OBJECTIVE:To investigate changes in quality of life (QoL) dimensions and their relationship with seizure outcome, depression, and suicidality after the addition or substitution of an anti-seizure medication (ASM) in adults with drug-resistant focal epilepsy. METHODS:A total of 665 consecutively enrolled patients were followed prospectively and assessed with Quality of Life in Epilepsy Inventory 31 (QOLIE-31) and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). QoL changes over time for the overall population and seizure outcome categories were analyzed with analysis of variance (ANOVA), whereas factors affecting QoL changes were assessed by using a linear regression model. RESULTS:Seizure freedom was associated with a marked improvement across all QoL domains, ranging from 11 points for Seizure worry to 4 points for Emotional well-being. The presence of depression before starting medication and its persistence during the observation period was associated with a global worsening of QoL across all domains, ranging from 10 points worse for Social functioning, almost 8 points for Energy and fatigue, 6 points for Cognitive functioning, and to nearly 5 points for Seizure worry. The new development of depression during treatment was associated with worsening in specific QoL domains such as Cognitive functioning, Social functioning, and Overall QoL subscales. Persistent positive suicidality screening was associated with progressive worsening in the domain Emotional well-being. SIGNIFICANCE:Seizure freedom can improve all domains of QoL, but mainly Seizure worry, although this can be negatively affected by depressed mood. Improvement in the domain of Social functioning requires a period of sustained seizure freedom longer than 6 months to improve, and it is negatively influenced by persistent depressed mood. In contrast, changes in Emotional well-being are negatively influenced by suicidality. Clinical and demographic variables, including duration of epilepsy and number of comorbidities or concomitant medical problems, showed no correlation with changes in QoL.

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. 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. 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

OBJECTIVE:To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after the addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy.METHODS:Seven hundred seventy consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model.RESULTS:At baseline, 50% of patients had a positive screening test result for depression and 13% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. In addition, the number of ASMs taken at baseline correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients who were initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to the type of ASM introduced, sociodemographic variables, or seizure outcomes.SIGNIFICANCE:Almost 1 in 5 adults with drug-resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. At re-assessment 6 months later, 6.1% who screen initially negative for passive suicidal ideation become positive. These changes in screening status are independent of type of ASM introduced or seizure outcomes but correlate with psychiatric status at baseline.

Objective Head-to-head randomized controlled trials (RCTs) are the gold standard for assessing comparative treatment effects. In the absence of direct comparisons between all possible antiepileptic drugs (AEDs), however, clinical decision-making in focal (partial onset) epilepsy relies on alternative evidence borne from indirect comparisons including network meta-analyses (NMAs) and from real-world evidence (RWE) studies. We review NMAs and observational RWE studies comparing AEDs in the adjunctive setting to compare the robustness of these methods and to formulate recommendations for future evidence development. Methods A literature review identified NMAs and RWE studies comparing AEDs for the adjunctive treatment of focal seizures published between January 2008 and October 2018. NMAs were evaluated for robustness using a framework based on guidelines from the National Institute for Health and Care Excellence Decision Support Unit and the International Society for Pharmacoeconomics and Outcomes Research. RWE studies were evaluated using the GRACE checklist. Results From a total of 1993 records, 11 NMAs and six RWE studies were eligible. Key limitations identified in the NMAs include nonsystematic selection of RCTs, unexplored heterogeneity between included RCTs in terms of study and patient characteristics, and selection of AEDs and AED doses or dosing strategies that are not reflective of clinical practice. The main limitations of RWE studies concern sample size, design, and analysis methods. Approximately 90% of comparisons between individual AEDs were nonsignificant in the NMAs. None of the RWE studies adjusted for baseline differences between comparator groups; therefore, they lack the validity to make comparative conclusions. Significance Current NMAs and RWE studies provide only nominal comparative evidence for AED treatments in focal epilepsy, and should be used with caution for decision-making due to their methodological limitations. To overcome these hurdles, adherence to methodological guidelines and concerted efforts to collect relevant outcome data in the real world are needed.

BACKGROUND: The cost of epilepsy is usually reported as total expenditure over a certain period. However, with the increased availability of acute treatments for use in the community setting, intermittent, single-seizure treatment is now possible in addition to the chronic epilepsy drug treatment paradigm. Data on the cost of discrete health care encounters are needed to substantiate the cost-benefit of these new treatments. OBJECTIVE: To estimate the health plan-paid costs of discrete epilepsy-related health care encounters in patients with epilepsy. METHODS: This retrospective cohort study utilized IBM MarketScan Commercial Claims, Medicare Supplemental and Coordination of Benefits (Medicare patients with supplemental insurance), and Multi-State Medicaid research databases. The primary analysis determined health plan-paid cost (adjudicated claims) of discrete epilepsy-related health care encounters, defined as having a primary diagnosis code of epilepsy or convulsion, from 2013 to 2018, in patients with epilepsy aged ≥ 12 years. Costs were adjusted to 2018 prices. Epilepsy cases were defined using ICD-CM codes. We excluded patients on capitated insurance plans as their cost per health care encounter is unknown. RESULTS: In total, 353,530 commercially insured, 378,051 Medicaid, and 69,176 Medicare plus supplemental insurance patients with epilepsy were included. More than 160,000 epilepsy-related emergency transportations, 225,000 emergency department (ED) visits, 49,000 hospitalizations, 700 urgent care visits, and ~2.5 million office visits were analyzed. 37.4% of epilepsy-related hospitalizations included care in the intensive care unit (ICU). In commercially insured patients, epilepsy-related health care encounters had median health plan-paid costs of $22,305 (Q1-Q3 = $14,336-$36,096, hospitalization); $3,375 ($565-$9,095, ICU visit); $1,913 ($417-$4,163, ED visit); $687 ($415-$1,083, emergency transportation); $95 ($23-$232, office visit); and $57 ($0-$171, urgent care visit). The median length of stay for epilepsy-related hospitalizations in working age, commercially insured patients was 4 (Q1-Q3 = 2-5) days. CONCLUSIONS: This is the first study to report health plan-paid cost per epilepsy-related health care encounter. These data can serve as a basis for more granular cost-benefit analyses of not only chronic but also acute treatments of epilepsy. DISCLOSURES: This analysis was funded by UCB Pharma. The sponsor had a role in the identification, design, conduct, and reporting of the analysis. Borghs, Beaty, Boudiaf, and Loewendorf are employees of UCB Pharma. Kalilani and Parekh were employees of UCB Pharma at the time of the analysis. Borghs, Beaty, and Loewendorf have received UCB Pharma stock from their employment. Kalilani and Parekh had received UCB Pharma stock at the time of employment, but no longer hold any. This work was presented in part as a poster at the 73rd Annual Meeting of the American Epilepsy Society; December 7, 2019; Baltimore, MD.

Objective To evaluate long-term safety/tolerability of brivaracetam at individualized doses <= 200 mg/d (primary) and maintenance of efficacy over time (secondary) in adults with focal seizures or primary generalized seizures (PGS) enrolled in phase 3, open-label, long-term follow-up trial N01199 (NCT00150800). Methods Patients >= 16 years of age who had completed double-blind, placebo-controlled adjunctive brivaracetam trials NCT00175825, NCT00490035, NCT00464269, or NCT00504881 were eligible. Outcomes included safety, efficacy, and quality of life. Results The safety set included 667 patients (focal seizures, 97.8%; PGS, 2.2%); the efficacy set included 648 patients with focal seizures and 15 patients with PGS. Overall, 49.2% of patients had >= 48 months of exposure. Treatment-emergent adverse events (TEAEs) occurred in 91.2% of all patients (91.3% of focal seizures group), brivaracetam discontinuation due to TEAEs in 14.8%, drug-related TEAEs in 56.7%, and serious TEAEs in 22.8%. The most common TEAEs in the focal seizures group (>= 15%) were headache (25.3%) and dizziness (21.9%). Mean changes from baseline in Hospital Anxiety and Depression Scale scores at last value during 2-year evaluation were -0.7 (standard deviation [SD] = 4.3) and -0.2 (SD = 4.4) overall. In the focal seizures group, median reduction from baseline in focal seizure frequency/28 days was 57.3%, 50% responder rate was 55.6%, and 6-month and 12-month seizure freedom rates were 30.3% and 20.3%, respectively. Efficacy outcomes improved by exposure duration cohort and then stabilized through the 108-month cohort. Mean improvement from baseline in Patient-Weighted Quality of Life in Epilepsy Inventory total score (efficacy set) was 5.7 (SD = 16.1, Cohen's d = 0.35) at month 12 and 6.5 (SD = 18.0, Cohen's d = 0.36) at month 24. Significance Adjunctive brivaracetam was well tolerated, with a good safety profile in long-term use in adults with epilepsy at individualized doses. Approximately half of the patients remained in the trial at 4 years. Brivaracetam reduced focal seizure frequency versus baseline. Efficacy improved with increasing exposure duration and remained stable through the 9-year cohort.

The quality-adjusted-life-year (QALY) is an established means of value assessment, providing a generic measure of benefits of a product on both length and quality of life. However, posited QALY lacks sensitivity to heterogeneity between diseases in patient priorities regarding their health, poses ethical challenges by possibly being discriminatory on the basis of age and disability, and fails to capture value elements beyond what can be translated in utility values; hence, the use of QALYs as the value measure may lead to a discrepancy between payer and patient perceptions of value. A literature review revealed the extent to which current value frameworks can serve the purpose of enabling more holistic value assessments. This research introduces an innovative framework that builds on these findings and proposes an approach whereby stakeholders (patients, physicians and payers) engage to agree on a jointly accepted, holistic definition of value that moves beyond the inherent limitations of analyses purely based on the QALY measurement. Three components of value, namely, clinical outcomes, patient experience and public health impact are scored between 0 and 5 by patients, physicians and payers through a transparent dialogue to understand each stakeholder's view at the time of an intervention's assessment for reimbursement coverage. The jointly agreed individual value component scores are weighted according to relative importance as derived by patient preference studies to generate a Score of Patient Value (SPV). Payers can use the SPV to make an informed decision as to the price they are willing to pay for the value an innovation offers. This approach offers greater sensitivity to the patient voice and integrating the framework in reimbursement decision-making creates confidence that investment of scarce payer resources is aligned to where the most value is truly offered, because "value" has been determined jointly, holistically and with the patient at the center.

Objective: To estimate the relative efficacy, safety and tolerability of adjunctive brivaracetam and other antiepileptic drugs (AEDs) using a Bayesian network meta-analysis (NMA) approach. Methods: A systematic literature review (SLR) identified randomized controlled trials of AEDs treating focal (partial-onset) seizures for >= 8 weeks and assessed them for inclusion in the NMA. Bayesian random-effects NMA was performed for several outcomes. All interventions within the licensed dose range were included in the network of evidence. Results: The SLR identified 82 studies; 65 were included in the NMA. These studies had baseline mean age 33.1-38.0 years, mean duration of epilepsy 18.7-23.0 years and median seizure frequency/28 days 8.1-11.8. All AEDs had significantly higher odds than placebo of achieving >= 50% responder rates (odds ratios 1.83-3.58) and all AEDs had a trend of higher odds than placebo of achieving seizure freedom (odds ratios 1.36-5.73), most being statistically significant. Tolerability outcomes were comparable between AEDs; most AEDs had higher odds than placebo of treatment-emergent adverse events leading to discontinuation, serious AEs, nausea, fatigue, dizziness and somnolence. Conclusions: This NMA would appear to show relative equivalence in efficacy, safety and tolerability outcomes of the included AEDs. However, patient heterogeneity within trials and in clinical practice should be considered when interpreting these results. While NMAs are based on the best available evidence the authors suggest that, due to the inability of NMAs to capture unmeasured confounding factors and population heterogeneity, NMAs must not be the sole basis for comparative treatment recommendations.

OBJECTIVE:To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures. METHODS:In 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. RESULTS:Three 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%). CONCLUSIONS:Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures. CLINICALTRIALSGOV IDENTIFIER:NCT01921205. CLASSIFICATION OF EVIDENCE:This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.

May 6, 2019April 9, 2019Free AccessPediatric Focal Epilepsy: Patient Characteristics, Treatment Choices, Healthcare Resource Use and Costs by Developmental Delay and Behavioral Disorders Comorbidity Subgroups: A US Claims Database Analysis (P2.5-035)Solene Thieffry, Simon Borghs, Li Wang, Sulena Shrestha, and Nadia FoskettAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P2.5-035 Letters to the Editor

OBJECTIVE:To assess the evolution of antiepileptic drug (AED) treatment patterns and seizure outcomes in England from 2003 to 2016.DESIGN, SETTING AND PARTICIPANTS:Retrospective cohort study of electronic medical records from Clinical Practice Research Datalink and National Health Service Digital Hospital Episode Statistics databases. Patients newly diagnosed with epilepsy were identified and followed until end of data availability. Three eras were defined starting 1 April 2003 (first National Institute for Health and Care Excellence (NICE) guideline); 1 September 2007 (Standard and New Antiepileptic Drugs publication); and 1 January 2012 (second NICE guideline).OUTCOME MEASURES:Time from diagnosis to first AED; AED sequence; time from first AED to first 1-year remission period (no new AED attempts and no seizure-related healthcare events); time from first AED to refractoriness (third AED attempt regardless of reason); Kaplan-Meier analysis of time-to-event variables.RESULTS:4388 patients were included (mean follow-up: 6.8, 4.2 and 1.7 years by era). 84.6% of adults (≥16 years), 75.5% of children (<16) and 89.1% of elderly subgroup (65+) received treatment within 1 year; rates were generally stable over time. Treatment trends included reduced use of carbamazepine (adult first line, era 1: 34.9%; era 3: 10.7%) and phenytoin, earlier line and increased use of levetiracetam (adult first line, era 1: 2.6%; era 3: 26.2%) and lamotrigine (particularly in adults and elderly subgroup), and a larger number of different AEDs used. Valproate use shifted somewhat to later lines. Rates of 1-year remission within 2 years of starting treatment increased in adults (era 1: 71.9%; era 3: 81.4%) and elderly (era 1: 76.1%; era 3: 81.7%). Overall, 55.5% of patients relapsed after achieving 1-year remission. Refractoriness rates remained stable over time (~26% of adults within 5 years).CONCLUSION:Treatment trends often were not aligned with era-relevant guidance. However, our results suggest a slight improvement in epilepsy treatment outcomes over the 13-year period.

Electronic health records and health insurance claims, providing observational data on millions of patients, offer great opportunities, and challenges, for population health studies. The objective of this study is identifying subpopulations that are likely to benefit from a given treatment using observational data. We refer to these subpopulations as “better responders” and focus on characterizing these using linear scores with a limited number of variables. Building upon well-established causal inference techniques for analyzing observational data, we propose two algorithms that generate such scores for identifying better responders, as well as methods for evaluating and comparing these scores. We applied our methodology to a large dataset of ~135,000 epilepsy patients derived from claims data. Out of this sample, 85,000 were used to characterize subpopulations with better response to next-generation (“Newer”) anti-epileptic drugs (AEDs), compared to an alternative treatment by first-generation (“Older”) AEDs. The remaining 50,000 epilepsy patients were then used to evaluate our scores. Our results demonstrate the ability of our scores to identify large subpopulations of epilepsy patients with significantly better response to newer AEDs.

Background In elderly patients (≥65 years of age) with epilepsy who take medications for comorbid conditions, some antiepileptic drugs (AEDs) may alter the metabolism of other treatments and increase the risk of adverse consequences and healthcare utilisation. This analysis compares healthcare costs associated with enzyme-inducing AEDs (EIAEDs) and non-enzyme active AEDs (nEAAEDs) use in elderly patients with epilepsy. Methods This retrospective matched cohort study used the Clinical Practice Research Datalink (CPRD) of UK primary care medical records, linked to the Hospital Episode Statistics (HES) database. Selected patients with epilepsy were ≥ 65 years and prescribed an EIAED or nEAAED between 2001 and 2010 (index) after ≥1 year without AEDs (baseline) and followed until the first occurrence of the following: end of HES data coverage, end of GP registration, or death; practice’s up-to-standard status or addition of an AED belonging to another cohort or discontinuation of the last AED of that cohort. Propensity score matching reduced confounding factor effects between cohorts. Key outcomes included time to cohort treatment failure, time to index AED treatment failure, and direct healthcare costs in 2014 Pound Sterling (£) values. Results Overall, 1425 elderly patients were included: 964 with EIAEDs and 461 with nEAAEDs. At baseline, the EIAED cohort was older (mean age, 76.2 vs. 75.1 years) and a higher proportion were male. Baseline direct healthcare costs were similar. After matching ( n = 210 each), and over the entire follow-up period, median monthly direct healthcare costs were higher for patients taking EIAEDs than nEAAEDs (£403 vs. £317; p = 0.0150, Mann-Whitney U). Costs were higher for patients remaining in the EIAED cohort after 3 follow-up years. The median time to cohort treatment failure for the EIAED cohort was 1110 days vs. 1175 days for the nEAAED cohort. Conclusion Newly treated elderly patients with epilepsy were more likely to be prescribed EIAEDs than nEAAEDs. In matched cohorts, elderly patients with epilepsy treated with EIAEDs had higher average total direct and epilepsy-related healthcare costs than nEAAED-treated patients; this difference was greater than previously reported in the overall adult population. Changing treatment practices could improve patient care and reduce costs.

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 52 week retention rate (modal doses 50-200 mg/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.

Lacosamide was previously compared to other anti-epileptic monotherapies in adults with focal seizures in a network meta-analysis (NMA). The number of clinical trials in this NMA was too limited to assess the impact of heterogeneity on outcomes. To overcome the similarity assumption of the NMA, we performed a patient level data analysis of lacosamide and levetiracetam in newly-diagnosed adult epilepsy patients. Pooled patient-level data from two clinical trials –evaluating lacosamide and levetiracetam monotherapy versus controlled-release carbamazepine (carbamazepine-CR)– were analyzed to assess efficacy (6 and 12-month seizure-freedom) and tolerability (discontinuations due to adverse events [AEs]) outcomes. A propensity score was calculated to adjust for confounding factors. Carbamazepine-CR arm outcomes were compared to assess residual confounding in the lacosamide-levetiracetam comparison. In total, 444 and 285 patients were treated with lacosamide and levetiracetam. Lacosamide treatment resulted in a higher probability of being seizure free for 6-months (OR 0.69; 95%CI 0.44-1.08 for not being seizure free) and a lower risk of discontinuations due to AEs (OR 0.59; 95%CI 0.31-1.11) compared to levetiracetam. After adjusting for confounding factors, patients treated with carbamazepine-CR in the lacosamide trial had a higher probability of being seizure free for 6-months (OR 0.81; 95%CI 0.50-1.32) and lower risk of discontinuations due to AEs (OR 0.55; 95%CI 0.32-0.95) compared to patients treated with carbamazepine-CR in the levetiracetam trial. These results were consistent in various propensity score models, subgroup analyses and 12-months seizure freedom outcomes. Carbamazepine-CR outcomes differed between the trials after propensity score adjustment, indicating residual confounding that prevents a meaningful lacosamide-levetiracetam comparison. Comparative assessments derived from NMAs are not biased by such confounding (randomization holds); however, they describe the average treatment effect in a population without reflecting on differences in treatment response between individuals and subgroups of patients with distinct epilepsy characteristics.

BACKGROUND AND OBJECTIVE:Patients with focal seizures recruited into adjunctive antiepileptic drug (AED) trials have become more refractory and severe over time; concurrently, placebo responses have increased. To attempt to account for heterogeneity among trials, propensity-score weighted patient-level data were used to indirectly compare placebo responses reported in brivaracetam and levetiracetam trials.METHODS:Patient-level data from randomised, placebo-controlled brivaracetam (recruited 2007-2014) and levetiracetam (1993-1998) trials were pooled. Consistent inclusion/exclusion criteria were applied and outcomes were defined consistently. Potentially confounding baseline characteristics were adjusted for using propensity score weighting. Weighting success was assessed using placebo response.RESULTS:In total, 707 and 473 active drug and 399 and 253 placebo patients comprised the brivaracetam and levetiracetam groups, respectively. Before weighting, several baseline variables were significantly different between groups; after weighting, prior vagal nerve stimulation, co-morbid depression and co-morbid anxiety remained different. Before weighting, median seizure frequency reduction was 21.7 and 3.9% in the brivaracetam and levetiracetam placebo arms, respectively; after weighting, median reduction was 15.0 and 6.0%. The comparison of non-randomised groups could be biased by unobserved confounding factors and region of residence. Lifetime AED history was unavailable in the brivaracetam trials and excluded from analysis.CONCLUSIONS:Placebo responses remained different between brivaracetam and levetiracetam trials after propensity score weighting, indicating the presence of residual confounding factors associated with placebo response in these trials. It therefore remains problematic to conduct reliable indirect comparisons of brivaracetam and levetiracetam given the current evidence base, which may apply to comparisons between other AED trials.