Time-course of drug-related psychiatric and behavioral treatment-emergent adverse events during brivaracetam treatment in adults with focal-onset seizures.

OBJECTIVE: We previously analyzed data from three phase lll trials of adjunctive brivaracetam (BRV) in adults showing that the incidence and prevalence of drug-related central nervous system treatment-emergent adverse events (TEAEs) quickly peaked and decreased over several weeks following BRV treatment initiation. However, that analysis did not assess psychiatric and behavioral side effects which can occur with antiseizure medication (ASM) treatment. Here, we investigate the time-course of psychiatric and behavioral TEAEs by week of BRV treatment and how these TEAEs were managed. METHODS: Data were pooled from three trials (N01252 [NCT00490035]; N01253 [NCT00464269]; N01358 [NCT01261325]) in adult patients (≥16 years of age) with focal-onset seizures receiving BRV adjunctive therapy. This post hoc analysis reports data on the incidence and prevalence of drug-related psychiatric or behavioral TEAEs over time in patients who received BRV doses of 50-200 mg/day (without titration) or placebo (PBO) during the 12-week treatment period. A logistic regression model was used to determine if psychiatric or behavioral comorbid conditions were predictors for drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. RESULTS: A total of 803 patients received BRV 50-200 mg/day, and 459 patients received PBO. Drug-related psychiatric or behavioral TEAEs were reported by 11.0 % of patients during adjunctive BRV treatment (PBO: 4.8 %) with onset early after BRV initiation (median time to onset of first drug-related psychiatric or behavioral TEAE: 15 days). Incidence peaked at week 1 and decreased over the first 4 weeks following BRV initiation. Prevalence peaked at week 4 and then remained stable between weeks 5-12. In an analysis excluding patients on concomitant levetiracetam (BRV: n = 744; PBO: n = 422), the incidence of drug-related psychiatric or behavioral TEAEs was similar to the incidence in the overall population. The most common drug-related psychiatric or behavioral TEAEs were irritability, insomnia, depression, and anxiety. Only 2 % of patients discontinued BRV due to psychiatric or behavioral TEAEs (PBO: 1.3 %), while most patients on BRV who reported drug-related psychiatric or behavioral TEAEs did not require a change in dose (84.1 %; PBO: 63.6 %). A history of psychiatric or behavioral comorbid conditions (not ongoing at BRV initiation) was not associated with an increased likelihood of drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. Ongoing psychiatric or behavioral comorbid conditions at BRV initiation increased the likelihood of drug-related psychiatric or behavioral TEAEs, but not the likelihood of BRV discontinuation due to psychiatric or behavioral TEAEs. CONCLUSIONS: Drug-related psychiatric and behavioral TEAEs occurred early during BRV treatment, and most patients did not require a change in BRV dose. These data can help guide clinician monitoring and patient expectations after starting BRV.

Retrospective Multicenter Cohort Study on Safety and Electroencephalographic Response to Lacosamide for Neonatal Seizures.

BACKGROUND: There is growing evidence supporting the safety and effectiveness of lacosamide in older children. However, minimal data are available for neonates. We aimed to determine the incidence of adverse events associated with lacosamide use and explore the electroencephalographic seizure response to lacosamide in neonates. METHODS: A retrospective cohort study was conducted using data from seven pediatric hospitals from January 2009 to February 2020. For safety outcomes, neonates were followed for ≤30 days from index date. Electroencephalographic response of lacosamide was evaluated based on electroencephalographic reports for ≤3 days. RESULTS: Among 47 neonates, 98% received the first lacosamide dose in the intensive care units. During the median follow-up of 12 days, 19% of neonates died, and the crude incidence rate per 1000 patient-days (95% confidence interval) of the adverse events by diagnostic categories ranged from 2.8 (0.3, 10.2) for blood or lymphatic system disorders and nervous system disorders to 10.5 (4.2, 21.6) for cardiac disorders. Electroencephalographic seizures were observed in 31 of 34 patients with available electroencephalographic data on the index date. There was seizure improvement in 29% of neonates on day 1 and also in 29% of neonates on day 2. On day 3, there was no change in 50% of neonates and unknown change in 50% of neonates. CONCLUSIONS: The results are reassuring regarding the safety of lacosamide in neonates. Although some neonates had fewer seizures after lacosamide administration, the lack of a comparator arm and reliance on qualitative statements in electroencephalographic reports limit the preliminary efficacy results.

Efficacy and Tolerability of Adjunctive Brivaracetam in Patients with Focal-Onset Seizures on Specific Concomitant Antiseizure Medications: Pooled Analysis of Double-Blind, Placebo-Controlled Trials.

INTRODUCTION: This article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure medications (ASMs) taken as part of their treatment regimen. METHODS: This was a post hoc analysis of pooled data from double-blind, placebo-controlled trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in patients with uncontrolled focal-onset seizures randomized to BRV (50-200 mg/day) or placebo on the most common concomitant ASMs at trial initiation. RESULTS: Nine concomitant ASMs were analyzed: carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), oxcarbazepine (OXC), topiramate (TPM), phenytoin (PHT), lacosamide (LCM), clobazam (CLB), and phenobarbital (PHB). Reduction over placebo in focal-onset seizure frequency per 28 days with BRV ranged from 11.7% (concomitant OXC) to 33.5% (concomitant PHB). The median percentage reduction from baseline in focal-onset seizure frequency per 28 days ranged from 25.5% to 42.8% in patients on BRV (placebo 4.4-21.2%); 50% responder rates ranged from 31.9% to 44.9% in patients on BRV (placebo 11.4-25.2%). In patients on BRV, seizure freedom ranged from 1.4% (concomitant PHT) to 12.5% (concomitant LCM); seizure freedom ranged from 0% to 1.2% in patients on placebo. All efficacy endpoints analyzed were consistently numerically higher in patients on BRV versus placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was generally similar across subgroups by specific concomitant ASMs in patients on BRV (range 60.8-74.5%) or placebo (range 53.8-66.7%). Drug-related TEAEs were numerically higher across all subgroups by concomitant ASM in patients on BRV (range 35.2-48.3%) versus placebo (range 23.9-37.1%). Discontinuations due to TEAEs ranged from 2.9% to 13.3% in patients on BRV and was 0-5.7% for patients taking placebo across subgroups. CONCLUSION: BRV was efficacious and well tolerated regardless of the specific concomitant ASMs used as part of their treatment regimen. These data show that in patients with focal-onset seizures, BRV provides additional efficacy to a broad range of ASMs.

Efficacy and tolerability of lacosamide and controlled-release carbamazepine monotherapy in patients with newly diagnosed temporal lobe epilepsy: Post hoc analysis of a randomized, double-blind trial.

PURPOSE: Temporal lobe epilepsy (TLE) is often associated with drug-resistant seizures. We evaluated the efficacy and tolerability of lacosamide (LCM) versus controlled-release carbamazepine (CBZ-CR) monotherapy in adults with newly diagnosed TLE. METHODS: Exploratory post hoc analysis of patients with temporal focus of localization (indicated as the only localization focus) in a double-blind, noninferiority, phase 3 trial (SP0993; NCT01243177) in patients aged ≥ 16 years with newly diagnosed epilepsy randomized 1:1 to LCM or CBZ-CR monotherapy. RESULTS: Of 886 treated patients in this trial, temporal lobe focus of localization (TLE) was reported as the single focus for 287 (32.4%) patients (LCM 134, CBZ-CR 153). A similar proportion of patients with TLE on LCM (82  [61.2%]) and CBZ-CR (99  [64.7%]) completed the trial. Kaplan-Meier estimates for 6- and 12-month seizure freedom at the last evaluated dose level (stratified by number of seizures in the 3 months before screening  [≤2 or >2 seizures]) were similar with LCM and CBZ-CR (6 months overall: 88.7% and 89.7%; 12 months overall: 78.3% and 81.7%). Treatment-emergent adverse events (TEAEs) were reported by fewer patients on LCM (73.9%) than CBZ-CR (81.0%). Drug-related TEAEs (assessed by the investigator) were reported in 41.8% of patients on LCM and 52.3% of patients on CBZ-CR; 11.2% of patients on LCM and 15.0% on CBZ-CR discontinued due to TEAEs. CONCLUSION: Lacosamide was efficacious and generally well tolerated as monotherapy in patients with TLE with efficacy outcomes comparable with CBZ-CR, and fewer patients on LCM reported any TEAEs, drug-related TEAEs, or discontinued due to TEAEs.

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.

OBJECTIVE: To 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). METHODS: Post 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. RESULTS: Seven 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. CONCLUSIONS: The 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.

Tolerability and efficacy of adjunctive brivaracetam in adults with focal seizures by concomitant antiseizure medication use: Pooled results from three phase 3 trials.

OBJECTIVE: This study was undertaken to evaluate safety/tolerability and efficacy of adjunctive brivaracetam (BRV) in patients on one or two concomitant antiseizure medications (ASMs) and in patients on one specific concomitant ASM. METHODS: Post hoc analysis was made of double-blind trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in adults with focal seizures randomized to BRV (50-200 mg/day; approved therapeutic dose range for adults) or placebo with concomitant ASM regimen unchanged throughout a 12-week evaluation period. Outcomes were analyzed in patients on one or two concomitant ASMs, and those on concomitant carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), or valproate (VPA) only. RESULTS: Patients randomized to BRV with one or two concomitant ASMs, respectively (n = 181/557), reported similar incidences of treatment-emergent adverse events (TEAEs; 68.0%/66.4%), drug-related TEAEs (41.4%/41.5%), and TEAEs leading to discontinuation (6.6%/5.4%). Respective values for patients randomized to placebo with one or two concomitant ASMs (n = 95/331) were 60.0%/60.7% (TEAEs), 32.6%/30.2% (drug-related TEAEs), and 2.1%/4.5% (TEAEs leading to discontinuation). The incidences of TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation by specific concomitant ASM (CBZ, LTG, OXC, VPA) were similar to the overall incidences in patients taking one concomitant ASM. In patients on one or two concomitant ASMs, respectively, 50% responder rates were numerically higher on BRV (42.3%/36.8% [n = 175/511]) versus placebo (18.3%/19.5% [n = 93/298]). Patients with one or two ASMs on BRV (n = 175/509) versus placebo (n = 92/298) also had numerically higher 100% responder rates (BRV, 9.1%/4.5%; placebo, 1.1%/.3%) and seizure freedom (6.9%/3.7%; 1.1%/0). For patients taking concomitant CBZ, LTG, OXC, or VPA, efficacy was numerically higher with BRV (n = 54/30/27/27) versus placebo (n = 34/13/10/14-15; 50% responder rates: BRV, 31.5%/30.0%/40.7%/70.4%; placebo, 17.6%/7.7%/20.0%/33.3%; 100% responder rates: BRV, 5.6%/10.0%/11.1%/11.1%; placebo, 0 for all; seizure freedom: BRV, 3.7%/6.7%/7.4%/11.1%; placebo, 0 for all). SIGNIFICANCE: Therapeutic doses of BRV were efficacious and well tolerated regardless of the number of concomitant ASMs (one or two) or specific concomitant ASM (CBZ, LTG, OXC, VPA).

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.

INTRODUCTION: 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. METHODS: Data were pooled from patients with focal seizures on 1-2 concomitant antiseizure medications (ASMs) randomized to BRV 50, 100, 200 mg/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). RESULTS: In ≥ 5 previous ASMs subgroup (BRV 50, 100, 200 mg/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 50 mg/day (p = 0.38), 18.1% for 100 mg/day (p = 0.006), 19.8% for 200 mg/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 50-200 mg/day, respectively (placebo: 13.2%); odds ratios versus placebo were statistically significant (p < 0.05) for BRV 100, 200, and 50-200 mg/day. In 0-4 previous ASMs subgroup (BRV 50, 100, 200 mg/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 in the ≥ 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%). CONCLUSION: Adjunctive BRV showed efficacy and was generally well tolerated in adults with focal seizures independent of the number of previous ASMs.

Towards realizing the vision of precision medicine: AI based prediction of clinical drug response.

Accurate and individualized prediction of response to therapies is central to precision medicine. However, because of the generally complex and multifaceted nature of clinical drug response, realizing this vision is highly challenging, requiring integrating different data types from the same individual into one prediction model. We used the anti-epileptic drug brivaracetam as a case study and combine a hybrid data/knowledge-driven feature extraction with machine learning to systematically integrate clinical and genetic data from a clinical discovery dataset (n = 235 patients). We constructed a model that successfully predicts clinical drug response [area under the curve (AUC) = 0.76] and show that even with limited sample size, integrating high-dimensional genetics data with clinical data can inform drug response prediction. After further validation on data collected from an independently conducted clinical study (AUC = 0.75), we extensively explore our model to gain insights into the determinants of drug response, and identify various clinical and genetic characteristics predisposing to poor response. Finally, we assess the potential impact of our model on clinical trial design and demonstrate that, by enriching for probable responders, significant reductions in clinical study sizes may be achieved. To our knowledge, our model represents the first retrospectively validated machine learning model linking drug mechanism of action and the genetic, clinical and demographic background in epilepsy patients to clinical drug response. Hence, it provides a blueprint for how machine learning-based multimodal data integration can act as a driver in achieving the goals of precision medicine in fields such as neurology.

Adjunctive Brivaracetam in Indian Patients with Uncontrolled Focal Epilepsy: Results from a Pooled Analysis of Two Double-Blind, Randomized, Placebo-Controlled Trials.

BACKGROUND: Nearly one-third of patients don't achieve seizure control with existing antiepileptic drugs. Brivaracetam (BRV) is a new member of the racetam class of drug, designed to selectively target SV2A, with binding affinity 15- to 30-fold greater than that of levetiracetam. OBJECTIVE: This pooled analysis reports efficacy and tolerability data of adjunct BRV (50, 100, and 200 mg/day) compared with placebo in Indian patients with uncontrolled focal epilepsy. METHODS: Data of 104 patients (aged 16-80 years) from 2 studies (N01252 and N01358) were pooled for this analysis. The studies comprised an 8-week prospective baseline period, and a 12-week treatment period. The study endpoints included median percent reduction from baseline in focal seizure frequency/28-days, ≥50% responder rate, and seizure freedom (all seizure types). The safety analysis included treatment-emergent adverse events (TEAEs). RESULTS: The efficacy population comprised 101 patients. In the Indian sub-group population, median percent reduction from baseline in focal seizure frequency/28-days was greater in the BRV dose groups: 39.7% (p = 0.00868), 46.8% (p = 0.00180) and 48.2% (p = 0.05224), for BRV 50, 100, 200 mg/day, respectively, compared with 20.6% for placebo. Responder rates (≥50%) were 38.1%, 45.7%, and 45.5% for BRV 50, 100, and 200 mg/day, respectively, compared with 11.7% for placebo. Complete seizure freedom was reported by 4.8% (1/21) and 2.9% (1/35) of patients on BRV50 and 100 mg/day, respectively, and none out of the 11 and 34 patients on BRV200 mg/day and placebo, respectively. In the safety population (n = 104), most commonly reported TEAEs (reported by ≥5% of patients taking brivaracetam) were headache and cough; most TEAEs were mild or moderate in intensity. CONCLUSION: This pooled analysis has provided evidence that adjunct brivaracetam, was effective and well-tolerated in Indian patients with uncontrolled focal epilepsy.

Long-term safety and efficacy of brivaracetam in adults with focal seizures: Results from an open-label, multinational, follow-up trial.

BACKGROUND: This long-term follow-up (LTFU) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses (maximum of 200 mg/day) in patients with focal seizures. The secondary objective was to evaluate the efficacy of BRV over time. METHODS: Two Phase III, randomized, double-blind, historical-controlled conversion-to-monotherapy trials (N01276: NCT00698581; N01306: NCT00699283) were conducted in patients aged ≥16 years with uncontrolled focal seizures. Patients who completed either of these core trials or who met a protocol-defined exit criterion could enter this LTFU trial (N01315; NCT00761774). Patients entered LTFU at a recommended BRV dose of 100 mg/day, with flexible dosing of 50-200 mg/day, as monotherapy or adjunctive therapy; additional AEDs could be prescribed and adapted in dose if clinically indicated. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables included duration of continuous monotherapy, reduction in focal seizure frequency and seizure freedom. Safety and efficacy variables were assessed for all patients in the safety set or efficacy set, respectively, regardless of BRV treatment regimen. In addition, a post hoc subgroup analysis was conducted for patients who completed the BRV monotherapy period in either core trial, and entered the LTFU on BRV monotherapy. For this subgroup, TEAEs were summarized by 3-month time intervals over the first 12 months of LTFU. RESULTS: 108 patients were enrolled in the LTFU trial between November 2008 and February 2010. 79 (73.1 %) patients discontinued the LTFU trial, most commonly due to lack of efficacy [37 (34.3 %)] and adverse events [16 (14.8 %)]. At core trial baseline, patients had a median of 6.3 focal seizures/28 days and 53 (49.1 %) had failed ≥5 previous lifetime AEDs. During LTFU, 70 (64.8 %) patients had ≥12 months and 56 (51.9 %) patients had ≥24 months of BRV treatment. TEAEs were reported by 98 (90.7 %) patients; most commonly (≥15 % of patients) convulsion (17.6 %), nasopharyngitis (17.6 %), depression (16.7 %) and fatigue (15.7 %). Median percent reduction from baseline in focal seizure frequency/28 days was 56.8 %. Among 86 patients who completed at least 6 months of treatment, 29 (33.7 %) patients were seizure-free for ≥6 months and 22 (25.6 %) were seizure-free for ≥12 months. 50/108 patients were included in the BRV monotherapy subgroup; 33/50 (66.0 %) patients reported a TEAE in the core trials, while 26/50 (52.0 %), 15/37 (40.5 %), 14/33 (42.4 %) and 9/27 (33.3 %) patients reported any TEAE during LTFU months 1-3, 4-6, 7-9 and 10-12, respectively. In the BRV monotherapy subgroup, the most common TEAEs (≥5% of patients) during LTFU months 1-3 were fatigue [3/50 (6.0 %)] and dizziness [3/50 (6.0 %)]. INTERPRETATION: Results from the LTFU trial support the long-term safety of BRV at individualized doses of up to 200 mg/day as a well-tolerated, and effective treatment for patients with focal seizures. Efficacy analyses indicate that seizure reductions with brivaracetam were generally maintained over time.

Effect of lifetime antiepileptic drug treatment history on efficacy and tolerability of adjunctive brivaracetam in adults with focal seizures: Post-hoc analysis of a randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal seizures by the number of lifetime (previous and concomitant) antiepileptic drugs (AEDs). METHODS: Post-hoc analysis of data from N01358 (NCT01261325), a randomized, double-blind, placebo (PBO)-controlled Phase III trial evaluating BRV 100 and 200 mg/day in patients ≥16 years of age with uncontrolled focal seizures. Efficacy and tolerability outcomes were assessed for the 12-week Treatment Period in subgroups of patients with 1-2, 3-4, 5-6, or ≥7 lifetime AEDs. RESULTS: 764 patients received at least one dose of trial medication (BRV: 503; PBO: 261; Safety Set), of whom 14.3% had 1-2, 20.8% had 3-4, 21.3% had 5-6, and 43.6% had ≥7 lifetime AEDs. In all lifetime AED subgroups, >85% of patients completed the trial. Patients with a higher number of lifetime AEDs had a younger age at epilepsy onset, longer epilepsy duration, and higher baseline seizure frequency. In patients on BRV, 50% responder rates were 49.3%, 44.4%, 47.2% and 27.4% in patients with 1-2 (n = 75), 3-4 (n = 99), 5-6 (n = 108) and ≥7 (n = 219) lifetime AEDs; 75% responder rates were 36.0%, 21.2%, 22.2% and 12.3%. In patients on PBO, 50% responder rates were 35.3%, 25.9%, 20.4% and 15.9% in patients with 1-2 (n = 34), 3-4 (n = 58), 5-6 (n = 54) and ≥7 (n = 113) lifetime AEDs; 75% responder rates were 26.5%, 6.9%, 3.7% and 4.4%. The Kaplan-Meier estimated probability of patients achieving a sustained 50% or 75% response from the first day of treatment was generally higher in patients with a lower number of lifetime AEDs (both in patients on BRV and PBO). In patients on adjunctive BRV, the incidence of drug related treatment-emergent adverse events (TEAEs) was 34.7%, 26.0%, 44.4% and 47.7% in patients with 1-2 (n = 75), 3-4 (n = 100), 5-6 (n = 108) and ≥7 (n = 220) lifetime AEDs; the incidence of discontinuations due to TEAEs was 1.3%, 3.0%, 8.3% and 10.5%. CONCLUSIONS: This post-hoc analysis suggests a numerically higher response to adjunctive BRV in patients with fewer lifetime AEDs. The lowest response was observed in patients with ≥7 lifetime AEDs, although these patients could also benefit from adjunctive BRV treatment. Patients with fewer lifetime AEDs had lower discontinuation of BRV due to TEAEs.

Time course of drug-related treatment-emergent adverse side effects of brivaracetam.

OBJECTIVE: Treatment-emergent adverse events (TEAEs) in clinical trials are typically reported for the full duration of the treatment period including titration and maintenance. Drug-related central nervous system (CNS) TEAEs are common with antiseizure medications (ASMs) and can affect drug tolerability. In this report, we test the hypothesis that drug-related CNS TEAEs have early onset and decrease with time. Unlike prior ASM clinical trials, a novel design was used for brivaracetam (BRV) without initial drug titration allowing assessment of habituation to TEAEs separate from dose titration. METHODS: Data were pooled from three studies (N01252 [NCT00490035], N01253 [NCT00464269], N01358 [NCT01261325]) in adult patients (≥16 years of age) with focal seizures receiving BRV adjunctive therapy. This post hoc analysis reports data on the prevalence and incidence of all drug-related CNS TEAEs and all TEAEs over time in patients who received BRV doses of 50-200 mg/day (without titration) vs. placebo during a 12-week treatment period. RESULTS: A total of 1262 patients received the following: placebo (n = 459), BRV 50 mg/day (n = 200), BRV 100 mg/day (n = 353), and BRV 200 mg/day (n = 250). Both the incidence (p < .0001) and prevalence (p < .0001) of drug-related CNS TEAEs (all with frequency ≥ 5%) changed across time with peak TEAEs in week 1 then significantly reducing over the first 6 weeks for prevalence and the first 3 weeks for incidence. CONCLUSIONS: Drug-related CNS TEAEs occurred early and substantially habituated over several weeks. TEAEs of ASMs might be better represented by division into early and late phases to guide clinician monitoring and patient expectations.

Time course of 75%-100% efficacy response of adjunctive brivaracetam.

BACKGROUND: Time to sustained seizure frequency reduction can provide clinically meaningful epilepsy outcomes. AIMS OF THE STUDY: To examine the time course of brivaracetam (BRV) efficacy in adults with focal seizures and focal to bilateral tonic-clonic seizures (FBTCS). METHODS: Post hoc analysis of data pooled from three randomized controlled trials of oral adjunctive BRV in adults with epilepsy. Patients with focal epilepsy and a subpopulation with FBTCS receiving BRV 50, 100, or 200 mg/d (initiated without up-titration) or placebo for 12 weeks were analyzed for time to sustained ≥75%, ≥90%, and 100% seizure reduction without interruption from first day until trial ends. RESULTS: Evaluation included 1160 patients with focal seizures, including 352 patients with FBTCS. Sustained ≥75%, ≥90%, and 100% response in focal seizures was higher from day 1 for BRV 100 and 200 mg/d vs placebo (P < .01). Sustained ≥75% and 100% FBTCS reduction from day 1 was higher for BRV 100 and 200-mg/d groups vs placebo (P < .01). CONCLUSIONS: The majority of patients achieving 75%-100% sustained seizure frequency reduction (all focal seizure types and the subpopulation with FBTCS) with oral BRV (100 or 200 mg/d) achieved this response on the first-treatment day.

Safety and tolerability of adjunctive brivaracetam in children with focal seizures: Interim analysis of pooled data from two open-label trials.

OBJECTIVE: To evaluate long-term safety and tolerability of adjunctive brivaracetam (BRV) in children with epilepsy. METHODS: This was an interim analysis (cut-off March 15, 2017) of pooled data from two open-label, single-arm, multicentre trials. N01263 (NCT00422422) was a 3-week trial of BRV 0.8-4 mg/kg/day in patients (1 month-<16 years) with epilepsy. Patients who completed this trial could continue into a long-term follow-up trial (N01266, NCT01364597) which also directly enrolled patients (4-<17 years) with focal seizures. After dose-escalation, patients received BRV 1-5 mg/kg/day (maximum 200 mg/day) during long-term evaluation. Data are reported for patients aged 4 to <16 years with focal seizures. RESULTS: The safety set comprised 149 patients: 34 from the initial trial (26 entered long-term trial) and 115 directly enrolled into the long-term trial. At the cut-off, 90 patients were receiving BRV (total exposure: 299.4 patient-years). Treatment-emergent adverse events (TEAEs) were reported by 140/149 (94.0%) patients, most commonly (≥20%) nasopharyngitis (24.8%), pharyngitis (22.1%), convulsion (21.5%), and pyrexia (20.1%). TEAEs considered drug-related by the investigator were reported by 56/149 (37.6%) patients, most commonly somnolence (6.0%). Two patients died; neither death was considered related to BRV. Mean changes from baseline in child behaviour rating scales were small; most patients remained in their baseline category. CONCLUSION: In this pooled analysis of two open-label trials including long-term data, adjunctive BRV was generally well tolerated in children aged 4 to <16 years with focal seizures. These findings supported approval of BRV as a new therapy option for children aged ≥4 years with focal seizures.

Effectiveness and safety of certolizumab pegol in rheumatoid arthritis patients in Canadian practice: 2-year results from the observational FαsT-CAN study.

BACKGROUND: The aim of this study was to assess the real-world effectiveness and safety of certolizumab pegol (CZP) in rheumatoid arthritis (RA) patients, and the impact on patients' productivity, pain, and fatigue, in Canadian practice. METHODS: FαsT-CAN, a 2-year prospective, observational study, evaluated CZP use in Canadian adults with moderate to severe, active RA. The primary objective was to assess the proportion of patients achieving 28-joint Disease Activity Scores (DAS28) <2.6 at Week 104. Secondary and additional endpoints assessed the improvements in Patients' Assessment of Arthritis Pain (PtAAP), fatigue, Health Assessment Questionnaire-Disability Index (HAQ-DI), and the proportion of patients achieving minimal clinically important differences (MCID) in HAQ-DI. Validated arthritis-specific Work Productivity Surveys (WPS-RA) assessed the RA-associated impact on productivity. Incidence of CZP-related treatment-emergent adverse events (TEAEs) was reported for patients receiving ⩾1 dose of CZP (safety set). RESULTS: The full analysis set (baseline DAS28 ⩾ 2.6, ⩾1 dose of CZP and ⩾1 valid post-baseline DAS28 measurement) included 451 of the 546 patients recruited into the study; a total of 229/451 (50.8%) patients completed Week 104. At Week 104, 90/451 (20.0%) patients achieved DAS28 < 2.6. Rapid improvements in disease activity, pain, and fatigue were observed. At Week 104, 66.2% of patients achieved HAQ-DI MCID. Patients employed at Week 104, reported reduced absenteeism, and improved productivity. CZP-related TEAEs were consistent with the known CZP safety profile. CONCLUSIONS: CZP was an effective RA treatment in Canadian practice, and no new CZP-related safety signals were identified. The improvements in household and workplace productivity are the first observations in a real-world Canadian setting.

Brivaracetam-induced elevation of carbamazepine epoxide levels: A post-hoc analysis from the clinical development program.

To assess the association, if any, between brivaracetam (BRV)-induced elevated carbamazepine-10,11-epoxide (CBZ-E) and toxicity and efficacy in patients with epilepsy. Data were pooled from three double-blind, placebo-controlled, Phase III studies of adjunctive BRV in adults with uncontrolled focal seizures (N01252/NCT00490035, N01253/NCT00464269, N01358/NCT01261325). Treatment-emergent adverse events (TEAEs) of interest (ataxia, diplopia, dizziness, nystagmus, somnolence, accidental overdose or poisoning, and toxicity), discontinuations due to TEAEs, and serious TEAEs (SAEs) were assessed in subgroups who did/did not receive carbamazepine (CBZ) at study entry (CBZ+ and CBZ-). Logistic regression analysis evaluated CBZ-E/CBZ plasma concentrations and TEAEs. SAEs suggestive of CBZ-E toxicity were summarized from the BRV safety database up to a cut-off of October 1, 2014. Percent reduction in focal seizure frequency over placebo was assessed in subgroups of CBZ-E/CBZ ratios. Data from 1558 patients were included in the pooled safety population. Of these, concomitant CBZ was received by 184/459 (40.1%) placebo-treated and 315/803 (39.2%) BRV-treated patients (≥50 mg/day). In BRV-treated patients, study completion rates were similar in the CBZ+ (92.7%) and CBZ- (88.7%) groups; incidence of TEAEs of interest was similar (CBZ+ 24.4%; CBZ- 24.2%), and did not appear affected by CBZ dosage; SAEs and discontinuations due to TEAEs were CBZ+ 1.6%; CBZ- 3.9% and 2.9%; 9.2%, respectively. Likelihood of TEAEs of interest decreased with increasing CBZ-E/CBZ ratio for BRV-treated patients: odds ratio 0.88 (95% confidence intervals 0.74, 1.03; p = 0.112). In the safety database, five SAEs suggestive of CBZ-E toxicity were identified. Efficacy outcomes did not appear to have a consistent pattern across CBZ-E/CBZ ratio subgroups. This post-hoc analysis does not support an association between CBZ-E levels and TEAEs potentially associated with CBZ-E toxicity, or with increases in efficacy. Overall, current evidence does not suggest that BRV dose adjustment is required with concomitant CBZ.

Efficacy, safety, and tolerability of brivaracetam with concomitant lamotrigine or concomitant topiramate in pooled Phase III randomized, double-blind trials: A post-hoc analysis.

OBJECTIVE: The objective was to assess the efficacy and safety of adjunctive brivaracetam (BRV) with concomitant use of lamotrigine (LTG) or topiramate (TPM) in patients with uncontrolled focal seizures. METHODS: Data were pooled from three randomized, placebo-controlled Phase III studies (NCT00490035/N01252, NCT00464269/N01253, NCT01261325/N01358) of adults with focal (partial-onset) seizures. Patients taking concomitant levetiracetam were excluded from the efficacy populations, but included in the safety populations. This post-hoc analysis reports data from patients taking BRV in the approved therapeutic range (50-200mg/day) concomitantly with LTG or TPM. RESULTS: The number of patients in each of the three BRV dosage groups was small, particularly for the TPM subgroup. Mean percent reduction over placebo in baseline-adjusted focal seizure frequency/28days for BRV 50, 100, and 200mg/day was 8.7, 5.3, and 8.9 in the LTG subgroup (n=220), and 8.4, 21.3, and -4.2 in the TPM subgroup (n=122). The ≥50% responder rate with concomitant LTG or TPM with BRV 50, 100, and 200mg/day or placebo was LTG: 28.1%, 36.1%, 34.1%, and 29.1%; and TPM: 14.3%, 44.4%, 25.0%, and 17.5%. There were numerically ≥50%, ≥75%, ≥90%, and 100% responder rates for patients taking BRV ≥50mg/day compared with placebo in both subgroups. In the LTG and TPM safety populations (n=245 versus n=125), treatment-emergent adverse events (TEAEs) were reported with LTG 68.7% versus 68.4%, and TPM 65.6% versus 57.8% (BRV ≥50mg/day versus placebo). Discontinuations due to TEAEs versus placebo were LTG 7.3% versus 6.3% and TPM 8.2% versus 4.7%. The three most frequently reported TEAEs for both subgroups were somnolence, dizziness, and fatigue. Of these, the incidence of fatigue in the LTG population appeared to increase with dose. SIGNIFICANCE: In this post-hoc pooled analysis, BRV administered with concomitant LTG or TPM reduced seizure frequency and was generally well tolerated for BRV doses of 50-200mg/day.

Long-term retention rates for antiepileptic drugs: A review of long-term extension studies and comparison with brivaracetam.

Antiepileptic drug (AED) retention rates are frequently reported in the literature and used to inform clinical decision-making, but methodological differences in the determination of retention rates make comparisons between trials difficult. Open-label extension (OLE) studies of AEDs in patients with focal epilepsy were identified from the literature. Retention calculation methods were reviewed, and published AED retention rates qualitatively compared with corresponding data for brivaracetam (BRV), a synaptic vesicle protein 2A ligand. The search identified 40 publications (corresponding to 17 studies of nine AEDs: eslicarbazepine, gabapentin, lacosamide, levetiracetam, oxcarbazepine, perampanel, pregabalin, topiramate and zonisamide) meeting eligibility criteria for inclusion in the review. Three methodologies to estimate retention rate were identified, which differed in whether patients randomised to placebo in the preceding randomised controlled trials (RCTs) were included or analysed separately, and whether retention was measured from the start of the OLE or of active treatment exposure. The most robust, conservative approach included all patients and measured retention from start of active treatment exposure, whether during the blinded RCT or at the start of the OLE (placebo RCT patients). Data using this method was available for five AEDs in this review, including BRV. The corresponding BRV 52week retention rate (modal doses 50-200mg/day; therapeutic range) was 69.8% (63.3-66.7% for other AEDs at this time point). No statistical indirect comparison was performed, as study populations were clinically heterogeneous. To avoid inconsistencies in methodologies, and allow comparison between AEDs when OLE data are the only long-term data available, retention rate analyses would benefit from the development of consistent reporting standards and guidelines.