in the intent‐to‐treat (ITT) population (PBO n = 98, BRV 5 mg/day n = 97, BRV 20 mg/day n = 100, BRV 50 mg/day n = 101) and 392 comprised the modified ITT (mITT) population. A total of 361 (91.2%) of 396 patients completed the study. Most patients (78.3%) were receiving two concomitant AEDs. Percent reduction in partial‐onset seizure frequency/week over PBO was −0.9% (p = 0.885) for BRV 5 mg/day, 4.1% (p = 0.492) for BRV 20 mg/day, and 12.8% (p = 0.025) for BRV 50 mg/day (mITT population). Statistical significance was also achieved for the percent reduction over PBO in baseline‐adjusted partial‐onset seizure frequency/28 days for BRV 50 mg/day (22.0%; p = 0.004) but not for the other BRV dose groups. In the BRV 50 mg/day group, statistical significance was also seen for the ≥50% responder rate (BRV 32.7% vs. PBO 16.7%; p = 0.008) and median percent reduction from baseline in partial‐onset seizure frequency/week (BRV 30.5% vs. PBO 17.8%; p = 0.003). In the exploratory subanalysis by seizure subtype, median percent reduction from baseline in seizure frequency/week and ≥50% responder rate were numerically greater than PBO in the BRV 20 and 50 mg/day groups for simple partial, complex partial, and secondarily generalized seizures. BRV was generally well tolerated, with the majority of TEAEs being mild‐to‐moderate in intensity. Of the TEAEs reported by ≥5% patients, those with a frequency >3% higher than PBO for any dose of BRV compared with PBO were somnolence, dizziness, fatigue, influenza, insomnia, nasopharyngitis, vomiting, diarrhea, urinary tract infection, and nausea.SignificanceAdjunctive BRV at a daily dose of 50 mg was associated with statistically significant reductions in seizure frequency compared with PBO. All doses of BRV showed good tolerability throughout the study.

Abstract licence: CC BY-NC 4.0

SummaryPurposeBrivaracetam (BRV) is a novel high‐affinity synaptic vesicle protein 2A ligand in clinical development for the treatment of epilepsy. This phase III study (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients aged 16–70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage.MethodsThis was a double‐blind, randomized, placebo‐controlled trial conducted across Europe and India. Eligible patients had two or more focal seizures/month for 3 months prior to screening and eight or more focal seizures during the 8‐week prospective baseline. Concomitant use of levetiracetam was limited to 20% of randomized patients. Patients were randomized (1:1:1:1) to BRV 20, 50, 100 mg/day or PBO with no up‐titration for 12 weeks, followed by down‐titration or entry into a long‐term follow‐up study. The primary efficacy end point was percent reduction over PBO in baseline‐adjusted focal seizure frequency/week over the 12‐week treatment period. Comparison of BRV with PBO was sequential to control for multiplicity (50, 100, 20 mg/day), and thus required BRV to demonstrate superiority over PBO at 50 mg/day to meet the primary efficacy end point. Secondary efficacy variables were median percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate, and seizure freedom (all seizure types). Safety assessments included treatment‐emergent adverse events (TEAEs).Key FindingsOf 399 randomized patients, 398 were included in the intent‐to‐treat (ITT) and safety populations. Overall, 367 (92.2%) of 398 patients completed the study (BRV: 93.9%, 88.9%, and 94.0% for 20, 50, and 100 mg/day, respectively; PBO: 92.0%) and 345 (86.7%) of 398 patients continued into long‐term follow‐up studies (BRV: 87.9%, 82.8%, and 88.0% for 20, 50, and 100 mg/day, respectively; PBO: 88.0%). The study did not meet its primary efficacy end point based on the predefined sequential testing strategy. Indeed, percent reduction over PBO in baseline‐adjusted focal seizure frequency/week (primary efficacy analysis) was 6.8% (p = 0.239), 6.5% (p = 0.261), and 11.7% (p = 0.037) for BRV 20, 50, and 100 mg/day, respectively. Median percent reduction from baseline in focal seizure frequency/week was 30.0% (p = 0.019), 26.8% (p = 0.092), and 32.5% (p = 0.004) for BRV 20, 50, and 100 mg/day, respectively, compared with 17.0% for PBO. Responder rates (≥50%) were 27.3% (p = 0.339), 27.3% (p = 0.372), and 36.0% (p = 0.023) for BRV 20, 50, and 100 mg/day, respectively, compared with 20.0% for PBO. Complete seizure freedom was reported by 2/99, 0/99, and 4/100 patients on BRV 20, 50, and 100 mg/day, respectively, compared with 0/100 on PBO. The incidence of TEAEs was higher for BRV 20 (56/99, 56.6%), 50 (62/99, 62.6%), and 100 mg/day (63/100, 63.0%) than PBO (53/100, 53.0%); most TEAEs were mild or moderate in severity. The most frequently reported TEAEs in the BRV groups were headache, somnolence, dizziness, and fatigue.SignificanceIn this study of adjunctive BRV (20–100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline‐adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. BRV 20–100 mg/day was well tolerated without up‐titration, with a high completion rate.

Abstract licence: CC BY-NC-ND 4.0

ObjectiveAntiseizure medications (ASMs) are the cornerstone of epilepsy treatment. However, evidence on direct comparison of ASMs is lacking. This network meta-analysis evaluated the comparative efficacy and safety of approved and investigational add-on third-generation ASMs for focal epilepsy in adolescents and adults.MethodsData were retrieved through an extensive literature search of PubMed, Embase, Cochrane Library, and ClinicalTrial.gov databases from inception through August 2025. Findings were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline (CRD420251180027). Primary efficacy outcomes were ≥50 % and 100 % responder rates at 12-weeks maintenance duration. Secondary outcomes were corresponding responder rates at 8-weeks maintenance duration. Tolerability was assessed as retention rate. Treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were the safety outcomes.ResultsThe literature search retrieved 345 studies, of which 35 studies were included. All ASMs showed significantly higher responder rates compared with placebo. Significantly higher 100 % responder rate was observed with cenobamate (CNB; 400mg/d: Risk ratio [RR] 15; 95 % CI, 7.0-39; 200mg/d: RR 8.7; 95 % CI, 3.9-22) at a maintenance duration of 12 weeks and 8 weeks (400mg/d: RR 15; 95 % CI, 7.0-41; 200mg/d: RR 8.6; 95 % CI, 4.0-24). All ASMs showed a patient retention rate comparable with placebo. For overall TEAEs, brivaracetam (BRV; 50mg/d) and BRV ranked the lowest for individual and pooled doses, respectively; placebo ranked the highest in both cases. For TEAEs leading to treatment discontinuation, CNB ranked lower than the placebo.SignificanceAll approved and investigational ASMs were effective add-on treatments for focal epilepsy, with CNB demonstrating the greatest likelihood of achieving seizure freedom.

Abstract licence: CC BY

ObjectiveCurrent recommendations for prescribing combined oral contraceptives (COCs) to people with epilepsy are often conflicting, particularly for weak inducers of cytochrome P450 3A4. We aimed to critically review the literature and compare the antiseizure medication (ASM)-induced changes in exposure to COC components.MethodsIn this systematic review and network meta-analysis (PROSPERO: CRD42024513792), in accordance with PRISMA 2015/2020, we searched PubMed, EMBASE, Cochrane, and FDA documents up to January 2026. Eligible studies were clinical trials assessing induction (≥ 5 days) of ethinylestradiol combined with progestins by ASMs. The areas under the concentration-time curve (AUC) of individual hormones with/without the ASM were indirectly compared. The point estimate was the standardized mean difference (SMD; significant when the 95% confidence interval does not encompass zero). Bias risk was assessed using the PKclin tool.ResultsThe 17 studies (16 reports) involving 399 individuals and 15 ASMs were all conducted with COCs containing the two progestins least sensitive to enzyme induction and ≥ 30 μg ethinylestradiol. Nine ASMs were studied at doses 13-75% lower than the recommended maximum (median 50%). Brivaracetam (100 mg/day) reduced the exposure to ethinylestradiol more than 1000 mg/day levetiracetam (SMD -10; 95% confidence interval - 0.20-0). The effects of 300 mg/day lamotrigine on ethinylestradiol and levonorgestrel were greater than those of 400 mg/day lacosamide (0.18; 0.11-0.25, 0.28; 0.20-0.37). Low-dose (50 mg/day) and high-dose (200 mg/day) topiramate were comparable in their effects on ethinylestradiol and norethindrone, and the low dose did not differ from weak inducers in altering ethinylestradiol exposure.SignificanceCurrent recommendations may underestimate ASM effects on exposure to COC components, especially those in newer COCs. Greater caution is recommended with low-dose topiramate. For individuals treated with weak COC inducers without additional contraceptive means, COCs containing levonorgestrel or norethindrone might be preferable given their lower vulnerability to induction.

Abstract licence: CC BY-NC-ND