Efficacy, safety, and tolerability of adjunctive eslicarbazepine acetate in patients with focal to bilateral tonic-clonic seizures.

OBJECTIVE: To report the efficacy, safety, and tolerability of adjunctive eslicarbazepine acetate (ESL) treatment in reducing focal to bilateral tonic-clonic seizures (FBTCS). METHODS: Data were pooled from 3 randomized clinical trials (RCTs) of adjunctive ESL in patients with focal seizures. Patients treated with 800 or 1200 mg/day ESL and who experienced ≥ 1 FBTCS during baseline were included. Efficacy was measured using FBTCS standardized seizure frequency (SSF), responder rates (≥50%, ≥75%, and 100%), and time to first FBTCS. Adverse events (AEs) were tabulated for each subgroup. RESULTS: Of the original 1447 patients, 438 patients in the safety population were included with ≥ 1 FBTCS at baseline (efficacy population, n = 429). Patients with ≥ 2 FBTCS (safety, n = 354; efficacy, n = 346) and ≥ 3 FBTCS (safety, n = 294; efficacy, n = 288) at baseline were also analyzed. The 1200 mg/day ESL group experienced lower least squares mean SSF vs placebo in patients with ≥ 1 baseline FBTCS (P = 0.0395) and ≥ 3 baseline FBTCS (P = 0.0091). The 50% responder rates improved for 1200 mg/day ESL vs placebo (≥1 FBTCS, P = 0.005; ≥2 FBTCS, P = 0.0063; ≥3 FBTCS, P = 0.0016). The 75% responder rates improved with 1200 mg/day ESL vs placebo (≥1 FBTCS, P = 0.0315; ≥2 FBTCS, P = 0.0215; ≥3 FBTCS, P = 0.0099), and with 800 mg/day ESL for ≥ 2 FBTCS at baseline (P = 0.0486). The 100% responder rate was higher in patients treated with 1200 mg/day ESL (not significant). Time to first FBTCS was longer with both 800 (P = 0.0008) and 1200 mg/day (P = 0.0020) ESL vs placebo for the ≥ 1 FBTCS subgroup, and with 1200 mg/day ESL for ≥ 2 FBTCS (P = 0.0060) and ≥ 3 FBTCS (P = 0.0152) subgroups. Overall, AEs occurred at similar rates across subgroups, and were lower than the original RCTs. CONCLUSION: Adjunctive ESL produced a robust response in patients with FBTCS, a seizure type associated with SUDEP and high injury rates. Adjunctive ESL was well tolerated in patients who experienced FBTCS.

Time to sustained responder status in patients with focal seizures treated with adjunctive eslicarbazepine acetate.

Rapid and sustained clinical responses are critical in improving long-term outcomes in epilepsy. While a 50 % reduction from baseline in standardized seizure frequency (SSF) is often cited as a measure of clinically meaningful efficacy, sustained response (SR) is an alternative method that allows the assessment of onset and durability of the response. Time to sustained response in SSF of ≥ 50 %, ≥ 75 %, ≥ 90 %, and 100 % was assessed for pooled data from 3 similar randomized clinical trials of adjunctive eslicarbazepine acetate (ESL). Patients with focal seizures on stable doses of 1-2 antiseizure medications were randomized to placebo, ESL 800 mg/day, or ESL 1200 mg/day. SR50, SR75, SR90, and SR100 were defined as a ≥ 50 %, ≥ 75 %, ≥ 90 %, and 100 % reduction, respectively, in SSF compared to baseline occurring anytime during the 12-week maintenance period, sustained through the end of the maintenance period. Safety signals were assessed for patients with SR50 onset within the first 2 weeks of the maintenance period (early responders) and any point following the first 2 weeks (later responders). A total of 1221 patients were included in this analysis. SR50 was achieved as early as Day 1 (placebo, 4.7 %; ESL 800 mg/day, 8.8 %; ESL 1200 mg/day, 10.4 %). After 84 days, SR50 was achieved by 32.1 % of the placebo group, 46.9 % of the ESL 800 mg/day group (p = 0.0002 vs placebo), and 53.7 % of the ESL 1200 mg/day group (p < 0.0001 vs placebo). Both ESL groups demonstrated earlier SR50 onset compared with placebo (p < 0.0001). Time to SR50 onset was not statistically different between the 800 and 1200 mg/day ESL dose groups. SR75 (p = 0.0001), SR90 (p = 0.0019), and SR100 (p = 0.0014) were achieved significantly earlier in the ESL 1200 mg/day groups vs placebo. SR75 was achieved significantly earlier in the ESL 800 mg/day group vs placebo (p = 0.0188), while achievements of SR90 (p = 0.0525) and SR100 (p = 0.0540) trended toward earlier occurrence. A greater proportion of patients in the ESL groups compared to the placebo group achieved an SR50 during the maintenance period, and those patients in the ESL groups also achieved SR50 and SR75 sooner than placebo treated patients. Additionally, patients treated with the higher ESL dose achieved SR90 and SR100 sooner than those treated with placebo.

Long-term quality of life in patients with focal seizures treated with adjunctive eslicarbazepine acetate.

By controlling seizures, anti-seizure medications can improve health-related quality of life (HRQOL). Data from a post-hoc pooled analysis of adjunctive eslicarbazepine acetate (ESL) was used to describe HRQOL measures, including overall quality of life, seizure worry, emotional well-being, energy/fatigue, cognitive functioning, medication effects, social function, and overall score over a period of up to one year. Patients who completed a double-blind treatment phase (Part 1) of these trials were eligible to enter the open label extension (OLE; Part 2). Patients who continued into the OLE initiated adjunctive ESL at 800 mg/day for 1 month before investigators could titrate dosages based on efficacy and tolerability. HRQOL was measured at baseline and at the last assessment using the Quality of Life in Epilepsy Inventory (QOLIE-31) in all patients who entered the 1-year OLE and in patients who completed the 1-year OLE. The mean QOLIE-31 scores and mean change in scores were analyzed using paired t-tests. The percentage of patients with improvements in QOLIE-31 scores beyond the minimally important change (MIC) threshold from baseline to end of 1-year OLE is described. Of 1410 patients in the intent-to-treat population, 1120 patients continued to part 2, and 795 patients completed the OLE. In patients who entered the OLE, mean improvements in scores for seizure worry, overall quality of life, emotional well-being, medication side effects, social functioning, and total score were statistically significant. In patients who completed the OLE, the mean change to final assessment was statistically significantly improved for all QOLIE categories. In patients who entered the OLE with a final assessment, the percentage of patients meeting the MIC for social functioning was the highest (46.9%), followed by medication effects (44.9%), and seizure worry (42.9%). Patients who completed the OLE with a final assessment found a similar rank ordering in QOLIE scale improvements compared with those who entered the OLE with a final assessment. For both sets of patient groups, the least number of subjects met MIC criteria for the energy/fatigue QOLIE category. Treatment with therapeutic doses of adjunctive ESL in patients with focal seizures was associated with improvements in HRQOL for a period of up to one year.

The economic and humanistic burden of bipolar disorder in adults in the United States.

BACKGROUND: Bipolar disorder is associated with functional impairment and diminished health-related quality of life (HRQoL). The purpose of this study was to estimate the annual per patient direct healthcare costs, indirect costs, and HRQoL of patients with bipolar disorder by depressive symptom severity and overall compared to the general population in the US. METHODS: This cross-sectional study used self-reported data from the 2020 US National Health and Wellness Survey. Adult respondents who reported bipolar disorder symptoms in the past 12 months and/or a diagnosis of bipolar disorder were identified (bipolar disorder cohort) and were further classified by depressive symptom severity based on Patient Health Questionnaire (PHQ-9) scores (none/mild = 0-9, moderate = 10-14, severe = 15-27). Annualized direct healthcare costs and indirect costs were calculated from 6-month healthcare resource utilization and work productivity, respectively. A general population cohort was constructed using 2:1 propensity score matching. Multivariate regression models of all-cause hospitalizations in the past 6 months, annualized direct healthcare costs, annualized indirect costs, and HRQoL (eg, EuroQol 5-Dimension Health Questionnaire (EQ-5D)) controlled for confounders (demographic and clinical characteristics). RESULTS: Of 3583 adults meeting pre-specified criteria for bipolar disorder, 1401 (39.1%) reported none/mild, 889 (24.8%) moderate, and 1293 (36.1%) severe depressive symptom severity. Additionally, 3285 (91.7%) were matched to 6570 adults in the general population. Compared to the general population, adjusted mean hospitalizations (0.53 vs. 0.30), annualized per patient direct healthcare costs ($20,846 vs. $11,391), and indirect costs ($14,795 vs. $9274) were significantly greater for the bipolar disorder cohort (all p < 0.001); adjusted HRQoL (EQ-5D: 0.69 vs. 0.79) was significantly worse (p < 0.001). By depressive symptom severity, adjusted mean hospitalizations (none/mild = 0.30, moderate = 0.50, severe = 0.46), direct healthcare costs ($14,389, $22,302, $21,341), and indirect costs ($10,799, $17,109, $18,470) were significantly greater for moderate and severe compared to none/mild depressive symptom severity (all p < 0.01); adjusted HRQoL (EQ-5D: 0.77, 0.67, 0.59) was significantly worse (p < 0.001). CONCLUSIONS: Among respondents with bipolar disorder, those with moderate to severe depression had greater direct healthcare costs and indirect costs as well as worse HRQoL than those with mild or no depressive symptoms. Treatment targeting reduction in depressive symptoms may reduce the economic and humanistic burden of bipolar disorder.

Time to baseline seizure count in patients with focal seizures receiving adjunctive eslicarbazepine acetate in a phase IV clinical trial.

BACKGROUND: The efficacy and tolerability of eslicarbazepine acetate (ESL), a once-daily, orally-administered, anti-seizure medication (ASM), have primarily been established in treatment-resistant epilepsy patients, the population most often enrolled in clinical trials of anti-seizure medications. More recently, ESL was also shown to be effective and well-tolerated as first adjunctive therapy in non-treatment-resistant patients in an open-label, non-randomized, Phase IV, 24-week study of ESL using standard efficacy parameters in adults with focal seizures. OBJECTIVE: To determine the time required to reach baseline seizure count, as an alternative method of assessing the efficacy of adjunctive ESL in patients with relatively low baseline monthly seizure frequencies. This additional analysis was undertaken, as subtle changes and improvements are difficult to analyze using standard efficacy parameters, such as standardized seizure frequency reduction when the baseline frequency of seizures is particularly low. METHODS: This was a post-hoc analysis of the Phase IV study data, which investigated time to baseline seizure count in patients aged ≥ 18 years with focal seizures as an alternative measure of anti-seizure efficacy. In the Phase IV trial, patients had been enrolled into 2 groups: Arm 1: ESL as first adjunctive therapy to levetiracetam (LEV) or lamotrigine (LTG), the two most commonly-prescribed ASMs, in patients with inadequate response to treatment; Arm 2: ESL as a later adjunctive therapy, following prior use of 1-2 ASMs in patients who required an additional therapeutic option. RESULTS: The time to reach individual baseline seizure count was longer in patients with focal seizures receiving ESL as a first (Arm 1) versus later (Arm 2) adjunctive therapy (p = 0.005). Patients who received ESL as a first adjunctive therapy had a longer time to ESL discontinuation than patients who received ESL as a later adjunctive therapy (p = 0.04). In Arm 1, patients receiving concomitant LTG reported treatment-emergent adverse events (TEAEs) significantly earlier than those receiving LEV (p = 0.02). Compared to patients receiving concomitant LTG, a greater number of patients in Arm 1 who were taking concomitant LEV had a modal ESL dose > 1200 mg and completed the full maintenance period. A greater number of patients in Arm 1 who were receiving concomitant LEV and completed the 24-week maintenance period reached a maximum ESL dose of 1600 mg, compared to those taking LTG, who reached a maximum ESL dose of 1200 mg. CONCLUSIONS: This analysis of the Phase IV clinical trial data provides an alternative way of assessing efficacy beyond standardized seizure frequency reduction, in the context of relatively low monthly median seizure frequencies at baseline (SSF 2.0-2.4). These results provide further support for the use of ESL as an earlier or later adjunctive therapy to LEV or LTG.

Implementing Digital Technologies in Clinical Trials: Lessons Learned.

Multiple digital health technologies have been evaluated across clinical development programs, including external, wearable, implantable, and ingestible devices and sensors, along with digital mobile health applications (apps) that are accessible via users' personal electronic devices (e.g., smartphones, tablets, and computers). Several of these technologies have been incorporated into our ongoing neurology and respiratory clinical development programs. Based on our experience, one of the greatest potential benefits of digital health technologies is the ability to collect objective and/or biological data continuously or at regular intervals outside of office visits during a patient's normal daily activities to provide additional efficacy and safety information, versus data capture from traditional episodic, time point-based office visits. Many challenges encountered with digital health technologies can be successfully addressed by providing the appropriate training to staff and patients, ensuring availability of appropriate infrastructure support, and conducting pilot studies before scaling up to larger trials. Overall, our experience with digital health technologies demonstrated their potential to increase the amount of objective data collected in clinical trials, expand patient access to trials, and facilitate further improvement of clinical outcomes.

Psychiatric adverse events in three phase III trials of eslicarbazepine acetate for focal seizures.

OBJECTIVE: Eslicarbazepine acetate (ESL) is a once-daily (QD), oral anti-seizure medication for the treatment of focal (partial-onset) seizures. Here, we evaluate risk factors for the development of psychiatric treatment-emergent adverse events (TEAEs) in clinical trials of adjunctive ESL in adults with focal seizures. METHODS: This post-hoc analysis evaluated data pooled from three Phase III, randomized, double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients were randomized equally to receive placebo, ESL 400 mg (not reported here), 800 mg, or 1200 mg QD (up to 2-week titration; 12-week maintenance; optional open-label extension [OLE]). Incidences of psychiatric TEAEs were evaluated according to three separate criteria: medical history of psychiatric disorders (yes/no); baseline use of psychotropic drugs (yes/no); Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline (0-6: normal; 7-19: mild depression; 20-34: moderate depression). RESULTS: The analysis populations comprised 1251 patients for the controlled study period and 1137 patients for the 1-year OLE. Psychiatric TEAE incidence was similar between patients taking ESL and placebo in the controlled and OLE study periods and was not related to ESL dose. Psychiatric TEAEs generally occurred more frequently in patients with a medical history of psychiatric disorders, using psychotropic drugs, or with depressive symptoms than in those without a history, not using psychotropic drugs, or with no depressive symptoms. Depression and anxiety were the most frequently reported psychiatric TEAEs. SIGNIFICANCE: Overall, in clinical trials of ESL in adults with focal seizures, incidences of psychiatric events were not statistically different between patients taking ESL and placebo, were not related to ESL dose, and generally occurred more frequently in patients with baseline psychiatric symptoms or a history of psychiatric disorders. Long-term exposure to ESL was not associated with a marked increase in the incidence of psychiatric TEAEs.

Comparative economic outcomes in patients with focal seizures initiating eslicarbazepine acetate versus brivaracetam as their first adjunctive ASD.

AIMS: To study the association between initiation of first adjunctive therapy with eslicarbazepine acetate (ESL) vs. brivaracetam (BRV) on healthcare resource utilization (HCRU) and charges among patients with treated focal seizures (FS). MATERIALS AND METHODS: Symphony Health's Integrated Dataverse (IDV) claims data (1 April 2015 to 30 June 2018) were used to identify two cohorts as first adjunctive therapy with ESL or BRV following a generic anti-seizure drug (ASD). The index date was the earliest claim for a new ESL or BRV prescription. Key inclusion criteria were only 1 generic ASD in the 12 months before the index date; ≥1 medical claim with an FS diagnosis. Unit of analysis was the 90-day person-time-block. Changes in HCRU and charges were assessed using a difference-in-differences framework. Both unadjusted and adjusted analyses were performed. The adjusted model utilized person-specific fixed effects and propensity score-based weighting to control for differences in baseline covariates. Bias-corrected bootstrap confidence intervals (CIs) were calculated for charge outcomes. RESULTS: 208 and 137 patients initiated first adjunctive therapy with ESL (43.7 years, 51.9% female) or BRV (39.3 years, 51.8% female). Patients in the ESL cohort had numerically larger reductions in all-cause and FS-related inpatient hospitalizations and outpatient visits and FS-related emergency department visits. Compared to patients initiating BRV, patients treated with ESL had significantly larger reductions in total charges (-$3,446, CI: -$13,716, -$425), all-cause (-$3,166, CI: -$13,991, -$323) and FS-related (-$2,969, CI: -$21,547, -$842) medical charges, all-cause (-$3,397, CI: -$15,676, -$818) and FS-related (-$2,863, CI: -$19,707, -$787) outpatient charges, and non-ASD-related prescription charges (-$420, CI: -$1,058, -$78). LIMITATIONS: Claims may be missing, or miscoded; outcomes may be influenced by variables not accounted for in the analysis; only information on submitted charges was included. CONCLUSIONS: Among patients with FS, initiation of first adjunctive therapy with ESL was associated with significantly larger reductions in medical and non-ASD-related prescriptions charges compared to BRV.

Comparative Economic Outcomes in Patients with Focal Seizure Initiating First-Line Eslicarbazepine Acetate Monotherapy versus Generic Antiseizure Drugs.

OBJECTIVE: To examine the association between initiating first-line (1L) monotherapy with eslicarbazepine acetate (ESL) vs a generic antiseizure drug (ASD) and healthcare resource utilization (HCRU) and charges in adults with treated focal seizures (FS). METHODS: This was a retrospective analysis of Symphony Health's Integrated Dataverse® open-source claims data. Two cohorts were identified as having initiated 1L monotherapy with ESL or literature-defined generic ASDs. Linear regression models with person fixed effects and inverse probability treatment weights assessed the relative additional changes in HCRU and charges among patients who received ESL compared to generic ASD. RESULTS: A total of 250 and 43,220 patients initiated ESL (48.3 years; 57.2% female) or a generic ASD (54.5 years; 58.1% female), respectively. Compared to patients initiating a generic ASD, patients treated with ESL had additional reductions of 11.8 percentage points in the likelihood of any all-cause outpatient visits (P<0.001), 7.4 percentage points in the likelihood of any emergency department (ED) visits (P=0.013), and 22.7 percentage points in the likelihood of any FS-related outpatient visits (P<0.001). Patients initiating ESL had greater reductions in mean charges for all-cause medical ($2620; P=0.002), outpatient ($1995; P=0.005), and non-FS-related medical ($2708; P<0.001) services. Patients initiating ESL had greater relative increases in mean total prescription ($1368; P<0.001) and ASD-related prescription ($1636; P<0.001) charges, but greater relative reductions in non-ASD prescription ($269; P=0.032) charges. The increases in prescription charges were of a lower magnitude than the decreases in medical charges. CONCLUSION: Initiation of ESL as 1L monotherapy was associated with statistically significantly greater reductions in any use of several all-cause and FS-related services, number of visits, and charges compared to initiation of a generic ASD as 1L monotherapy in patients with FS. Initiation of a generic ASD as 1L monotherapy was associated with significantly smaller increases in total prescription charges and ASD-related prescription charges.

Efficacy and safety of eslicarbazepine acetate as a first or later adjunctive therapy in patients with focal seizures.

INTRODUCTION: We report outcomes from an open-label, non-randomized, 24-week study of eslicarbazepine acetate (ESL) in adults at earlier and later stages of their treatment history for focal seizures, conducted in a real-world clinical setting. METHODS: ESL was taken as the first adjunctive therapy to levetiracetam (LEV) or lamotrigine (LTG) monotherapy (Arm 1), or as a later adjunctive therapy in treatment-resistant patients (Arm 2). The primary objective was to evaluate the effectiveness of ESL (by retention rates). Secondary objectives were to evaluate efficacy (seizure frequency), safety, tolerability, behavioral changes, mood, and health-related quality of life (HRQoL) associated with ESL treatment. RESULTS: The modified intent-to-treat population included 96 patients (Arm 1: n = 41; Arm 2: n = 55) and the safety population included 102 patients (Arm 1: n = 44; Arm 2: n = 58). Overall, 81.8 % of patients in Arm 1 and 63.8 % of patients in Arm 2 completed the 24-week maintenance period. Median reductions in standardized seizure frequency (SSF) were markedly higher in Arm 1 (72.8 %) than Arm 2 (22.8 %), as were responder rates (≥50 % reduction in SSF; Arm 1: 62.5 %; Arm 2: 38.5 %) and rates of seizure freedom (Arm 1: 25.0 %; Arm 2: 9.6 %). Efficacy outcomes were generally more favorable in patients taking ESL in combination with LEV versus other anti-seizure medications (ASMs). Treatment-emergent adverse events (TEAEs; 81 % vs 73 %) and TEAEs leading to discontinuation (16 % vs 2 %) were reported more frequently in Arm 2 than Arm 1, respectively. Serious adverse events were reported infrequently (Arm 1: 0; Arm 2: 7 %). The most common TEAEs were dizziness, nausea, headache, somnolence, fatigue, nasopharyngitis, vomiting, and anxiety. There were no notable changes in depressive symptoms, mood status, or aggression throughout the study. Health and HRQoL scores were generally high at baseline and did not change throughout the study. However, on average, both clinicians and patients perceived improvement in illness over the course of the study. CONCLUSIONS: ESL was effective and well tolerated both as the first adjunctive therapy to either of the most prescribed first-line ASMs, LEV or LTG, and as a later adjunctive therapy in treatment-resistant patients.

Comparative analysis of the safety and tolerability of eslicarbazepine acetate in older (≥60 years) and younger (18-59 years) adults.

OBJECTIVE: To investigate the safety and tolerability of eslicarbazepine acetate (ESL), a once-daily oral anti-seizure drug (ASD), in older and younger adult patient populations. METHODS: Two post-hoc pooled data analyses were performed: one from three Phase III studies in patients with focal (partial-onset) seizures who were taking 1-3 concomitant ASDs; the other from five Phase II studies in patients from non-epilepsy populations not taking other ASDs chronically and/or at a clinically-effective anti-seizure dose. The frequencies of treatment-emergent adverse events (TEAEs) were calculated for the older (≥60 years) and younger (18-59 years) adults separately. RESULTS: In the focal seizures study pool, 4.1 % of patients (58/1431) were aged ≥60 years. The overall frequency of TEAEs was 77.5 % in older ESL-treated patients and 72.6 % in younger ESL-treated patients (p = 0.495). For patients who received placebo, the overall frequency of TEAEs was 50.0 % in the older adults and 57.5 % in the younger adults (p = 0.531). The overall placebo-adjusted frequency of TEAEs was 27.5 % in older adults and 15.1 % in younger adults. The placebo-adjusted frequencies of the TEAEs dizziness, somnolence, headache, nausea, diplopia, blurred vision, and ataxia were ≥5 % higher, and frequencies of vomiting and vertigo were ≥2 % higher in older than younger adults. The overall frequency of TEAEs leading to discontinuation was 15.0 % in older ESL-treated patients and 17.6 % in younger ESL-treated patients (p = 0.647); the frequency increased with increasing ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 5.6 % in older adults and 6.6 % in younger adults (p = 0.847). In the non-epilepsy study pool, 30.2 % of patients (515/1705) were aged ≥60 years. The overall frequency of TEAEs was 56.9 % in older ESL-treated patients and 58.8 % in younger ESL-treated patients. The placebo-adjusted frequencies were 14.9 % in older and 15.1 % in younger ESL-treated patients. The placebo-adjusted frequencies of the TEAEs nausea, vomiting, fatigue, and vertigo were ≥2 % higher in older adults, whereas somnolence was ≥2 % higher in younger adults. The overall frequency of TEAEs leading to discontinuation was 18.3 % in older ESL-treated patients and 12.1 % in younger ESL-treated patients (p = 0.003); frequencies were not related to ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 8.0 % in older adults and 5.6 % in younger adults (p = 0.407). CONCLUSION: Analyses of adverse event data support the safety and tolerability of ESL in adults aged ≥60 years. In the limited number of older patients with focal seizures taking ESL plus concomitant ASDs (n = 40), the frequency of TEAEs was generally higher than in younger adults. However, in the non-epilepsy patient group (in which the number of older patients was ten times larger; 427 patients taking ESL without concomitant ASDs), no marked age-related TEAE differences were observed, suggesting that increased ASD load associated with adjunctive therapy may complicate treatment selection in older patients, due to risk of increased adverse events. As is common practice for all ASDs, balancing clinical response and tolerability is needed in this vulnerable group of patients.

Long-term safety and tolerability of adjunctive eslicarbazepine acetate in children with focal seizures.

OBJECTIVE: The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive eslicarbazepine acetate (ESL) in children with focal seizures. METHODS: Safety data from patients aged 4-17 years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1-2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5 years total duration). The OLEs evaluated the safety and tolerability of ESL (10-30 mg/kg/day; maximum 1200 mg/day). RESULTS: The 1-year OLE and post-1-year OLE safety populations comprised 337 and 177 ESL-treated patients, respectively. The overall incidence of treatment-emergent adverse events (TEAEs) with ESL was 64.1% during the 1-year OLE and 52.5% during the post-1-year OLE. Nasopharyngitis, partial seizures, vomiting, pyrexia, headache, somnolence, and respiratory tract infection were the most frequently reported TEAEs during the 1-year OLE. The overall incidence of serious adverse events (AEs) was 8.9% during the 1-year OLE and 10.2% during the post-1-year OLE. Partial seizures (1.2%) and pneumonia (1.2%) were the most frequently reported serious AEs during the 1-year OLE. The overall incidence of TEAEs leading to discontinuation was 4.2% during the 1-year OLE and 0.6% during the post-1-year OLE. Partial seizures (1.5%) was the most frequently reported TEAE leading to discontinuation during the 1-year OLE. CONCLUSIONS: Overall, long-term treatment with ESL was generally well tolerated in pediatric patients aged 4-17 years with focal seizures. TEAEs were comparable to those observed in adults with no new events of concern.

Impact of Early Initiation of Eslicarbazepine Acetate on Economic Outcomes Among Patients with Focal Seizure: Results from Retrospective Database Analyses.

INTRODUCTION: This study assessed the association between early initiation of eslicarbazepine acetate (ESL) as first-line therapy (1L cohort) or as first adjunctive regimen to either levetiracetam (LEV) or lamotrigine (LTG) (add-on cohort), and healthcare resource utilization (HCRU) and charges among adults with treated focal seizures (FS). METHODS: This retrospective, longitudinal cohort analysis used Symphony Health's Integrated Dataverse (IDV®) claims data to identify patients aged ≥ 18 years with a diagnosis of FS who had a new prescription for ESL between April 2015 and June 2018. Baseline was the 90-day period immediately prior to the date of the first-dispensed claim for ESL (index date) with a follow-up of 1-4 consecutive 90-day periods. Linear regression models were estimated to assess changes in HCRU and charge outcomes. RESULTS: There were 274 and 153 patients who received ESL in the 1L cohort and add-on cohort, respectively. The 1L cohort experienced significant reductions from baseline during follow-up in all-cause inpatient (IP; P < 0.0001), emergency room (ER; P < 0.0001), and outpatient (OP; P < 0.0001) visits; FS-related IP (P = 0.006) and OP (P < 0.0001) visits; total, medical, all-cause ER and OP, and FS-related medical charges (P < 0.05); and significant increases in total prescription and anti-seizure drug (ASD)-related prescription (P < 0.001) charges. The add-on cohort experienced significant reductions in all-cause IP (P = 0.009) and all-cause and FS-related OP visits (P < 0.0001 for both) and significant increases in total prescription and ASD-related prescription (P < 0.001) charges during the follow-up period. In both cohorts, the increases in prescription charges were smaller than the reduction in total medical charges. CONCLUSION: Early initiation of ESL as 1L or add-on therapy was associated with statistically significant reductions in all-cause IP and all-cause and FS-related OP visits during follow-up compared to baseline. The 1L cohort also had statistically significant reductions in all-cause ER visits, FS-related IP visits, and total, medical, all-cause ER and OP, and FS-related medical charges. Knowledge of healthcare resource utilization (HCRU) and costs of care in patients taking anti-seizure drugs (ASDs) is required to inform prescribing and formulary decision-making. Levetiracetam (LEV) and lamotrigine (LTG) are the most widely used first-line (1L) ASDs in the USA. Eslicarbazepine acetate (ESL), a third-generation ASD with sodium channel-modulating activity, is typically used in later lines of therapy. Sodium channel-blocking anti-seizure drugs may represent an effective treatment option for patients with epilepsy in the 1L setting. This study assessed the association between early initiation of ESL as 1L therapy (1L cohort) or as first adjunctive therapy to either LEV or LTG (add-on cohort), and HCRU and charges among adults with treated focal seizures (FS). The results showed that following ESL initiation the 1L cohort experienced significant reductions in all-cause inpatient (IP), emergency room (ER), and outpatient (OP) visits; FS-related IP and OP visits; and total, medical, all-cause ER and OP, and FS-related medical charges, and significant increases in total prescription and ASD-related prescription charges. The add-on cohort showed significant reductions in all-cause IP and all-cause and FS-related OP visits and significant increases in total prescription and ASD-related prescription charges. In both cohorts, the increases in prescription charges were smaller than the reduction in total medical charges. These data imply that use of ESL as 1L therapy in adult patients with FS could help conserve scarce healthcare resources and reduce the burden on healthcare budgets. These findings may inform selection of ASD therapy in this patient population.

Associations between seizure severity change and patient characteristics, changes in seizure frequency, and health-related quality of life in patients with focal seizures treated with adjunctive eslicarbazepine acetate: Post hoc analyses of clinical trial results.

The relationships between seizure severity change and patient characteristics, changes in seizure frequency, and health-related quality of life (HRQoL) may be important for determining the overall impact of medication therapy on patients with epilepsy. The objectives of these post hoc analyses of the global Phase III 093-0304 trial (NCT00988429, Study 304) of adjunctive eslicarbazepine acetate (ESL) in patients with refractory focal (partial-onset) seizures (FS) were to evaluate associations between seizure severity change, measured by the Seizure Severity Questionnaire (SSQ), and 1) patient characteristics, 2) seizure frequency change, standardized as the seizure frequency (SSF) per 28-day period, and 3) change in HRQoL, evaluated by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) and the Montgomery-Åsberg Depression Rating Scale (MADRS). The analyses were conducted on the per-protocol population (PPP) of patients who were randomized to a placebo arm (n = 188) or an ESL-active group that included treatment with adjunctive ESL 800 mg once daily (QD; n = 184) or adjunctive ESL 1200 mg QD (n = 175). General linear models (GLM) were used to measure the association between SSQ change and patient baseline characteristics or percentage change in the SSF from baseline. Associations between changes in the SSQ and changes in the QOLIE-31 and MADRS were examined using GLM with patient baseline characteristics as covariates. Subgroup analyses were performed for patients in the ESL-active group and those treated with ESL 800 mg or ESL 1200 mg. Minimal clinically important difference (MCIDs) thresholds were used to assess improvements in SSQ scores. The analyses included 547 per-protocol patients. Patients using 1 antiepileptic drug (AED) at baseline had greater improvements in the SSQ compared with those receiving 2 AEDs (P = 0.0606). Treatment with ESL 1200 mg was significantly associated with clinically meaningful improvements in the SSQ (P = 0.0005). The SSQ improvements were significantly associated with an SSF reduction of ≥75%, compared with no reduction (P < 0.0001). In the PPP and the ESL-active group, SSQ improvements were significantly associated with improvements in QOLIE-31 Total Score (TS; P < 0.0001) and the Seizure Worry (SW; P < 0.0001) and Social Functioning (SF; P = 0.0030) subscales. In the ESL 1200 mg subgroup, SSQ improvements were significantly associated with improvements in QOLIE-31 TS (P < 0.0001) and the SW (P < 0.0001) and Energy/Fatigue (EF; P = 0.0007) subscales. In the ESL 800 mg subgroup, improvements in the SSQ were significantly associated with improvements in QOLIE-31 TS (P = 0.0362) and the SW (P = 0.0241) subscale. There was no significant association between changes in the SSQ and changes in the MADRS in patients treated with ESL. These findings demonstrated that in this clinical trial population, adding ESL to baseline AED therapy had utility for decreasing seizure severity and improving HRQoL. There were no significant associations between changes in seizure severity and changes in depressive symptoms in patients with FS.

Analysis of cutaneous allergic reactions in clinical trials of eslicarbazepine acetate.

OBJECTIVES: To evaluate cutaneous allergic reactions in clinical trials of adjunctive eslicarbazepine acetate (ESL) for focal seizures. MATERIALS AND METHODS: Data were analyzed from three phase III randomized, double-blind, placebo-controlled studies of adjunctive ESL in adults (placebo, n = 426; ESL, n = 1021) and two randomized, double-blind, placebo-controlled studies (and open-label extensions [OLEs]) of adjunctive ESL in children aged 4-17 years (placebo, n = 160; ESL, n = 202; OLE, n = 337). RESULTS: Adult studies: Rash (ESL 1.9%, placebo 0.9%) and pruritus (ESL 1.2%, placebo 0.9%) were the most frequent rash-related treatment-emergent adverse events (TEAEs). Most rash-related TEAEs were mild or moderate in severity. Incidence of rash increased with increasing ESL dose, but was not higher for patients who initiated treatment with higher ESL doses. Pediatric studies: Allergic dermatitis (ESL 3.0%, placebo 0) and rash (controlled studies: ESL 1.0%, placebo 1.3%; OLE periods: ESL ≤1.2%) were the most frequent rash-related TEAEs. There was one case of DRESS in the ESL group. Most rash-related TEAEs were mild or moderate in severity and judged as not related to treatment with ESL. CONCLUSIONS: Serious skin rashes were rare during adult and pediatric clinical trials of ESL. Although the incidence of rash with ESL was low, it is important for patients/caregivers to be made aware of the potential signs and symptoms associated with serious skin rashes.

Safety and Tolerability of Adjunctive Eslicarbazepine Acetate in Pediatric Patients (Aged 4-17 Years) With Focal Seizures.

OBJECTIVE: To evaluate the safety and tolerability of adjunctive eslicarbazepine acetate (ESL) in pediatric patients (aged 4-17 years) with refractory focal seizures. METHODS: Pooled safety data from patients aged 4-17 years in Study 208 (NCT01527513) and Study 305 (NCT00988156) were analyzed. Both were randomized, double-blind, placebo-controlled studies of ESL as adjunctive treatment in pediatric patients with refractory focal seizures receiving 1 or 2 antiepileptic drugs. Incidences of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs of special interest were evaluated. RESULTS: The safety population comprised 362 patients (placebo, n = 160; ESL, n = 202). The overall incidence of TEAEs was similar between the ESL (67.8%) and placebo groups (65.6%), with no clear dose-response relationship. The most frequently reported TEAEs with ESL were headache, somnolence, vomiting, and diplopia. Overall incidences of SAEs and TEAEs leading to discontinuation were higher with ESL versus placebo (9.9% vs 5.0% and 5.9% vs 2.5%, respectively). The majority of SAEs with ESL occurred in Study 305. Two deaths were reported, 1 with ESL (0.5%) due to cluster seizures (resulting in herniation of the cerebellar tonsils) and 1 with placebo (0.6%) due to asphyxia. TEAEs related to allergic reaction, hyponatremia, hypothyroidism, cytopenia, seizure exacerbation, cognitive dysfunction, psychiatric disorders, or suicide occurred infrequently (<9%). CONCLUSION: Adjunctive ESL was generally well tolerated in children aged 4-17 years with focal seizures. The safety profile of ESL in children was comparable to that observed in adults.

Markers of bone and lipid metabolism with eslicarbazepine acetate monotherapy.

OBJECTIVE: To evaluate the impact of eslicarbazepine acetate (ESL) monotherapy on markers of bone and lipid metabolism. METHODS: We conducted a post-hoc analysis of data pooled from two Phase III, dose-blind, conversion-to-ESL (1600 mg and 1200 mg) monotherapy studies in patients with focal seizures. Laboratory measurements included lipids (total cholesterol [TC]; high-density lipoprotein cholesterol [HDL-C]; low-density lipoprotein cholesterol; and triglycerides) and markers of bone metabolism (alkaline phosphatase; 25-hydroxyvitamin D; osteocalcin; and parathyroid hormone [PTH]); measurements were taken at baseline, Week 18, and Month 12, and analyzed according to enzyme-inducing antiepileptic drugs (EIAEDs) use at baseline (+EIAED and -EIAED subgroups). RESULTS: Data from 337 treatment-compliant patients were used for the Week 18 analyses (+EIAED subgroup, n = 119; -EIAED subgroup, n = 218); data from 161 treatment-compliant patients were used for the Month 12 analyses (+EIAED subgroup, n = 53; -EIAED subgroup, n = 108). At baseline, alkaline phosphatase and PTH concentrations were higher in the + EIAED versus -EIAED subgroup. Changes from baseline in markers of bone turnover were generally insignificant, except for some elevation in alkaline phosphatase in the -EIAED subgroup (18 weeks and 12 months) and osteocalcin in both subgroups (18 weeks only). Regarding lipids, TC and HDL-C concentrations were higher in the + EIAED versus -EIAED subgroup at baseline. Concentrations of markers of lipid metabolism fell in the + EIAED group and rose in the -EIAED group, reaching very similar values that were intermediate between the -EIAED and + EIAED baseline values. CONCLUSIONS: Based on this retrospective analysis, ESL seems to have had only a modest and primarily clinically insignificant impact on plasma lipids. More prospective data are needed to definitively ascertain the effects of ESL on bone metabolism.

Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy.

OBJECTIVE: To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal- (partial-) onset seizures. METHODS: This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400-1200 mg once daily), two phase 3 trials of ESL monotherapy (1200-1600 mg once daily), and their open-label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+ ]), incidences of hyponatremia-related treatment-emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. RESULTS: The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open-label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+ ] measurement ≤125 mEq/L, <9% had a >10 mEq/L decrease in [Na+ ] from baseline, <6% had a hyponatremia-related TEAE, and <2% discontinued the controlled trials due to a hyponatremia-related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator-reported TEAE of "hyponatremia" or "blood sodium decreased" did not have a corresponding laboratory [Na+ ] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+ ] measurement ≤125 mEq/L. SIGNIFICANCE: Reductions in serum sodium concentrations and hyponatremia-related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+ ] measurements.

Long-term safety and efficacy following conversion to eslicarbazepine acetate monotherapy in adults with focal seizures.

OBJECTIVE: To assess the long-term safety and efficacy of eslicarbazepine acetate (ESL) monotherapy in adults with focal seizures (FS). METHODS: Study 050 was a long-term, multicenter, open-label (OL) safety extension of two conversion-to-ESL monotherapy studies in adults with refractory FS. After participating in Study 045 or 046, patients started on ESL 1600 mg once daily (QD) (or 1200 mg if they previously had a dose reduction), and could adjust the dose 400 mg/week to a dose between 800-2400 mg QD. Patients could add up to two additional antiepileptic drugs (AEDs). This post-hoc analysis focuses on the actual monotherapy subgroup, which included patients in Studies 045/046/050 who did not add additional AEDs. Study endpoints included treatment retention time, time on ESL monotherapy, change in standardized seizure frequency (SSF), change in quality of life (QoL) in epilepsy (QOLIE-31) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores, and incidence of treatment-emergent adverse events (TEAEs); serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs related to allergic reaction, hyponatremia and thyroid function were also evaluated. RESULTS: There were 274 patients in the Study 050 full intent-to-treat (ITT) population and 140 patients in the actual monotherapy subgroup. Median treatment retention time and time on ESL monotherapy were both >5 years. Median reduction in SSF from baseline was 66.4% in the full ITT population and 78.3% in the actual monotherapy subgroup; responder (≥50% reduction in SSF) rates were 62.4% and 74.3%, respectively. QOLIE-31 scores increased from baseline in the full ITT population and the actual monotherapy subgroup (4.1- and 7.5-point increases, respectively). MADRS scores decreased from baseline in both the full ITT population and the actual monotherapy subgroup (0.7- and 2.9-point decreases, respectively). TEAEs occurred in 85.4% of patients in the full ITT population and 81.4% of patients in the actual monotherapy subgroup. Incidences of SAEs and TEAEs leading to discontinuation, as well as dizziness, depression, fall, partial seizures with secondary generalization, and complex partial seizures, were higher in the full ITT population than in the actual monotherapy subgroup. Allergic reactions, hyponatremia, and hypothyroidism were infrequent, particularly in the actual monotherapy subgroup. CONCLUSIONS: The results of this post-hoc analysis suggest that long-term treatment with ESL was effective and well tolerated, both as a monotherapy and in combination with other AEDs for FS. QoL and tolerability appeared to be better, and incidence of depression lower, in the patient population taking ESL as a monotherapy, compared with the population that included patients taking ESL as an adjunctive therapy.

Tolerability of adjunctive eslicarbazepine acetate according to concomitant lamotrigine or carbamazepine use: A subgroup analysis of three phase III trials in adults with focal (partial-onset) seizures.

OBJECTIVE: To evaluate and compare the effects of concomitant lamotrigine (LTG) or carbamazepine (CBZ) on the incidence of treatment-emergent adverse events (TEAEs) in patients taking adjunctive eslicarbazepine acetate (ESL) for focal (partial-onset) seizures (FS). METHODS: These post-hoc analyses of data pooled from three randomized, double-blind, placebo-controlled studies of adjunctive ESL (BIA-2093-301, -302 and -304) included adults (≥16 years) with FS refractory to 1-3 antiepileptic drugs (AEDs). Patients were randomized equally to placebo, ESL 400 mg (Studies 301 and 302 only), 800 mg, or 1200 mg once daily (8-week baseline, 2-week titration, and 12-week maintenance periods). TEAEs, TEAEs leading to discontinuation, and serious AEs (SAEs) were evaluated in patients taking, or not taking, LTG (excluding those taking CBZ or phenytoin [PHT]; i.e., the +LTG and -LTG/-CBZ subgroups), or CBZ (excluding those taking LTG or PHT; i.e., the +CBZ and -LTG/-CBZ subgroups) at baseline. RESULTS: LTG was used concomitantly by 248 patients (+LTG; placebo, n = 81; ESL, n = 167) and CBZ by 613 patients (+CBZ; placebo, n = 172; ESL, n = 441); 361 patients were taking neither LTG nor CBZ (-LTG/-CBZ; placebo, n = 109; ESL, n = 252). The overall incidence of TEAEs with ESL (any dose) was numerically higher for +CBZ (77%) than for +LTG (73%) or -LTG/-CBZ (68%; statistical significance not tested). Among patients taking ESL, dizziness, diplopia, and vomiting were reported more frequently in the +CBZ subgroup (30%, 14%, and 10%, respectively) than in the +LTG (16%, 8%, 5%) or -LTG/-CBZ (11%, 3%, 5%) subgroups. The overall incidence of TEAEs leading to discontinuation with ESL was higher for +CBZ (21%) than for +LTG (13%) or -LTG/-CBZ (15%). Dizziness leading to discontinuation with ESL was reported more frequently in the +CBZ subgroup than in the +LTG or -LTG/-CBZ subgroups (9%, 3%, and 3%, respectively). The overall incidence of SAEs in patients taking ESL was comparable across subgroups (+LTG, 5%; +CBZ, 6%; -LTG/-CBZ, 5%). The results were similar when evaluating placebo-adjusted incidences. CONCLUSION: There was a potential pharmacodynamic interaction between AEDs with a putatively similar mechanism of action, with a seemingly lesser interaction between ESL and LTG versus ESL and CBZ. If combining ESL with LTG or CBZ, clinicians should be aware of the potential risk for an increased incidence of TEAEs typically associated with voltage-gated sodium channel inhibitors (e.g., dizziness, blurred vision, vertigo, diplopia, headache, or vomiting).