Adjunctive Brivaracetam Research Articles

Treatment with brivaracetam has no apparent long-term effects on body weight in pediatric patients with epilepsy.

The objective of this study is to evaluate possible long-term effects of treatment with brivaracetam (BRV) on body weight in children with epilepsy. Post hoc analysis of data from patients (aged 1 month to <17 years) with ≥6 months of BRV treatment in a long-term, open-label trial (N01266 [NCT01364597]). Outcomes included body weight and body mass index (BMI) over time (z-score growth curves), and treatment-emergent adverse events (TEAEs). Previous/ongoing medical conditions that may affect body weight (gastrointestinal and metabolic/nutritional disorders); concomitant antiseizure medications (ASMs) were also evaluated. Two hundred nine patients (mean [standard deviation] age 7.9 [4.6] years) were analyzed. Most (154 [73.7%]) had focal-onset seizures. At study initiation, median (range) BRV dose was 1.0 (0.4-7.5) mg/kg/day. Overall, 189 (90.4%) patients had a previous or ongoing medical condition (gastrointestinal disorders: 43 [20.6%]; metabolism/nutritional disorders: 26 [12.4%]). Most patients followed z-score curves for body weight and BMI during BRV treatment, although there were outliers in both directions. Incidences of appetite/weight-change TEAEs were low. Twenty-three (11.0%) patients had a TEAE of decreased appetite and 14 (6.7%) had a TEAE of weight decreased. Long-term adjunctive BRV was well tolerated in growing children with no indication of detrimental effects on body weight. Brivaracetam is an antiseizure medication (ASM) used to treat seizures in people with epilepsy. Some ASMs can lead to changes in people's appetite and weight. Knowing the effect a drug has on appetite and weight is particularly important in children. We looked at 209 children with epilepsy taking brivaracetam and studied changes in their body weight and body mass index over time. The number of reported side effects related to appetite or weight change was low. There was no apparent long-term effect on their body weight, even when taking their medical history and use of other ASMs into account.

Narrative Review of Brivaracetam: Preclinical Profile and Clinical Benefits in the Treatment of Patients with Epilepsy.

One third of patients with epilepsy will continue to have uncontrolled seizures despite treatment with antiseizure medications (ASMs). There is therefore a need to develop novel ASMs. Brivaracetam (BRV) is an ASM that was developed in a major drug discovery program aimed at identifying selective, high-affinity synaptic vesicle protein 2A (SV2A) ligands, the target molecule of levetiracetam. BRV binds to SV2A with 15- to 30-fold higher affinity and greater selectivity than levetiracetam. BRV has broad-spectrum antiseizure activity in animal models of epilepsy, a favorable pharmacokinetic profile, few clinically relevant drug-drug interactions, and rapid brain penetration. BRV is available in oral and intravenous formulations and can be initiated at target dose without titration. Efficacy and safety of adjunctive BRV (50-200mg/day) treatment of focal-onset seizures was demonstrated in three pivotal phase III trials (NCT00490035/NCT00464269/NCT01261325), including in patients who had previously failed levetiracetam. Efficacy and safety of adjunctive BRV were also demonstrated in adult Asian patients with focal-onset seizures (NCT03083665). In several open-label trials (NCT00150800/NCT00175916/NCT01339559), long-term safety and tolerability of adjunctive BRV was established, with efficacy maintained for up to 14years, with high retention rates. Evidence from daily clinical practice highlights BRV effectiveness and tolerability in specific epilepsy patient populations with high unmet needs: the elderly (≥ 65years of age), children (< 16years of age), patients with cognitive impairment, patients with psychiatric comorbid conditions, and patients with acquired epilepsy of specific etiologies (post-stroke epilepsy/brain tumor related epilepsy/traumatic brain injury-related epilepsy). Here, we review the preclinical profile and clinical benefits of BRV from pivotal trials and recently published evidence from daily clinical practice.

Efficacy, safety, and tolerability of adjunctive brivaracetam in adult Asian patients with uncontrolled focal-onset seizures: A phase III randomized, double-blind, placebo-controlled trial.

Evaluate efficacy, safety, and tolerability of adjunctive brivaracetam (BRV) in adult Asian patients with focal-onset seizures (FOS). Phase III, randomized, double-blind, placebo-controlled study (EP0083; NCT03083665) evaluating BRV 50 mg/day and 200 mg/day in patients (≥16-80 years) with FOS with/without secondary generalization (focal to bilateral tonic-clonic seizures) despite current treatment with 1 or 2 concomitant antiseizure medications. Following an 8-week baseline, patients were randomized 1:1:1 to placebo, BRV 50 mg/day, or BRV 200 mg/day, and entered a 12-week treatment period. Efficacy outcomes: percent reduction over placebo in 28-day FOS frequency (primary); 50% responder rate in FOS frequency; median percent reduction in FOS frequency from baseline; seizure freedom during treatment period (secondary). Primary safety endpoints: incidences of treatment-emergent adverse events (TEAEs); TEAEs leading to discontinuation; serious TEAEs. In this study, 448/449 randomized patients (mean age, 34.5 years; 53.8% female) received ≥1 dose of study medication (placebo/BRV 50 mg/BRV 200 mg/day: n = 149/151/148). Percent reduction over placebo in 28-day adjusted FOS frequency was 24.5% (p = 0.0005) and 33.4% (p < 0.0001) with BRV 50 mg/day and 200 mg/day, respectively, 50% responder rate was 19.0%, 41.1%, and 49.3% with placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p < 0.0001 for both BRV groups vs. placebo). Median percent reduction in FOS frequency from baseline was 21.3%/38.9%/46.7% in patients on placebo/BRV 50 mg/BRV 200 mg/day, respectively. Overall, 0, 7 (4.6%), and 10 (6.8%) patients were classified as seizure-free during the treatment period on placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p = 0.0146/p = 0.0017 for BRV 50 mg/200 mg/day vs. placebo, respectively). TEAE incidences were similar between patients on placebo (58.4%) and all patients receiving BRV (58.5%); TEAE incidences for BRV 50 mg/day and BRV 200 mg/day were 57.0% and 60.1%, respectively. Overall, 0.7% of patients on placebo and 2.0% of all patients on BRV reported serious TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 1.3% and 2.7%, respectively), 20.1% of patients on placebo and 33.1% of all patients on BRV reported drug-related TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 26.5% and 39.9%, respectively), and 4.7% of patients on placebo and 3.0% of all patients on BRV discontinued due to TEAEs (discontinuation incidences for BRV 50 mg/day and BRV 200 mg/day were 2.6% and 3.4%, respectively). Adjunctive BRV was efficacious and well tolerated in adult Asian patients with FOS. Efficacy and safety profiles were consistent with BRV studies in predominantly non-Asian populations. Brivaracetam is used to treat partial or focal seizures in people with epilepsy. Most studies with brivaracetam tablets have involved people from non-Asian racial backgrounds. In this study, 449 Asian adults with epilepsy took part. One third took 50 mg of brivaracetam, one third took 200 mg of brivaracetam, and one third took a placebo each day for 12 weeks. On average, those who took brivaracetam had fewer seizures than those given the placebo. Most of the side effects were mild and the number and type of side effects seen were as expected for this medication.

A prospective, observational, multicentre study to evaluate the efficacy of brivaracetam as adjuvant therapy for epilepsy: The Bravo study.

Epilepsy is a persistent tendency to experience epileptic seizures and can lead to various neurobiological disorders, with an elevated risk of premature mortality. This study evaluates the efficacy of brivaracetam adjuvant therapy in patients with epilepsy. A prospective observational multicentre study that was conducted in Pakistan from March to September 2022, by using a non-probability convenience sampling technique. The population consisted of 543 individuals with a diagnosis of epilepsy for whom adjunctive brivaracetam (Brivera; manufactured by Helix Pharma Pvt Ltd., Sindh, Pakistan) was recommended by the treating physician. The research sample was drawn from various private neurology clinics of Karachi, Lahore, Rawalpindi, Islamabad and Peshawar. Data originating from routine patient visits, and assessments at three study time points, were recorded in the study case report form. Across 18 clinical sites, 543 individuals participated, with a mean age of 32.9 years. The most prescribed dosages were 50 mg BD, followed by 100 mg BD. Notably, brivaracetam combined with divalproex sodium was the most prevalent treatment, followed by brivaracetam with levetiracetam. At both the 14th and 90th day assessments, a significant reduction in seizure frequency was observed, with 63.1% of individuals showing a favourable response by day 90. Treatment-naive individuals exhibited higher rates of seizure freedom and response compared with treatment-resistant individuals. The study demonstrates the effectiveness of brivaracetam combination therapy in epilepsy management, with notable reductions in seizure frequency and favourable clinical responses observed, particularly in treatment-naive individuals.

Adjunctive brivaracetam and sustained seizure frequency reduction in very active focal epilepsy

AbstractObjectiveThis study aimed to explore the effectiveness of brivaracetam (BRV) according to baseline seizure frequency and past treatment history in subjects with focal epilepsy who were included in the Brivaracetam Add‐On First Italian Network Study (BRIVAFIRST).MethodsBRIVAFIRST was a 12‐month retrospective, multicenter study including adults prescribed adjunctive BRV. Study outcomes included sustained seizure response (SSR), sustained seizure freedom (SSF), and the rates of treatment discontinuation and adverse events (AEs). Baseline seizure frequency was stratified as &lt;5, 5–20, and &gt;20 seizures per month, and the number of prior antiseizure medications (ASMs) as &lt;5 and ≥6.ResultsA total of 994 participants were included. During the 1‐year study period, SSR was reached by 45.8%, 39.3%, and 22.6% of subjects with a baseline frequency of &lt;5, 5–20, and &gt;20 seizures per month (p &lt; .001); the corresponding figures for the SSF were 23.4%, 9.8%, and 2.8% (p &lt; .001). SSR was reached by 51.2% and 26.5% participants with a history of 1–5 and ≥6 ASMs (p &lt; .001); the corresponding rates of SSF were 24.7% and 4.5% (p &lt; .001). Treatment discontinuation due to lack of efficacy was more common in participants with &gt;20 seizures compared to those with &lt;5 seizures per month (25.8% vs. 9.3%, p &lt; .001), and in participants with history of ≥6 prior ASMs compared to those with history of 1–5 ASMs (19.6% vs. 12.2%, p = .002). There were no differences in the rates of BRV withdrawal due to AEs and the rates of AEs across the groups of participants defined according to the number of seizures at baseline and the number of prior ASMs.SignificanceThe baseline seizure frequency and the number of previous ASMs were predictors of sustained seizure frequency reduction with adjunctive BRV in subjects with focal epilepsy.

Long-term safety and efficacy of adjunctive brivaracetam in pediatric patients with epilepsy: An open-label, follow-up trial.

To evaluate the long-term safety, tolerability, and efficacy of adjunctive brivaracetam (BRV) treatment in pediatric patients with epilepsy. Phase 3, open-label, multicenter, long-term follow-up trial (N01266; NCT01364597; patients aged 1 month to <17 years at core trial entry; direct enrollers aged 4 to <17 years) treated with BRV. Outcomes included treatment-emergent adverse events (TEAEs), behavior assessments (Achenbach Child Behavior Checklist [CBCL]; Behavior Rating Inventory of Executive Function [BRIEF-P/BRIEF]), and efficacy outcomes (percent change in focal seizure frequency, 50% responder rate for all seizure types for patient subgroups <2 years and ≥2 years of age using daily record card data). Of 257 patients with ≥1 dose of BRV (141 [54.9%] male; mean age: 8.0 years [SD 4.5]), 36 patients were <2 years of age, and 72.0% of patients had a history of focal seizures. Mean BRV exposure was 3.2 patient-years. At least one TEAE occurred in 93.4% patients and 32.3% had serious TEAEs. Seven patients died during the trial; no deaths were considered treatment related. Patients ≥2 years of age had a median decrease in 28-day adjusted focal seizure frequency of 62.9%, and 50.9% had a ≥50% response in all seizures. Patients <2 years of age had a median decrease in 28-day adjusted focal seizure frequency of 96.9%, and 68.2% had a ≥50% response in all seizures. Kaplan-Meier estimated treatment retention was 72.7%, 64.5%, 57.8%, 53.3%, 50.1%, and 44.8% at 1, 2, 3, 4, 5, and 6 years, respectively. Mean changes (baseline to last evaluation) for all Achenbach CBCL and BRIEF-P/BRIEF subscale scores were negative, reflecting stability/slight improvement. Long-term adjunctive BRV treatment was generally well tolerated, efficacious in reducing seizure frequency, and had high retention rates, with generally stable cognitive/behavioral scores in pediatric patients with epilepsy.

The efficacy and tolerability of adjunctive brivaracetam for the treatment of adult epilepsy: An Australian multi-center retrospective real-world observational cohort study

ObjectiveAssess the efficacy and tolerability of add-on therapy brivaracetam (BRV) in adult patients with epilepsy in a real-world setting. MethodsThis multi-center retrospective observational cohort study examined all adult patients who commenced on BRV at 11 Australian epilepsy centers between 2017 and 2020. Primary outcomes were seizure response (≥50% reduction in frequency) and seizure freedom 12 months post BRV commencement, and tolerability. We report three approaches to missing data (complete case analysis, CCA; last observation carried forward, LOCF; and intention to treat, ITT). Secondary outcomes included the durability of early BRV response and continuous seizure freedom from BRV initiation. Subgroup analysis examined patients with focal and generalized epilepsy and patients with refractory (≥4 prior ASMs) and highly refractory (≥7 prior ASMs) epilepsy. Outcomes were also assessed at ‘personalized’ seizure outcome time points based on baseline seizure frequency. ResultsBaseline and follow-up data were available for 228 patients. The mean age was 41.5 years (IQR 30, 50). Most had focal epilepsy (188/228, 82.5%). Median number of previous ASMs was 4 (2, 7), and concomitant ASMs 2 (2, 3). Twelve-month responder rate was: 46.3% using CCA (95% CI 34.0, 58.9); 39.5% using LOCF (33.1, 46.1); and 15.4% using ITT (10.9, 20.7). Twelve-month seizure freedom was: 23.9% using CCA (14.3, 35.9); 24.6% using LOCF (19.1, 30.7); and 7.9% using ITT (4.7, 12.1). The most frequent adverse effects were sedation or cognitive slowing (33/228, 14.5%), irritability or aggression (16/228, 7.0%), and low mood (14/228, 6.1%). Outcomes were similar using continuous outcome definitions and ‘personalized’ outcome assessment time points. Early responses were highly durable, with 3-month response maintained at all subsequent time points at 83%, and seizure freedom maintained at 85%. Outcomes were similar in focal (n = 187) and generalizsed (n = 25) subgroups. Outcomes were similar in refractory patients (n = 129), but lower in the highly refractory group (n = 62), however improvement with BRV was still observed with 12-month seizure freedom of 8.3% using CCA (1.0, 27), 6.5% using LOCF (1.8, 15.7); and 3.2% using ITT (0.4, 11.2). ConclusionsMeaningful real-world responder and seizure freedom rates can be still observed in a refractory epilepsy population. Brivaracetam response can occur early and appears to be maintained with minimal later relapse. The results should be interpreted with caution given the retrospective nature of the study and the quantities of missing data at later time points.

Cognitive and Behavioral Effects of Adjunctive Brivaracetam in Children and Adolescents with Focal Seizures: Final Data From an Open-label Follow-up Trial (P14-1.007)

<h3>Objective:</h3> Evaluate cognitive and behavioral effects of long-term adjunctive brivaracetam (BRV) in children with focal seizures. <h3>Background:</h3> Children with epilepsy are at increased risk for cognitive and behavioral problems. <h3>Design/Methods:</h3> Post-hoc analysis of phase 3, open-label, follow-up trial (N01266; NCT01364597; patients &lt;16 years at core trial entry; ≤5 mg/kg/day BRV tablet/oral solution [≤200 mg/day]). Planned trial duration ≥3 years. Outcomes included Achenbach Child Behavior Checklist (CBCL; ages 1.5–5 and 6–18 years), Behavior Rating Inventory of Executive Function (BRIEF; ages 2–&lt;5 [BRIEF-P] and 5–16 years). <h3>Results:</h3> 140 patients were included (mean age 9.5 years; 22.9% aged 1.5–5 years [median exposure 3.6 years], 77.1% aged 6–16 years [median exposure 3.5 years]). Mean changes (baseline to last evaluation) for all Achenbach CBCL and BRIEF-P/BRIEF subscale scores were negative, reflecting stability/slight improvement. The largest decreases in CBCL were for aggressive behavior and anxious/depressed (both age groups) and other problems (1.5–5 years). The largest decreases in BRIEF-P/BRIEF scores were for inhibit and working memory (both age groups) and emotional control (2–&lt;5 years). Most patients had no shift in T-score category (baseline to last evaluation) for each CBCL subscale (between normal and borderline clinical range [BCR]) and BRIEF-P/BRIEF subscale (between normal and potential clinical significance [PCS]). For all CBCL subscales, higher proportion of patients changed from BCR to normal than from normal to BCR. Changes for BRIEF-P were mostly PCS to normal; for BRIEF, similar proportions of patients changed in either direction. Treatment-emergent adverse events (TEAEs) were reported in 100% and 95.4% of patients aged 1.5–5 and 6–16 years (drug-related TEAEs 31.3%, 30.6%; discontinuations due to TEAEs 6.3%, 9.3%). <h3>Conclusions:</h3> Cognitive and behavioral functioning scores in children and adolescents with focal seizures during long-term adjunctive BRV therapy were generally stable or slightly improved. BRV was generally well tolerated. <b>Disclosure:</b> Dr. Elshoff has nothing to disclose. Ms. Fleyshman has nothing to disclose. The institution of Mrs. De la Loge has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for IPSEN. The institution of Mrs. De la Loge has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for UCB. Dr. Dickson has received personal compensation for serving as an employee of UCB. Dr. Reichel has received personal compensation for serving as an employee of UCB Pharma. Dr. Reichel has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for UCB Biosciences. Dr. Reichel has received stock or an ownership interest from UCB Pharma. Dr. Floricel has received personal compensation for serving as an employee of UCB Biosciences GmbH. Dr. Floricel has received stock or an ownership interest from UCB Biosciences GmbH. Dr. SMEYERS has nothing to disclose.

Retention, efficacy, tolerability, and quality of life during long-term adjunctive brivaracetam treatment by number of lifetime antiseizure medications: A post hoc analysis of phase 3 trials in adults with focal seizures

ObjectiveTo evaluate long-term retention, reasons for discontinuation, efficacy, tolerability, and health-related quality of life (HRQOL) during adjunctive brivaracetam (BRV) treatment in adults with focal seizures by number of lifetime antiseizure medications (ASMs). MethodsPost hoc analyses of a randomized, double-blind, placebo-controlled trial (N01358; NCT01261325) and corresponding open-label extension (OLE) (N01379; NCT01339559) of adjunctive BRV in adults (16–80 years of age) with focal seizures. Outcomes were assessed from the first day of BRV treatment in the double-blind (patients randomized to BRV) or open-label trial (patients randomized to placebo) by number of lifetime ASMs (1–2, 3–4, 5–6, or ≥ 7). Lifetime ASMs were defined as previous (stopped before BRV initiation) and concomitant ASMs at BRV initiation. ResultsSeven hundred and forty patients received adjunctive BRV (safety set [SS]; median modal dose: 200 mg/day [N = 737]; median treatment duration: 2.67 years), of whom 13.8 % had 1–2, 20.8 % had 3–4, 21.1 % had 5–6 and 44.3 % had ≥7 lifetime ASMs. Patients with a higher number of lifetime ASMs had a younger age at epilepsy onset, longer epilepsy duration, and higher baseline seizure frequency. Kaplan-Meier estimated retention on BRV at 12 (83.2–65.9 %) and 36 months (63.0–44.1 %) was highest in patients with 1–2 lifetime ASMs and decreased with the number of lifetime ASMs. The estimated proportions of patients who discontinued BRV due to lack of efficacy or treatment-emergent adverse events (TEAEs) increased with the number of lifetime ASMs. Efficacy analyses included seven hundred and thirty eight patients (intention-to-treat set [ITT]). Median percentage reductions from baseline in focal seizure frequency/28 days (76.3–39.6 %), 50 % responder rates (66.7–39.8 %), 75 % responder rates (51.0–19.6 %), and continuous seizure freedom for ≥12 months at any time during BRV treatment (35.3–6.1 %) were highest in patients with 1–2 lifetime ASMs and decreased by the number of lifetime ASMs. The overall incidence of TEAEs (SS) was generally similar in each lifetime ASM subgroup (84.4–90.5 %). Discontinuations due to TEAEs increased with the number of lifetime ASMs (7.8–20.1 %). The greatest improvements in QOLIE-31-P scores occurred in the Seizure Worry and Daily Activities/Social Function subscales, with no clear pattern by the number of lifetime ASMs at 12 months and with the highest improvement in patients with 1–2 lifetime ASMs at 24 months. At 24 months, the Hospital Anxiety and Depression Scale (HADS) Anxiety subscale scores improved in patients (SS) with 1–2 and 3–4 lifetime ASMs. HADS Depression subscale scores were generally stable independent of the number of lifetime ASMs. ConclusionsThe balance between efficacy, tolerability, and HRQOL was most favorable in patients with focal seizures who had been exposed to one or two ASMs before BRV initiation. However, patients exposed to ≥7 ASMs before BRV initiation also benefitted from long-term adjunctive BRV treatment.

Brivaracetam as Early Add-On Treatment in Patients with Focal Seizures: A Retrospective, Multicenter, Real-World Study.

In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1-2 (early add-on) and ≥ 3 (late add-on) prior antiseizure medications. A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12months was 125 (100-200) mg in the early add-on group and 200 (100-200) in the late add-on group (p < 0.001). Sustained seizure response was reached by 97/161 (60.3%) of patients in the early add-on group and 286/833 (34.3%) of patients in the late add-on group (p < 0.001). Sustained seizure freedom was achieved by 51/161 (31.7%) of patients in the early add-on group and 91/833 (10.9%) of patients in the late add-on group (p < 0.001). During the 1-year study period, 29 (16.5%) patients in the early add-on group and 241 (28.3%) in the late add-on group discontinued BRV (p = 0.001). Adverse events were reported by 38.7% and 28.5% (p = 0.017) of patients who received BRV as early and late add-on treatment, respectively. Brivaracetam was effective and well tolerated both as first add-on and late adjunctive treatment in patients with focal epilepsy.

A Systematic Review of the Cost-effectiveness of Perampanel in the Treatment of Epilepsy

A Systematic Review of the Cost-effectiveness of Perampanel in the Treatment of Epilepsy

Time-course of Treatment-emergent Adverse Events Potentially Associated with Behavioral Disorders during Adjunctive Brivaracetam Treatment of Adults with Focal Seizures (P17-8.003)

Time-course of Treatment-emergent Adverse Events Potentially Associated with Behavioral Disorders during Adjunctive Brivaracetam Treatment of Adults with Focal Seizures (P17-8.003)

Cognitive and Behavioral Effects and Tolerability of Adjunctive Brivaracetam in Children and Adolescents with Focal Seizures: Pooled Interim Analysis (P13-8.004)

Cognitive and Behavioral Effects and Tolerability of Adjunctive Brivaracetam in Children and Adolescents with Focal Seizures: Pooled Interim Analysis (P13-8.004)

Brivaracetam as add-on treatment in patients with post-stroke epilepsy: real-world data from the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST).

Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy and accounts for about 10-15% of all newly diagnosed epilepsy cases. However, evidence about the clinical profile of antiseizure medications in the PSE setting is currently limited. Brivaracetam (BRV) is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A. The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive BRV in patients with PSE treated in a real-world setting. This was a subgroup analysis of patients with PSE included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). The BRIVAFIRST was a 12-month retrospective, multicentre study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure-freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Patients with PSE included in the BRIVAFIRST were 75 and had a median age of 57 (interquartile range, 42-66) years. The median daily doses of BRV at 3, 6, and 12 months from starting treatment were 100 (100-150) mg, 125 (100-200) mg and 100 (100-200) mg, respectively. At 12 months, 32 (42.7%) patients had a reduction in their baseline seizure frequency by at least 50%, and the seizure freedom rates was 26/75 (34.7%). During the 1-year study period, 10 (13.3%) patients discontinued BRV. The reasons of treatment withdrawal were insufficient efficacy in 6 (8.0%) patients and poor tolerability in 4 (5.3%) patients. Adverse events were reported by 13 (20.3%) patients and were rated as mild in 84.6% and moderate in 15.4% of cases. Adjunctive BRV was efficacious and generally well-tolerated when used in patients with PSE in clinical practice. Adjunctive BRV can be a suitable therapeutic option for patients with PSE.

Adjunctive Brivaracetam in Older Patients with Focal Seizures: Evidence from the BRIVAracetam add‑on First Italian netwoRk Study (BRIVAFIRST).

BackgroundThe management of epilepsy in older adults has become part of daily practice because of an aging population. Older patients with epilepsy represent a distinct and more vulnerable clinical group as compared with younger patients, and they are generally under-represented in randomized placebo-controlled trials. Real-world studies can therefore be a useful complement to characterize the drug’s profile. Brivaracetam is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A and approved as adjunctive therapy for focal seizures in adults with epilepsy.ObjectiveThe aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive brivaracetam in older patients (≥65 years of age) with epilepsy treated in a real-world setting.MethodsThe BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a 12-month retrospective multicenter study including adult patients prescribed adjunctive brivaracetam. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events and the incidence of adverse events. Data were compared for patients aged ≥65 years of age (‘older’) vs those aged <65 years (‘younger’).ResultsThere were 1029 patients with focal epilepsy included in the study, of whom 111 (10.8%) were aged ≥65 years. The median daily dose of brivaracetam at 3 months was 100 [interquartile range, 100–175] mg in the older group and 100 [100–200] mg in the younger group (p = 0.036); it was 150 [100–200] mg in both groups either at 6 months (p = 0.095) or 12 months (p = 0.140). At 12 months, 49 (44.1%) older and 334 (36.4%) younger patients had a reduction in their baseline seizure frequency by at least 50% (p = 0.110), and the seizure freedom rates were 35/111 (31.5%) and 134/918 (14.6%) in older and younger groups, respectively (p < 0.001). During the 1-year study period, 20 (18.0%) patients in the older group and 245 (26.7%) patients in the younger group discontinued brivaracetam (p = 0.048). Treatment withdrawal because of insufficient efficacy was less common in older than younger patients [older: n = 7 (6.3%), younger: n = 152 (16.6%); p = 0.005]. Adverse events were reported by 24.2% of older patients and 30.8% of younger patients (p = 0.185); the most common adverse events were somnolence, nervousness and/or agitation, vertigo, and fatigue in both study groups.ConclusionsAdjunctive brivaracetam was efficacious, had good tolerability, and no new or unexpected safety signals emerged when used to treat older patients with uncontrolled focal seizures in clinical practice. Adjunctive brivaracetam can be a suitable therapeutic option in this special population.

Sustained seizure freedom with adjunctive brivaracetam in patients with focal onset seizures.

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real‐world practice. Patients with focal epilepsy prescribed add‐on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12‐month follow‐up. Nine hundred ninety‐four patients with a median age of 45 (interquartile range = 32–56) years were included. During the 1‐year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure‐free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12 months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy.

Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST)

BackgroundIn randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile.ObjectiveThis multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice.MethodsThe BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure‐freedom, seizure response (≥ 50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed.ResultsA total of 1029 patients with a median age of 45 years (33–56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p < 0.001); the corresponding values for ≥ 50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p < 0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%; p = 0.341) and seizure response (39.7% vs. 26.9%; p = 0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p = 0.017).ConclusionThe BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations.

Long-term efficacy and tolerability of adjunctive brivaracetam in adults with focal to bilateral tonic-clonic (secondary generalized) seizures: Post hoc pooled analysis

This post hoc analysis was conducted to evaluate the efficacy, tolerability, and health-related quality of life during long-term adjunctive brivaracetam (BRV) treatment in adult patients with focal to bilateral tonic-clonic seizures (FBTCS). Patients (≥ 16 years) were included in this post hoc analysis if they were randomized to BRV or placebo in double-blind, placebo-controlled (N01252 [NCT00490035], N01253 [NCT00464269], N01358 [NCT01261325]; core) trials, and received adjunctive BRV in the corresponding long-term follow-up (N01125 [NCT00175916], N01199 [NCT00150800], N01379 [NCT01339559]) trials, and reported FBTCS during the 8-week prospective baseline (core trial). Efficacy (concomitant levetiracetam excluded) and tolerability (concomitant levetiracetam included) were assessed from the first day of BRV in patients who initiated BRV at 50–200 mg/day.Two hundred and eighty-four patients reported FBTCS during baseline (core trials) and were included in the Efficacy Set. Patients (mean age of 37.0 years; 51.8% male; mean epilepsy duration of 22.4 years; median baseline frequency of 2.8 FBTCS per 28 days) received BRV for a median treatment duration of 2.5 years (range< 0.1–11.3) at a median modal dose of 150 mg/day. BRV was discontinued by 175 (61.6%) patients, most commonly (≥ 10% of patients) due to adverse event (18.3%), lack of efficacy (18.3%), and consent withdrawn (11.6%); the median time to discontinuation of BRV due to any reason was 358.5 days. The Kaplan-Meier (KM)-estimated retention on BRV at 1, 3, and 5 years, were 69.3%, 48.2%, and 37.3%, respectively. The KM-estimated proportion of patients not discontinuing BRV due to lack of efficacy or adverse event were 80.0%, 63.9%, and 57.2% at 1, 3, and 5 years, respectively. Overall, the median percentage reduction in FBTCS frequency from baseline was 76.2%, and the 50% and 75% responder rates for FBTCS were 68.7% and 50.7%, respectively, which were sustained over time across completer cohorts. Sustained 50%, 75%, and 100% response in FBTCS from day 1 of adjunctive BRV treatment during the entire first year was estimated for 32.5%, 21.1%, and 15.0% of patients, respectively (KM analysis), and showed maintenance or improvement in the response to BRV over time. For patients with ≥ 1 year of BRV exposure, 51.3% were free from FBTCS for ≥ 1 year during any time of the treatment period, and 22.8% of patients did not report FBTCS during the first year from the first day of treatment. Clinically meaningful improvements in total Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score were reported by 43.6% and 46.4% of patients after 1 and 2 years of treatment, respectively. The largest improvements in the QOLIE-31-P score, with > 50% of patients reporting a clinically meaningful improvement, were observed in the seizure worry and daily activities/social functioning subscales after 1 and 2 years of BRV treatment. Overall, 278/313 (88.8%; Safety Set) patients reported at least one treatment-emergent adverse event (TEAE), 170 (54.3%) had a drug-related TEAE, 88 (28.1%) had a serious TEAE, and 55 (17.6%) discontinued BRV due to a TEAE.Overall, long-term adjunctive BRV was generally well tolerated and reduced the frequency of FBTCS in adults, with 22.8% of patients (who completed ≥ 1 year of treatment) not reporting any FBTCS during the first year from the first day of BRV treatment.

Effect of Number of Previous Antiseizure Medications on Efficacy and Tolerability of Adjunctive Brivaracetam for Uncontrolled Focal Seizures: Post Hoc Analysis.

The aim was to evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with severely drug-resistant focal seizures versus adults with less drug-resistant disease. Data were pooled from patients with focal seizures on 1-2 concomitant antiseizure medications (ASMs) randomized to BRV 50, 100, 200mg/day, or placebo in 3 phase 3 trials (N01252 [NCT00490035], N01253 [NCT00464269], and N01358 [NCT01261325]) with a 12-week treatment period. Outcomes were assessed in patients with≥5 and 0-4 previous ASMs (stopped before trial drug initiation). In≥5 previous ASMs subgroup (BRV 50, 100, 200mg/day: n=26, n=137, n=120; placebo: n=151), percentage reduction over placebo in 28-day adjusted focal seizure frequency was 13.0% for 50mg/day (p=0.38), 18.1% for 100mg/day (p=0.006), 19.8% for 200mg/day (p=0.004), and 17.0% for all BRV-treated patients (p=0.001). The 50% responder rate was 26.9%, 29.9%, 30.0%, and 29.7% for BRV 50, 100, 200, and 50-200mg/day, respectively (placebo: 13.2%); odds ratios versus placebo were statistically significant (p<0.05) for BRV 100, 200, and 50-200mg/day. In 0-4 previous ASMs subgroup (BRV 50, 100, 200mg/day: n=135, n=195, n=129; placebo: n=267), all BRV dosages showed statistically significant (1) percentage reduction over placebo in 28-day adjusted focal seizure frequency (21.4-28.7%); (2) differences from placebo in median percentage reduction in 28-day adjusted focal seizure frequency from baseline (35.5-45.9%; placebo: 21.3%); and (3) odds ratios versus placebo (favoring BRV) for 50% responder rates. In BRV-treated patients, treatment-emergent adverse event (TEAE) incidence (73.8% [217/294] vs. 64.6% [329/509]) and discontinuation due to TEAEs (10.5% vs. 4.5%) were higher inthe ≥5 versus 0-4 previous ASMs subgroup; serious TEAEs were rare in both subgroups (≥5 previous ASMs: 3.1%; 0-4 previous ASMs: 2.9%). Adjunctive BRV showed efficacy and was generally well tolerated in adults with focal seizures independent of the number of previous ASMs.

Long-term safety, efficacy, and quality of life during adjunctive brivaracetam treatment in patients with uncontrolled epilepsy: An open-label follow-up trial

ObjectivesThe primary objective of this long-term follow-up (LTFU) trial was to evaluate the long-term safety and tolerability of brivaracetam (BRV). The secondary objective was to evaluate the maintenance of efficacy of BRV (including quality of life) over time. MethodsThis open-label, multicenter, flexible-dose trial (N01379 [NCT01339559]) was conducted in adults (≥16 years) with focal or generalized-onset seizures, who had participated in a placebo (PBO)-controlled trial of adjunctive BRV (N01258: NCT01405508 or N01358: NCT01261325). ResultsSeven hundred and sixty-six patients received BRV in this LTFU trial (753 had focal seizures and 13 had generalized-onset seizures). Kaplan–Meier-estimated retention was 71.9% at 12 months, and 53.7% at 36 months. Treatment-emergent adverse events (TEAEs) were reported by 643 (83.9%) patients, most commonly headache (104 [13.6%] patients) and dizziness (100 [13.1%] patients). Two hundred and fifty-seven (33.6%) patients had drug-related TEAEs, most commonly somnolence (49 [6.4%] patients) and dizziness (41 [5.4%] patients). Permanent discontinuation of BRV due to TEAEs occurred in 91 (11.9%) patients. Patients with focal seizures had a median percentage reduction in focal seizure frequency of 52.0% and 51.7% were 50% responders (sustained over time); 26.0% were seizurefree for 6 months, and 17.9% were seizurefree for 12 months. 42.4% of patients at 12 months and 46.8% at 24 months had clinically meaningful improvements in Patient Weighted Quality of Life in Epilepsy Questionnaire 31 total score. ConclusionsIn this select group of patients who entered the LTFU trial, BRV was generally safe and well tolerated. Results indicate the long-term efficacy of BRV in patients with focal seizures.