Sustained seizure freedom with adjunctive brivaracetam in patients with focal onset seizures.
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SUBMITTER: Lattanzi S
PROVIDER: S-EPMC9311068 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:INTRODUCTION:There is an unmet need for well-tolerated antiepileptic drugs (AEDs) that effectively control focal onset seizures. This study aimed to evaluate the economic value of new AEDs in the treatment of focal onset seizure, with or without secondary generalization, in Finnish adults and adolescents with epilepsy, comparing brivaracetam with perampanel as adjunctive AEDs. METHODS:Economic value was assessed using cost-utility analysis. Periods of AED initiation, titration, response assessment (seizure freedom,???50% reduction, no response), switching in no response or treatment-emergent adverse events (TEAEs), and death were simulated using a discrete-event simulation model. Responses and switching were simulated based on a comprehensive Bayesian network meta-analysis. The primary modeled outcome was the 3%/year discounted incremental cost-effectiveness ratio (ICER). Discounted quality-adjusted life-years (QALYs), payer costs (year 2017 Euro) per patient, and net monetary benefit (NMB) were secondary outcomes. Probabilistic and comprehensive deterministic sensitivity analyses were conducted. RESULTS:Brivaracetam was more efficacious and had fewer TEAEs than perampanel and other AEDs. Modeled average 5-year QALYs and costs were 3.671 and €28,297 for brivaracetam and 3.611 and €27,979 for perampanel, respectively. The resulting ICER for brivaracetam versus perampanel was only €5345/QALY gained in a deterministic base case scenario. Brivaracetam had a positive NMB and high probability of cost-effectiveness of €1190 and 71% or €1944 and 80% with the assumed willingness to pay of €25,358 or €38,036/QALY gained, respectively. The primary result was robust, with a positive NMB persistent in all sensitivity analysis scenarios. When switching from brivaracetam to perampanel was excluded from the modeling or switching from perampanel to brivaracetam was included, brivaracetam was cost-saving and more effective than perampanel (dominant). CONCLUSION:These simulated comparisons demonstrated that brivaracetam was more effective and potentially also more affordable than perampanel. Thus, brivaracetam is likely a cost-effective and net beneficial alternative to perampanel for treatment of focal onset seizures. Plain language summary available for this article.
| S-EPMC6979440 | biostudies-literature
Project description:Brivaracetam (Briviact): a novel adjunctive therapy for partial-onset seizures.
| S-EPMC5265234 | biostudies-literature
Project description:IntroductionThis 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.MethodsThis 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.ResultsNine 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.ConclusionBRV 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.
| S-EPMC10960767 | biostudies-literature
Project description:PurposePreference-based measures are required to measure the impact of interventions for cost-effectiveness analysis. This study assessed the psychometric performance of the EQ-5D-3L in adults with uncontrolled focal (partial-onset) seizures.MethodsData from three Phase III studies of an antiepileptic drug (adjunctive brivaracetam; n = 1095) were used. Analysis included correlations between EQ-5D-3L and Quality of Life in Epilepsy Inventory (QOLIE-31P) and seizure frequency. Known group validity was based on ability of the EQ-5D-3L to discriminate between baseline QOLIE-31P total scores, seizure type and number of antiepileptic drugs using effect sizes (ES). Responsiveness assessed proportions reporting highest or lowest scores, overall change using standardized response means (SRM) and change by responder and clinician/patient evaluation groups using ES.ResultsCorrelations were weak to moderate (ρ = 0.2-0.4) between EQ-5D-3L dimensions and QOLIE-31P subscales, apart from medication effects (ρ < 0.1); seizure frequency was not associated with either measure. Known group analysis had small ES. A quarter (24.9%) of patients had a baseline EQ-5D-3L utility score of 1 (full health) but lower average QOLIE-31P scores. SRMs were small (<0.1) in EQ-5D-3L compared with 0.1-0.4 for QOLIE-31P subscales. Results across the studies were mixed for responder status and clinician/patient evaluation of improvement for EQ-5D-3L.ConclusionsEQ-5D-3L had weak-to-moderate correlations with QOLIE-31P and varied with QOLIE-31P severity groups, but showed less responsiveness than QOLIE-31P. Given this lack of sensitivity, EQ-5D-3L may not be appropriate for measuring the impact of interventions in cost-effectiveness analysis in this population and disease-specific preference-based measures may be more appropriate.
| S-EPMC5309305 | biostudies-literature
Project description:The apparent unpredictability of epileptic seizures has a major impact in the quality of life of people with pharmacologically resistant seizures. Here, we present initial results and a proof-of-concept of how focal seizures can be predicted early in advance based on intracortical signals recorded from small neocortical patches away from identified seizure onset areas. We show that machine learning algorithms can discriminate between interictal and preictal periods based on multiunit activity (i.e. thresholded action potential counts) and multi-frequency band local field potentials recorded via 4 X 4 mm2 microelectrode arrays. Microelectrode arrays were implanted in 5 patients undergoing neuromonitoring for resective surgery. Post-implant analysis revealed arrays were outside the seizure onset areas. Preictal periods were defined as the 1-hour period leading to a seizure. A 5-minute gap between the preictal period and the putative seizure onset was enforced to account for potential errors in the determination of actual seizure onset times. We used extreme gradient boosting and long short-term memory networks for prediction. Prediction accuracy based on the area under the receiver operating characteristic curves reached 90% for at least one feature type in each patient. Importantly, successful prediction could be achieved based exclusively on multiunit activity. This result indicates that preictal activity in the recorded neocortical patches involved not only subthreshold postsynaptic potentials, perhaps driven by the distal seizure onset areas, but also neuronal spiking in distal recurrent neocortical networks. Beyond the commonly identified seizure onset areas, our findings point to the engagement of large-scale neuronal networks in the neural dynamics building up toward a seizure. Our initial results obtained on currently available human intracortical microelectrode array recordings warrant new studies on larger datasets, and open new perspectives for seizure prediction and control by emphasizing the contribution of multiscale neural signals in large-scale neuronal networks.
| S-EPMC6645464 | biostudies-literature
Project description:BackgroundCenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABAA receptors, binding at a non-benzodiazepine site.ObjectiveWe assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques.MethodsWe systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome.ResultsTwo trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67-2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93-7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85-2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08-4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02-1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia.ConclusionsAdjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.
| S-EPMC7658084 | biostudies-literature
Project description:ObjectiveThis post hoc analysis evaluated whether continued treatment with perampanel monotherapy beyond initial titration may be appropriate for patients with focal-onset seizures (FOS) with currently untreated epilepsy to achieve seizure freedom with an effective dose.MethodsStudy 342 (NCT03201900; FREEDOM) is a single-arm, open-label, Phase III study of perampanel monotherapy. Patients aged ≥12 years with untreated FOS received perampanel 4 mg/d in a 32-week Treatment Phase (6-week Titration and 26-week Maintenance Periods); in case of seizure(s) during Maintenance Period, patients could enter a 30-week Treatment Phase (4-week Titration and 26-week Maintenance Periods) to be up-titrated to perampanel 8 mg/d. The primary endpoint was seizure-freedom rate during Maintenance Period in the modified Intent-to-Treat (mITT) Analysis Set (patients who had ≥1 post-dose efficacy measurement during Maintenance Period); safety was monitored. This analysis of 4-mg/d efficacy data assessed the proportion of patients achieving seizure freedom during the Maintenance Period (responders) relative to patients with an early/later response (depending on seizure status during the Titration Period).ResultsIn the mITT population (n = 73), 46 patients were 4-mg/d responders; of whom, 37 (80.4%) were early responders and nine (19.6%) were later responders. The mean (standard deviation) percent reductions in FOS frequency from baseline at the end of the 4-mg/d Titration Period were 100.0% (0.0%; early responders) and 46.3% (97.3%; later responders). Among the 27 4-mg/d nonresponders, nine (33.3%) patients who had an early response experienced seizure(s) during the subsequent 4-mg/d Maintenance Period. Safety outcomes were similar, regardless of responder status, without new safety concerns.SignificanceSome patients with untreated FOS may benefit from continued treatment beyond initial titration of perampanel monotherapy to achieve seizure freedom, suggesting that it may not be appropriate to make treatment decisions to discontinue or switch from perampanel monotherapy solely based on seizure response before an effective dose has been reached.
| S-EPMC8886102 | biostudies-literature
Project description:ObjectiveThis 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.MethodsPost 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.ResultsPatients 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).SignificanceTherapeutic 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).
| S-EPMC9541390 | biostudies-literature
Project description:ObjectiveTo evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures.MethodsIn this double-blind trial (SP0969; NCT01921205), patients (age ≥4-<17 years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide/placebo. After a 6-week titration, patients who reached the target dose range for their weight (<30 kg: 8-12 mg/kg/d oral solution; ≥30-<50 kg: 6-8 mg/kg/d oral solution; ≥50 kg: 300-400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance.ResultsThree hundred forty-three patients were randomized; 306 (lacosamide 152 of 171 [88.9%]; placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1%; placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% (p = 0.0003). During maintenance, median percent reduction in focal seizure frequency per 28 days was 51.7% for lacosamide and 21.7% for placebo. Fifty percent responder rates (≥50% reduction) were 52.9% and 33.3% (odds ratio 2.17, p = 0.0006). During treatment, treatment-emergent AEs were reported by 67.8% lacosamide-treated patients (placebo 58.1%), most commonly (≥10%) somnolence (14.0%, placebo 5.2%) and dizziness (10.5%, placebo 3.5%).ConclusionsAdjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures.Clinicaltrialsgov identifierNCT01921205.Classification of evidenceThis trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.
| S-EPMC6808531 | biostudies-literature
Project description:ObjectiveTo evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs.MethodsIn this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment.ResultsTwo hundred twenty-two patients were randomized; 113 received cenobamate and 109 received placebo; and 90.3% and 90.8% of patients, respectively, completed double-blind treatment. Median baseline seizure frequency was 6.5 in 28 days (range 0-237). Compared to placebo, cenobamate conferred a greater median percent seizure reduction (55.6% vs 21.5%; p < 0.0001) The responder rate (≥50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo (p < 0.0001). Focal seizures with motor component, impaired awareness, and focal to bilateral tonic-clonic seizures were significantly reduced with cenobamate vs placebo. During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free. Treatment-emergent adverse events reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%).ConclusionAdjunctive treatment with cenobamate 200 mg/d significantly improved seizure control in adults with uncontrolled focal seizures and was well tolerated.Clinicaltrialsgov identifierNCT01397968.Classification of evidenceThis study provides Class I evidence that, for patients with uncontrolled focal seizures, adjunctive cenobamate reduces seizures.
| S-EPMC7357293 | biostudies-literature