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

OBJECTIVE
To evaluate long-term retention, reasons for discontinuation, efficacy, tolerability, and health-related quality of life (HRQOL) during adjunctive brivaracetam (BRV) treatment in adults with focal seizures by number of lifetime antiseizure medications (ASMs).


METHODS
Post hoc analyses of a randomized, double-blind, placebo-controlled trial (N01358; NCT01261325) and corresponding open-label extension (OLE) (N01379; NCT01339559) of adjunctive BRV in adults (16-80 years of age) with focal seizures. Outcomes were assessed from the first day of BRV treatment in the double-blind (patients randomized to BRV) or open-label trial (patients randomized to placebo) by number of lifetime ASMs (1-2, 3-4, 5-6, or ≥ 7). Lifetime ASMs were defined as previous (stopped before BRV initiation) and concomitant ASMs at BRV initiation.


RESULTS
Seven hundred and forty patients received adjunctive BRV (safety set [SS]; median modal dose: 200 mg/day [N = 737]; median treatment duration: 2.67 years), of whom 13.8 % had 1-2, 20.8 % had 3-4, 21.1 % had 5-6 and 44.3 % had ≥7 lifetime ASMs. Patients with a higher number of lifetime ASMs had a younger age at epilepsy onset, longer epilepsy duration, and higher baseline seizure frequency. Kaplan-Meier estimated retention on BRV at 12 (83.2-65.9 %) and 36 months (63.0-44.1 %) was highest in patients with 1-2 lifetime ASMs and decreased with the number of lifetime ASMs. The estimated proportions of patients who discontinued BRV due to lack of efficacy or treatment-emergent adverse events (TEAEs) increased with the number of lifetime ASMs. Efficacy analyses included seven hundred and thirty eight patients (intention-to-treat set [ITT]). Median percentage reductions from baseline in focal seizure frequency/28 days (76.3-39.6 %), 50 % responder rates (66.7-39.8 %), 75 % responder rates (51.0-19.6 %), and continuous seizure freedom for ≥12 months at any time during BRV treatment (35.3-6.1 %) were highest in patients with 1-2 lifetime ASMs and decreased by the number of lifetime ASMs. The overall incidence of TEAEs (SS) was generally similar in each lifetime ASM subgroup (84.4-90.5 %). Discontinuations due to TEAEs increased with the number of lifetime ASMs (7.8-20.1 %). The greatest improvements in QOLIE-31-P scores occurred in the Seizure Worry and Daily Activities/Social Function subscales, with no clear pattern by the number of lifetime ASMs at 12 months and with the highest improvement in patients with 1-2 lifetime ASMs at 24 months. At 24 months, the Hospital Anxiety and Depression Scale (HADS) Anxiety subscale scores improved in patients (SS) with 1-2 and 3-4 lifetime ASMs. HADS Depression subscale scores were generally stable independent of the number of lifetime ASMs.


CONCLUSIONS
The balance between efficacy, tolerability, and HRQOL was most favorable in patients with focal seizures who had been exposed to one or two ASMs before BRV initiation. However, patients exposed to ≥7 ASMs before BRV initiation also benefitted from long-term adjunctive BRV treatment.


Introduction
An increasing number of previous antiseizure medications (ASMs) is associated with a poorer response to a newly administered ASM [1]. Phase 3, placebo-controlled, regulatory trials of adjunctive treatment of focal seizures in adults usually enroll patients with long epilepsy durations and a relatively high number of lifetime ASMs. The response to placebo and active treatment could be affected by the number of lifetime ASMs to a varying extent, highlighting the importance of considering ASM treatment history when interpreting data from epilepsy clinical studies [2].
Brivaracetam (BRV) is indicated for the adjunctive treatment of focal (partial-onset) seizures in patients 2 years of age and older in the European Union [3] and as monotherapy and adjunctive therapy in patients 1 month of age and older in the United States [4]. BRV is also approved in several countries in the Asia Pacific region and North and South America. The efficacy and tolerability of adjunctive BRV in adults with focal seizures have been established in three phase 3 trials [5][6][7] and their corresponding open-label extensions [8][9][10]. A post hoc analysis of 12-week data from a double-blind trial of adjunctive BRV in adults with focal seizures (N01358) indicated that patients with fewer lifetime ASMs had a generally greater response to BRV and lower incidence of discontinuations due to treatment-emergent adverse events (TEAEs), though patients with !7 lifetime ASMs could also benefit from BRV treatment [2].
The objective of this analysis was to evaluate long-term retention, reasons for discontinuation, efficacy, tolerability, and health-related quality of life during adjunctive BRV treatment in adults with focal seizures by the number of lifetime ASMs. Data were pooled from the aforementioned double-blind trial N01358 [6] and its open-label extension (N01379) [10], allowing patients to be followed over the long term from the first day of adjunctive BRV treatment.

Methods
We conducted a post hoc analysis of a randomized, doubleblind, placebo-controlled trial (N01358; NCT01261325) [6] and a corresponding open-label extension trial (N01379; NCT01339559) [10]. The double-blind trial was the only phase 3 trial of adjunctive BRV in adults with focal seizures that collected data on lifetime (all previous and concomitant) ASMs [6]. The open-label extension trial collected long-term data from patients completing the double-blind trial [10].
The double-blind trial evaluated the efficacy, safety, and tolerability of adjunctive BRV at doses of 100 or 200 mg/day in adults with uncontrolled focal seizures despite current treatment with one or two concomitant ASMs [6]. Patients were eligible to enroll in the open-label extension if they had previously participated in N01358 or in a double-blind trial of adjunctive intravenous (IV) BRV (N01258; NCT01405508) [11]. Patients who entered the open-label trial from the double-blind IV trial did not have lifetime ASM data and were excluded from the current analyses. The trial methodologies are described in detail in the primary papers [6,10]. The trials were conducted in accordance with Good Clinical Practice, the Declaration of Helsinki, and local laws, and each patient and/or their legal guardian provided written informed consent for participation.

Trial design
The double-blind trial [6] enrolled patients !16-80 years of age, with well-characterized focal epilepsy or epileptic syndrome. Eligible patients had uncontrolled seizures despite treatment with one or two permitted concomitant ASMs at stable dosage for !1 month before screening (3 months for phenobarbital, phenytoin, and primidone), at least two focal seizures (with or without secondary generalization) per month during the 3 months before screening, and at least eight focal seizures during the 8-week baseline period, with at least two focal seizures during each 4-week interval. Patients were excluded if they had non-motor focal aware (nonmotor simple partial) seizures only, seizure clusters, a history or presence of status epilepticus during the year preceding screening, treatment with levetiracetam (ongoing or within 90 days before screening), or any medical or psychiatric condition that, in the opinion of the investigator, could have jeopardized the patient's ability to participate in the trial.
The double-blind trial comprised an 8-week prospective baseline and 12-week treatment period, followed by entry into the open-label extension trial or by a 4-week down-titration period and a 2-week drug-free period. Patients were treated with placebo, BRV 100 mg/day, or BRV 200 mg/day, initiated without uptitration. Patients completing the treatment period of the doubleblind trial who were expected to benefit from long-term BRV could enroll in the open-label extension. Patients entered the open-label extension on a dose of BRV 150 mg/day and were maintained on this dose for at least 2 weeks unless they were unable to tolerate treatment. The dose of BRV and concomitant ASMs could subsequently have been adjusted to optimize seizure control and tolerability, without exceeding a BRV dose of 200 mg/day.

Post hoc analyses
Outcomes were assessed from the first day of BRV treatment in the double-blind (patients randomized to BRV) or open-label trial (patients randomized to placebo) by the number of lifetime ASMs (1-2, 3-4, 5-6, or !7). Lifetime ASMs were defined as previous (stopped before BRV initiation) and concomitant ASMs ongoing at BRV initiation.
BRV retention, BRV discontinuation, and reasons for discontinuation during the overall treatment period and during the first, second, and third years of adjunctive BRV treatment; and Kaplan-Meier estimated time to discontinuation due to any reason, lack of efficacy or TEAEs were assessed.
Efficacy outcomes included median percentage reductions from baseline in focal seizure frequency/28 days and 50 % and 75 % responder rates (patients with a !50 % or !75 % reduction from baseline in focal seizure frequency/28 days). These outcomes were assessed for the overall population, and in cohorts of patients who completed 1 year (52 weeks), 2 years (104 weeks), and 3 years (156 weeks) of adjunctive BRV treatment. Continuous seizure freedom (all seizure types) for !12 months (52 weeks) at any time during BRV treatment was assessed for the overall population, in patients who completed !12 months of adjunctive BRV treatment, and in yearly completer cohorts. Patients were considered to be seizure free if they had a period of consecutive days with no seizures for at least 12 months, and if they had completed their seizure diary for !90 % of the BRV treatment interval under evaluation.
Tolerability outcomes included incidence of any TEAEs, drugrelated, serious, and severe TEAEs, and TEAEs leading to discontinuation.
BRV dose, number of concomitant ASMs and concomitant ASM load (calculated from actual and defined daily doses) were assessed in patients with !12 months seizure freedom, and in patients who discontinued BRV due to TEAEs.
Health-related quality of life was assessed using the Patientweighted Quality of Life in Epilepsy Inventory-31 (QOLIE-31-P) [12]. Mean change from baseline and proportion of patients with a meaningful improvement (based on minimally important change threshold) [13] in total score and subscale scores were assessed in patients completing 12 and 24 months of adjunctive BRV treatment. QOLIE-31-P scores range from 0 to 100 with higher scores indicating better function. The mean changes from baseline in the Hospital Anxiety and Depression Scale (HADS) [14] Anxiety and Depression subscale scores were assessed in patients completing 12 and 24 months of adjunctive BRV treatment. HADS scores range from 0 to 21 with higher scores indicating higher depression/anxiety. The standardized mean difference (SMD) according to Hedges' g was calculated for mean change from baseline in QOLIE-31-P and HADS scores.
BRV retention, reasons for discontinuation, tolerability, and HADS scores were assessed for the safety set (SS), which included all patients who received at least one dose of BRV in the doubleblind or open-label extension trial. Efficacy outcomes and QOLIE-31-P were analyzed for the intention-to-treat (ITT) set, which included all patients in the SS with at least one post-baseline seizure diary entry.

Patients
A total of seven hundred and forty patients received adjunctive BRV in the double-blind or open-label extension trial (SS), of whom 102 (13.8 %) had 1-2 lifetime ASMs, 154 (20.8 %) had 3-4 lifetime ASMs, 156 (21.1 %) had 5-6 lifetime ASMs, and 328 (44.3 %) had !7 lifetime ASMs. Patients with a higher number of lifetime ASMs had a younger age at epilepsy onset, longer epilepsy duration, and higher baseline seizure frequency (Table 1). Epilepsy with a temporal focus of localization was most common (41.9 % of all patients), with a numerically higher representation in patients with !5 lifetime ASMs. The focus of localization was unknown in 14.7 % of patients, with a numerically higher representation in patients with 4 lifetime ASMs. Generally, no differences were observed across the lifetime ASM subgroups in the proportions of patients with a frontal, parietal, occipital, or multifocal focus of localization (Table 1). Prior levetiracetam use (stopped before BRV initiation) was reported in 4 (3.9 %) patients with 1-2 lifetime ASMs, 32 (20.8 %) with 3-4 lifetime ASMs, 88 (56.4 %) with 5-6 lifetime ASMs, and 282 (86.0 %) with !7 lifetime ASMs ( Table 1).
The median BRV treatment duration was 3.04 years in patients with 1-2 lifetime ASMs, 3.05 years in patients with 3-4 lifetime Table 1 Baseline demographics and epilepsy characteristics by number of lifetime ASMs at BRV initiation (SS).  There were seven hundred and thirty-eight patients who had post-baseline seizure diary data and were included in the ITT set.
Overall, a higher proportion of patients discontinued during the first year of BRV treatment (30.4 %, n = 740) than during the second (15.3 %, n = 515) or third years (11.9 %, n = 436) ( Supplementary  Fig. 1). Discontinuations due to adverse events were most common during the first year and generally decreased over time in all lifetime ASM subgroups. Discontinuations due to lack of efficacy were generally similar or lower in the second and third years compared with the first year of BRV treatment.
The Kaplan-Meier estimated proportion of patients who discontinued BRV due to any reason, lack of efficacy, or TEAEs increased with the number of lifetime ASMs used before BRV initiation (Fig. 1). The estimated retention of BRV (based on analyses of time to discontinuation due to any reason) was 83.

Efficacy
During the BRV treatment period, median percentage reductions from baseline in focal seizure frequency/28 days (76.3-39.6 %), 50 % responder rates (66.7-39.8 %), and 75 % responder rates (51.0-19.6 %) were highest in patients with 1-2 lifetime ASMs and decreased by the number of ASMs used before BRV initiation (Fig. 2). Within each lifetime ASM subgroup, the efficacy response was similar in patients who completed 1, 2, and 3 years of adjunctive BRV treatment (completer cohorts) (Fig. 2). Across all completer cohorts, the response was consistently highest in adults with 1-2 lifetime ASMs and lowest in patients with !7 lifetime ASMs. Within each completer cohort, the median percent reduction from baseline in focal seizure frequency and 50 % and 75 % responder rates for focal seizures were sustained over time in all lifetime ASM subgroups ( Supplementary Fig. 2).
In patients with !12 months seizure freedom (at any time during BRV treatment), the median duration of the first !12-month seizure-free interval was 22.7 months in all patients, and 23.6, 23.1, 20.0, and 29.2 months in patients with 1-2, 3-4, 5-6, and !7 lifetime ASMs, respectively. Overall, most patients (72.7 %) had an increase in BRV dose prior to the first day of their first !12-month seizure-free interval (Supplementary Fig. 3). From 3 months before the last day of the first !12-month seizure-free interval to the last day of the seizure-free interval, the mean BRV dose decreased from 157.7 mg/day to 116.1 mg/day and 54.5 % patients had a decrease in BRV dose (Supplementary Fig. 3). In most cases, the mean number of concomitant ASMs and concomitant ASM load did not change before or during the seizure-free interval ( Supplementary Fig. 3).

Tolerability
The overall incidence of TEAEs was generally similar in each lifetime ASM subgroup (84.4-90.5 %), whereas the incidences of drug-related and severe TEAEs were higher in patients with !7 lifetime ASMs (57.9 % and 20.7 %, respectively) compared with those with fewer lifetime ASMs (35.7-46.2 % and 13.0-15.4 %, respectively) ( Table 2). The incidences of serious TEAEs and TEAEs leading to discontinuation generally increased with the number of lifetime ASMs (Table 2).
Overall, the most common TEAEs (!10 % of all patients) were somnolence (19. The proportion of patients who discontinued BRV treatment due to TEAEs increased with the number of ASMs used before BRV initiation (7.8-20.1 %) ( Table 2). Among patients who discontinued BRV due to TEAEs (n = 117), the mean BRV dose was 80 mg/day at BRV initiation and 111 mg/day at the time of discontinuation; 53.0 % of patients had an increase in BRV dose from BRV initiation to BRV discontinuation ( Supplementary  Fig. 4). Most patients who discontinued BRV due to TEAEs had no change in the number of concomitant ASMs (82.1 %) or concomitant ASM load (70.1 %) from BRV initiation to BRV discontinuation ( Supplementary Fig. 4). The most favorable balance between efficacy (!12-month seizure freedom) and intolerable adverse events (discontinuation due to TEAEs) was observed in patients who had 1-2 lifetime ASMs before BRV initiation (Fig. 4).

Health-related quality of life
After 12 months of BRV treatment, QOLIE-31-P assessments showed the highest improvements from baseline in mean Seizure Worry and Daily Activity/Social Function subscale scores in all lifetime ASM subgroups ( Supplementary Fig. 5). For the Seizure Worry subscale score, the mean change from baseline (+10.7-12.4 [SMD 0.39-0.46]) was similar across subgroups. For the Daily Activity/ Social Function subscale score, the mean change from baseline ranged from +4.5 (SMD 0.19) (!7 lifetime ASMs) to +8.7 (SMD 0.35) (5-6 lifetime ASMs). Meaningful improvements from baseline in Fig. 1. Kaplan-Meier estimated time to BRV discontinuation due to (A) any reason, (B) lack of efficacy, and (C) treatment-emergent adverse events (SS). a Includes adverse event, lack of efficacy, protocol violation, loss to follow-up, consent withdrawn, missing/unknown, and other; b Patients who discontinued for reasons other than lack of efficacy were censored. c Patients who discontinued for reasons other than TEAE were censored. Patients completing the trial were censored at end of treatment. 12 months = 364 days. ASM, antiseizure medication; BRV, brivaracetam; SS, safety set. QOLIE-31-P total scores were observed in 46.8 %, 39.8 %, 46.6 %, and 40.3 % of patients with 1-2, 3-4, 5-6, and !7 lifetime ASMs, respectively. In all lifetime ASM subgroups, over 50 % of patients reported a meaningful improvement from baseline in the Seizure Worry subscale score (52.3-60.5 %). Meaningful improvements from baseline in the Daily Activity/Social Function subscale score were also reported in over 50 % of patients with 1-6 lifetime ASMs (51.9-59.0 %) and 49.0 % of patients with !7 lifetime ASMs.
After 24 months of BRV treatment, substantial improvements from baseline in the mean QOLIE-31-P Seizure Worry subscale score were observed in all lifetime ASM subgroups; the mean increase from baseline was highest in patients with 1-2 lifetime ASMs (+15.5 [SMD 0.59]) and lowest in those with !7 lifetime ASMs (+9.9 [SMD 0.36]) ( Supplementary Fig. 5). Daily Activity/ Social Function subscale score also improved in all subgroups, with the highest mean change in patients with 1-2 lifetime ASMs (+10.0

Discussion
In this post hoc analysis of data from a randomized placebocontrolled trial and corresponding open-label extension, adults with focal seizures exposed to fewer ASMs before adjunctive BRV initiation had numerically higher retention rates over the first 3 years of BRV treatment and were less likely to discontinue long-term BRV treatment because of lack of efficacy or TEAEs.
Data analyses of open-label extension trials of ASMs usually exclude patients who discontinued during the initial doubleblind trial or did not continue into the open-label extension. This introduces a potential bias towards patients who better tolerate the study drug and/or who respond well to treatment. In this analysis, we included all patients who received at least one dose of BRV in either the initial double-blind trial or the open-label extension, thus providing long-term efficacy and tolerability data in a population more closely reflecting clinical practice.
As the Phase 3, regulatory trials of adjunctive ASMs in adults usually enroll patients with a relatively high number of lifetime ASMs, the overall efficacy and tolerability outcomes mainly reflect a more refractory population. Overall, 44.3 % of patients enrolled in the double-blind trial had !7 lifetime ASMs, 21.1 % had 5-6 ASMs, 20.8 % had 3-4 ASMs, and only 13.8 % were exposed to 1-2 ASMs.
Long-term efficacy in focal seizures during adjunctive BRV treatment was highest in patients with 1-2 lifetime ASMs (median percentage reduction 76.3 %; 50 % responder rate 66.7 %; 75 % responder rate 51.0 %) and decreased by the number of lifetime ASMs. A post hoc analysis of data from the 12-week double-blind trial also showed a generally higher efficacy response to adjunctive BRV in patients exposed to fewer ASMs before adjunctive BRV initiation and the lowest response in patients with !7 lifetime ASMs [2]. Although patients exposed to !7 lifetime ASMs had a generally lower efficacy response, they still showed benefit from long-term BRV treatment, with a median reduction in focal seizure frequency .0]) represents more severely affected epilepsy patients, with a markedly higher baseline focal seizure frequency, earlier age at epilepsy onset, and longer epilepsy duration than patients with fewer lifetime ASMs.
To assess the maintenance of efficacy during long-term BRV treatment, a completer cohort approach was used (patients treated with BRV for at least 1, 2, or 3 years). This approach minimizes the potential bias introduced by enrichment over time of the population with patients tolerating the ASM and/or experiencing better seizure control. In these completer analyses, the efficacy response to adjunctive BRV was sustained over time, independent of the number of lifetime ASMs.
The proportion of patients with !12-month seizure freedom (all seizure types; any time during BRV treatment) was highest in the 1-2 lifetime ASM subgroup (35.3 %) and decreased with an increasing number of lifetime ASMs (6.1 % in patients with !7 lifetime ASMs). These data are consistent with data from a retrospective study of adjunctive BRV in adults with focal epilepsy, which showed that a lower number of previous ASMs was associated with a higher likelihood of seizure freedom at 12 months [15] or sustained seizure freedom throughout 12-month follow-up [16]. Post hoc analyses showed a higher sustained seizure frequency reduction in patients who received BRV as an early add-on treatment (after 1-2 prior ASMs) compared to those who received BRV as late adjunctive treatment (!3 prior ASMs) [17].
In patients with !12-month seizure freedom, the median duration of the first 12-month seizure-free interval ranged from 20.0 (5-6 lifetime ASMs) to 29.2 months (!7 lifetime ASMs), suggesting that when seizure freedom was achieved, it was maintained longterm irrespective of the number of lifetime ASMs.
During the open-label extension trial, doses of BRV (up to 200 mg/day) and concomitant ASMs could be adjusted as needed to optimize seizure control and tolerability. In patients with !12 months seizure freedom, the first !12-month seizure-free interval was assessed to evaluate the potential impact of BRV dose, the number of concomitant ASMs, and ASM load on seizure-free status. Most patients did not adjust their concomitant ASM regimen before or during the seizure-free interval, 72.7 % had an increase in BRV dose before their first !12-month seizure-free interval, and 54.5 % had a decrease in BRV dose during the last 3 months of their seizure-free interval. Based on the available data, it cannot be determined whether this decrease in BRV dose was related to TEAEs or was intended to decrease the patient's overall ASM load. It is also unclear whether the BRV dose decrease had an impact on the patient's seizure freedom status. A 30-year longitudinal study (1982 -2012) showed an increased incidence of adverse events leading to the discontinuation of newly administered ASMs with an increasing number of ASM regimens tried [18]. This suggests that a history of intolerable reactions to previous ASMs could impact the tolerability of subsequent drug regimens. In the current analysis of long-term adjunctive BRV treatment, the incidences of drug-related, serious, and severe TEAEs, and TEAEs leading to discontinuation were highest in patients with !7 lifetime ASMs. These results are consistent with an analysis of data from the 12-week double-blind trial, [2] and provide further evidence that a patient's lifetime ASM history may inform physicians not only about the potential efficacy but also about the potential tolerability of a newly administered ASM.
In all lifetime ASM subgroups, the greatest improvements from baseline in mean QOLIE-31-P scores were observed in the Seizure Worry and Daily Activity/Social Function subscales at 12 and 24 months of BRV treatment. The percentages of patients with a meaningful improvement from baseline (based on minimally important change thresholds [13]) were also highest for these two subscales. These results are consistent with data from other long-term BRV trials [8,10,19]. Seizure Worry and Daily Activity/ Social Function scores showed no clear pattern by the number of lifetime ASMs at 12 months, while at 24 months the greatest improvements were observed in patients with 1-2 lifetime ASMs and the smallest in those with !7 lifetime ASMs. At 24 months, patients with 1-2 lifetime ASMs also had the greatest improvements from baseline in Total score and Medication Effects subscale score. The proportions of patients with meaningful improvements from baseline were numerically higher for Total score, Energy / Fatigue, and Emotional Well-Being in the 1-2 lifetime ASMs subgroup versus patients with 3 or more lifetime ASMs. Improvements in Seizure Worry and Daily Activities/Social Function scores may reflect BRV efficacy, while improved Medication Effects scores may be due to BRV's favorable tolerability profile; improvements in Energy/Fatigue scores may result from both BRV efficacy and tolerability.
Long-term open-label extension studies of BRV have reported stability [8] or small numerical improvement [9] in HADS anxiety scores at 24 months. In this analysis by the number of lifetime ASMs, the largest improvements (SMD > 0.3) in HADS anxiety score were seen in patients with 1-2 and 3-4 lifetime ASMs at 24 months. Long-term studies have shown stability in HADS depression scores during adjunctive BRV treatment [8][9][10]. The results of this analysis are consistent with the published data and did not reveal substantial differences by the number of lifetime ASMs used before BRV initiation.
These findings should be interpreted with caution as this was a post hoc analysis of data pooled from a double-blind and openlabel long-term follow-up trial. During the open-label trial, patients had a flexible-dose regimen of concomitant ASMs, and the analysis lacked a comparator group.
In conclusion, the results of this analysis showed that the balance between efficacy, tolerability, and health-related quality of life was most favorable in patients with focal seizures who had been exposed to one or two ASMs before BRV initiation. However, patients exposed to seven or more ASMs before BRV initiation still benefitted from long-term adjunctive BRV treatment.

Declaration of Competing Interest
S. Dimova, C. Laloyaux, X. Nondonfaz, and S. Elmoufti are employees of UCB Pharma and receive stock or stock options from their employment. C. Brandt has received personal compensation from Arvelle Therapeutics / Angelini Pharma, Desitin, Equilibre Biopharmaceuticals, GW Pharmaceuticals, Idorsia, Janssen-Cilag GmbH, Marinus Pharmaceuticals, and Xenon Pharmaceuticals for

Funding
This work was supported by UCB Pharma. The sponsor was responsible for the design of the N01358 and N01379 studies and the current post hoc analysis. Data were interpreted by the authors. The sponsor was involved in the review of the manuscript and the decision to submit it for publication. All authors approved the final version of the manuscript for publication.

Author contributions
Christian Brandt analyzed and interpreted the study data. Svetlana Dimova designed the post hoc analyses, analyzed and interpreted the study data, and drafted sections of the manuscript. Sami Elmoufti supported the design of the post hoc analyses and analyzed and interpreted the study data. Cédric Laloyaux analyzed and interpreted the study data. Xavier Nondonfaz analyzed and interpreted the study data. Pavel Klein analyzed and interpreted the study data. All authors critically reviewed the manuscript and approved the final version for submission.

Data-sharing statement
Underlying data from this manuscript may be requested by qualified researchers 6 months after product approval in the United States and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents, which may include: analysis-ready datasets, study protocol, annotated case report forms, statistical analysis plans, dataset specifications, and clinical study reports. Before the use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data-sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password-protected portal.

Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.yebeh.2022.108967.