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Epilepsy & Behavior
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Epilepsy ^Behavior
Adjunctive eslicarbazepine acetate: A pooled analysis of three phase III trials
Victor Biton a'*1, Joanne B. Rogin b1, Gregory Kraussc, Bassel Abou-Khalild, José F. Rocha e, Joana Moreira e, Helena Gama e, Eugen Trinkaf, Christian E. Elger g, Hailong Cheng h, Todd Grinnellh, David Blum h, On behalf of the Study 301, 302 and 304 Investigators
a Arkansas Epilepsy Program, Clinical Trials Inc., Little Rock, AR USA
b Midwest Center for Seizure Disorders, Minneapolis Clinic of Neurology, Golden Valley, MN, USA c The Johns Hopkins Hospital, Department of Neurology, Baltimore, MD, USA d Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA e BIAL - Portela & C, S.A., Coronado (S. Romao e S. Mamede), Portugal
f Department of Neurology, Christian Doppler Medical Centre, Paracelsus Medical University, Salzburg, Austria g Department ofEpileptology, University of Bonn Medical Centre, Bonn, Germany h Sunovion Pharmaceuticals Inc., Marlborough, MA USA
ARTICLE INFO ABSTRACT
Objective: To assess the safety and efficacy of once-daily (QD) adjunctive eslicarbazepine acetate (ESL). Methods: This post-hoc pooled analysis of three randomized, placebo-controlled trials (2093-301, -302, -304) involved adults with refractory partial-onset seizures (POS) receiving 1-3 antiepileptic drugs (AEDs). All studies included 8-week baseline, 2-week titration, and 12-week maintenance periods. Patients were randomized equally to placebo, ESL400 mg (studies 301,302), 800 mg, or 1200 mg QD. The primary endpoint was standardized seizure frequency (SSF; per 4 weeks); secondary endpoints included responder rates (maintenance period), and incidence of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, serious AEs (SAEs), and deaths. Results: The safety and efficacy analysis populations totaled 1447 and 1410 patients, respectively. SSF was significantly reduced versus placebo with ESL 800 mg (p = 0.0001) and 1200 mg (p < 0.0001) but not 400 mg (p = 0.81). There were no significant interactions between treatment effect and age, gender, race/ethnicity, geographic region, epilepsy duration, or concomitant AED use. Incidences of TEAEs and TEAEs leading to discontinuation increased with ESL dose. Incidences of the most frequent TEAEs were lower for patients who initiated dosing at 400 versus 800 mg QD, regardless of titration regimen and maintenance dose. SAE incidence was < 10%; there were 3 deaths (placebo, n = 2; ESL 800 mg, n = 1).
Conclusions: ESL (800 and 1200 mg QD) was effective and well tolerated as adjunctive therapy for adults with refractory POS.
© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
m CrossMark
Article history: Received 26 January 2017 Revised 29 March 2017 Accepted 8 April 2017 Available online xxxx
Keywords:
Eslicarbazepine acetate Antiepileptic drug Partial-onset seizures Efficacy Tolerability Refractory epilepsy
Abbreviations: AED, antiepileptic drug; ALT, alanine aminotransferase; CBZ, carbamazepine; CI, confidence interval; DRESS, drug reaction with eosinophilia and systemic symptoms; ESL, eslicarbazepine acetate; GCP, Good Clinical Practice; mITT, modified intent-to-treat; MoA, mechanism of action; POS, partial-onset seizures; QD, once daily; SAE, serious adverse event; SSF, standardized seizure frequency; SUDEP, sudden unexpected death in epilepsy; TEAEs, treatment-emergent adverse events; ULN, upper limit of normal; VGSC, voltage-gated sodium channel.
* Corresponding author at: Arkansas Epilepsy Program, Clinical Trials Inc., 2 Lile Court, Suite 100, Little Rock, AR 72205, USA.
E-mail addresses: vbiton@clinicaltrialsinc.com (V. Biton), joanne.rogin@mpls-clinic.com (J.B. Rogin), gkrauss@jhmi.edu (G. Krauss), bassel.abou-khalil@vanderbilt.edu (B. Abou-Khalil), jose.rocha@bial.com (J.F. Rocha), joana.moreira@bial.com (J. Moreira), helena.gama@bial.com (H. Gama), e.trinka@salkat (E. Trinka), christian.elger@ukb.uni-bonn.de (C.E. Elger), hailong.cheng@sunovion.com (H. Cheng), todd.grinnell@sunovion.com (T. Grinnell), david.blum@sunovion.com (d. Blum).
1 VB and JBR made equal contributions to the development of the paper.
1. Introduction
Despite the availability of a wide range of antiepileptic drugs (AEDs), some patients fail to achieve adequate seizure control and/or experience intolerable adverse reactions [1-3]. Therefore, there remains a need for new treatment options for patients with refractory epilepsy.
Eslicarbazepine acetate (ESL; Aptiom®, Sunovion Pharmaceuticals Inc., Marlborough, MA; Zebinix®, BIAL - Portela & Ca, S.A., S. Mamede do Coronado, Portugal) is a once-daily (QD) oral AED approved for the treatment of partial-onset seizures (POS). Four phase 111 randomized, controlled trials evaluated adjunctive ESL for patients with refractory POS (BIA-2093-301, -302, -303, -304) [4-7]. Data pooled from studies 301,302, and 303 were the basis of the Marketing Authorisation Application to the European Medicines Agency for ESL, and a pooled analysis
http: //dx.doi.org/10.1016/j.yebeh.2017.04.019
1525-5050/© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/40/).
of this data has been previously reported by Gil-Nagel et al. [8]. The results of study 303 were consistent with those of studies 301, 302, and 304, but were not included in the current analysis (which was submitted as part of the US Food and Drug Administration New Drug Application for ESL), as study 303 was deemed not in accordance with Good Clinical Practice (GCP) standards.
We report here a post-hoc analysis of data pooled from studies 301, 302, and 304. Study 304 [7] is the only adjunctive ESL trial to include North American patients, and data from this trial were not included in Gil-Nagel et al.'s pooled analysis of data from phase III trials of adjunctive ESL [8]. The large sample size created by pooling data allows evaluation of treatment effects in different patient subgroups, including efficacy and safety outcomes potentially related to concomitant AED use. It also allows the assessment of safety topics of special interest, such as psychiatric and cognitive events, hypersensitivity reactions, and CNS-related symptoms; detailed reports of these safety topics of special interest were not included in the previous publication of pooled data from phase III trials of adjunctive ESL [8].
2. Methods
2.1. Study design
The multinational, randomized, double-blind, placebo-controlled trials (301 [NCT00957684], 302 [NCT00957047], and 304 [NCT00988429]; registered atClinicalTrials.gov) were conducted between July 2004 and January 2012. Standard procedures for protocol approvals, registration, and patient consents are described in Appendix 1. The design (including sample size calculations) of each study has previously been described [4,5,7]. Briefly, each study comprised 8-week baseline, 2-week titration, and 12-week maintenance periods (Fig. S1). The ESL titration and tapering-off schedules differed slightly between studies (Fig. S1B). After the baseline period, eligible patients were randomized equally to receive placebo, ESL 400 mg (studies 301 and 302 only), 800 mg, or 1200 mg orally (in tablet form) QD; patients continued to receive stable dosages of baseline concomitant AEDs. Details of randomization and blinding and eligibility criteria are reported in Appendix 1. Patient inclusion and exclusion criteria have been reported previously [4,5,7].
2.2. Efficacy assessments
The efficacy analysis was based on the modified intent-to-treat (mITT) population, which included all randomized patients who received > 1 dose of the study drug and had > 1 post-baseline seizure frequency assessment, but excluded patients from two sites in Poland in study 301 (see Appendix 1). Patients were excluded from these sites as seizure diaries were not provided as source records.
The primary efficacy endpoint was standardized seizure frequency (SSF; seizure frequency per 4 weeks) during the 12-week maintenance period. Key secondary endpoints included 50% responder rate (percentage of patients with >50% reduction in SSF between baseline and maintenance) and percentage change in SSF during maintenance, versus baseline. Other secondary endpoints were 75% responder rate during maintenance and rate of seizure freedom (100% reduction in seizure frequency) during maintenance (among patients who completed maintenance).
2.3. Safety assessments
Safety data were analyzed for all patients who received > 1 dose of study drug. Further details of the safety assessments are described in Appendix 1.
Primary safety endpoints included the incidence of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, serious adverse events (SAEs), and deaths. Secondary safety endpoints
included incidence of TEAEs for safety topics of special interest ("allergic reaction"; hyponatremia; psychiatric TEAEs; cognition-related TEAEs; "hepatic toxicity"; and cardiac rhythm and conduction disorders [see Appendix 1]), and change in body weight and vital signs.
2.4. Statistical analysis
SSF was compared between treatment groups using an analysis of covariance that modeled natural log-transformed SSF as a function of treatment; natural logarithm of baseline SSF; number of concomitant AEDs at baseline; and study. Safety endpoints were analyzed using descriptive statistics. Further details of the statistical methods are detailed in Appendix 1.
3. Results
3.1. Patient disposition, demographics, and baseline characteristics
The safety and efficacy (mITT) analysis populations totaled 1447 and 1410 patients, respectively; patient disposition for the pooled analysis is outlined in Fig. S2. Completion rates for the double-blind phase were 87% (placebo), 89% (ESL 400 mg), 82% (ESL 800 mg), and 71% (ESL 1200 mg). Total exposure to ESL during double-blind treatment was 246 patient-years (safety population). Baseline demographic and clinical characteristics were generally balanced between treatment groups (Table 1). Carbamazepine (CBZ), lamotrigine, valproic acid, and levetiracetam were the most frequently used (by > 15% of patients) concomitant AEDs.
3.2. Efficacy
3.2.1. Efficacy outcomes
The primary efficacy endpoint, least squares mean SSF (95% confidence interval [CI]) during the maintenance period, was lower for each ESL treatment group (ESL 400 mg, 7.3 [6.3-8.5]; ESL 800 mg, 6.1 [5.4-6.8]; ESL 1200 mg, 5.7 [5.0-6.4]) than for placebo (7.7 [6.9-8.7]), and suggested a dose-response relationship (Table 2). Compared with placebo, SSF was significantly lower with ESL 800 mg (p = 0.0001) and 1200 mg (<0.0001), but not with ESL400 mg (Table 2). In addition, the median percentage reduction in SSF was numerically greater for all doses of ESL than for placebo; at higher ESL doses, the reduction in SSF was approximately double the magnitude that occurred with placebo (Table 2).
The 50% responder rate (95% CI) during the maintenance period was significantly greater with ESL 800 mg (32.3% [27.6-37.3%]; p = 0.0003) and ESL 1200 mg (40.9% [35.8-46.4%]; p < 0.0001), than with placebo (20.9% [17.1-25.2%]) (Table 2). The 50% responder rate with ESL 400 mg was not significantly different to that with placebo. The number-needed-to-treat to achieve a response (50% reduction in SSF) was 9 and 5 for ESL 800 mg and 1200 mg, respectively. The effect size (difference between placebo and ESL treatment group) for 50% responder rate was 11% for ESL 800 mg and 20% for ESL 1200 mg. Compared with placebo, the 75% responder rate was also significantly greater with ESL 800 mg and 1200 mg, but not with ESL 400 mg (Table 2). During the maintenance period, there was no significant difference in the rate of seizure freedom between treatment groups (Table 2).
3.3. Subgroup analyses
For the primary endpoint (SSF during the maintenance period), there were no statistically significant interactions between the effect of treatment and that of age (p = 0.7), gender (p = 0.6), race/ethnicity (p = 0.9), duration of epilepsy (p = 0.3), and geographic region (p = 0.9). Similarly, concomitant AED use during the baseline period (both number of AEDs and type of AED) had no statistically significant interaction with the effect of treatment on SSF. In particular, although
Table 1
Demographics and baseline characteristics (safety population).a
Placebo (n = 426) ESL 400 mg (n = 196) ESL 800 mg (n = 415) ESL 1200 mg(n = 410)
Age, years, median (range) 37 (16-68)b 37(18-70) 38 (16-75) 37(16-69)
Males, n (%) 212 (49.8) 89 (45.4) 214(51.6) 201 (49.0)
Race/ethnicity, n (%)
Caucasian 331 (77.7) 187 (95.4) 326 (78.6) 317 (77.3)
Black 14(3.3) 2(1.0) 14 (3.4) 17(4.1)
Asian 46 (10.8) 2(1.0) 41 (9.9) 44 (10.7)
Hispanic 7 (1.6) 1 (0.5) 5 (1.2) 6(1.5)
Other 28 (6.6) 4 (2.0) 29 (7.0) 26 (6.3)
Region, n (%)
Eastern Europe 132 (31.0) 95 (48.5) 126 (30.4) 131 (32.0)
Latin America 90 (21.1) 53 (27.0) 94 (22.7) 87 (21.2)
Western Europe 58 (13.6) 33 (16.8) 52 (12.5) 59 (14.4)
North America 81 (19.0) 0 (0.0) 78 (18.8) 77 (18.8)
Rest of World 65 (15.3) 15(7.7) 65 (15.7) 56 (13.7)
BMI, kg/m2, median (range) 24.5 (16.0-48.7)c 23.7 (15.2-41.1) 25.1 (16.0-54.0)d 24.8 (15.5-50.8)e
Duration of epilepsy, years, mean (SD) 21.6 (13.9)f 21.9 (12.0)g 21.9 (12.8)h 20.8 (12.6)'
SSF during baseline, mean (SD) 14.8 (18.0)f 13.1 (15.3)" 16.0 (26.8)k 15.3 (17.9)1
Baseline AEDs, n (%)
1 116 (27.3)b 63 (32.1) 107 (26.0)m 117 (28.6)n
2 297 (69.9)b 127 (64.8) 292 (70.9)m 280 (68.5)n
3 12 (2.8)b 6(3.1) 13 (3.2)m 12 (2.9)n
Baseline AEDso, n (%)
Carbamazepine 198 (46.5) 116 (59.2) 204 (49.2) 204 (49.8)
Lamotrigine 108 (25.4) 46 (23.5) 93 (22.4) 105 (25.6)
Valproic acid 95 (22.3) 37 (18.9) 95 (22.9) 86 (21.0)
Levetiracetam 89 (20.9) 23 (11.7) 80 (19.3) 73 (17.8)
AED, antiepileptic drug; BMI, body mass index; ESL, eslicarbazepine acetate; mITT, modified intent to treat; SSF, standardized seizure frequency. a All randomized patients who received at least one dose of study drug. b n = 425. c n = 424. d n = 414. e n = 408.
f mITT population: n = 418. g mITT population: n = 188. h mITT population: n = 407. 1 mITT population: n = 395. j mITT population: n = 189. k mITT population: n = 408. l mITT population: n = 394. m n = 412. n n = 409.
o Used by >15% of patients.
in some ESL groups patients taking concomitant CBZ (the most frequently used baseline AED) had less marked improvements in efficacy outcomes than those taking other concomitant AEDs [9], these differences in outcomes were not significant; concomitant CBZ use did not significantly influence the effect of ESL treatment on SSF (p = 0.2), change in SSF from baseline (p = 0.3), or responder rate (p = 0.6).
3.4. Efficacy of ESL by seizure type
Dose-dependent median reductions in SSF (from baseline) and 50% responses with ESL were apparent for simple partial seizures, complex partial seizures, and partial seizures evolving to secondarily generalized seizures (Table S1).
Table 2
Summary of primary and secondary efficacy endpoints (mITT population).
Study endpoint Treatment group
Placebo (n = 406) ESL 400 mg (n = 185) ESL 800 mg (n = 375) ESL 1200 mg(n = 352)
SSFa, LS mean (95% CI) 7.7 (6.9-8.7) 7.3 (6.3-8.5) 6.1 (5.4-6.8) 5.7 (5.0-6.4)
p-value (versus placebo)b n.s. 0.0001 <0.0001
% change in SSFa, median -16.7 -22.6 - 31.2 - 33.3c
p-value (versus placebo)b n.s. 0.0010 0.0004
50% responder ratea, % (95% CI) 20.9 (17.1-25.2) 22.2 (16.4-28.8) 32.3 (27.6-37.3) 40.9 (35.8-46.4)
p-value (versus placebo)d n.s. 0.0003 <0.0001
75% responder ratea, % (95% CI) 8.4(5.9-11.5) 4.3 (1.9-8.3) 14.4(11.0-18.4) 15.6 (12.0-19.9)
p-value (versus placebo)d n.s. 0.0081 0.0020
Seizure-free ratea-e, % (95% CI) 1.2 (0.4-2.9) 1.1 (0.1-3.9) 1.6 (0.6-3.4) 2.0 (0.8-4.1)
p-value (versus placebo)d n.s. n.s. n.s.
CI, confidence interval; ESL, eslicarbazepine acetate; LS, least squares; mITT, modified intent to treat; n.s., not significant; SSF, standardized seizure frequency. a During the 12-week maintenance period.
b p-values were calculated using the Dunnett's multiple comparison procedure. c n = 351.
d p-values are based on Cochran-Mantel-Haenszel test stratified by study. e Based on patients who completed the maintenance period.
3.5. Safety 3.5.1. TEAEs
The overall incidence of TEAEs with ESL was dose-related (Table 3). The median time to onset of TEAEs was 16 days for ESL (all doses combined) versus 31.5 days for placebo. There were no clinically meaningful differences in the median duration of individual TEAEs between treatment groups; median duration of dizziness (the most frequently reported TEAE with ESL) was 4 days for placebo, and 3 days, 5.5 days, and 5 days for ESL 400, 800, and 1200 mg, respectively. The most frequently reported TEAEs with ESL were dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, and blurred vision (Table 3); most TEAEs were mild or moderate in severity.
Regardless of eventual maintenance dose, the incidence of TEAEs during double-blind treatment was lower for patients who began taking ESL at an initial dose of 400 mg (followed by 400 mg increments to 800 or 1200 mg) versus 800 mg (either continuing on 800 mg, or increasing to 1200 mg) (Table 3).
TEAEs leading to discontinuation of treatment occurred in 28 patients taking placebo (6.6%) and in 179 patients taking ESL (17.5% overall; the discontinuation rate appeared to be dose-dependent) (Table 3). The overall incidence of SAEs with ESL was < 10% (Table 3). During the double-blind treatment period, two deaths occurred in the
placebo arm (acute respiratory failure and possible sudden unexpected death in epilepsy [SUDEP]), and one in the ESL 800 mg arm (while taking ESL 400 mg during titration [status epilepticus, subsequently classified as probable SUDEP]). One patient drowned during the baseline period of study 304 (without having taken ESL).
3.6. Impact of concomitant AED use
Patients taking concomitant CBZ had higher placebo-adjusted rates of dizziness, diplopia, vomiting, and nausea (ESL 800 and 1200 mg groups), and lower placebo-adjusted rates of somnolence and tremor (ESL 1200 mg group) than those not taking CBZ (Fig. 1). Concomitant lamotrigine, valproic acid, and levetiracetam did not substantially affect the incidence ofTEAEs.
3.7. Safety topics of special interest
3.7.1. Allergic reaction
The incidence ofTEAEs related to "allergic reaction" was comparable between the placebo and ESL treatment groups (placebo, 8.5%; ESL 400 mg, 9.2%; 800 mg, 9.2%; 1200 mg, 10.5%; Table 4). "Rash" was specifically reported for some of these patients (1.9% with ESL, 0.9% with placebo); incidence appeared to be dose dependent (Table 4). The
Table 3
Overall incidence of TEAEsa, individual TEAE incidences, serious TEAEs, and TEAEs leading to discontinuation.
TEAE, nb (%) Placebo (n = 426) ESL 400 mg (n = 196) ESL 800 mg (n = 415) ESL 1200 mg (n = 410)
Any TEAEc 244(57.3) 130 (66.3) 294 (70.8) 320 (78.0)
According to titration scheme
ESL dosing initiated at 400 mg 130 (66.3) 208 (66.2)d 67 (65.7)e
ESL dosing initiated at 800 mg NA 86 (85.1)f 253 (82.1)g
According to severity
Mild 101 (23.7) 53 (27.0) 115 (27.7) 104(25.4)
Moderate 109 (25.6) 49 (25.0) 131 (31.6) 147 (35.9)
Severe 21 (4.9) 19 (9.7) 38 (9.2) 55 (13.4)
Individual TEAE incidences'1
Dizziness 40 (9.4) 31 (15.8) 82 (19.8) 116 (28.3)
Somnolence 36 (8.5) 26 (13.3) 46 (11.1) 74 (18.0)
Nausea 22 (5.2) 17(8.7) 40 (9.6) 64 (15.6)
Headache 40 (9.4) 23 (11.7) 52 (12.5) 61 (14.9)
Diplopia 10 (2.3) 13 (6.6) 38 (9.2) 46 (11.2)
Vomiting 11 (2.6) 9 (4.6) 25 (6.0) 41 (10.0)
Fatigue 16 (3.8) 6(3.1) 18 (4.3) 28 (6.8)
Vertigo 2 (0.5) 6(3.1) 10 (2.4) 26 (6.3)
Ataxia 9(2.1) 7 (3.6) 18 (4.3) 25 (6.1)
Blurred vision 6 (1.4) 10 (5.1) 23 (5.5) 19 (4.6)
Any SAEc 12 (2.8) 14(7.1) 29 (7.0) 11 (2.7)
Individual SAE incidencesi
Nausea 1 (0.2) 1 (0.5) 2 (0.5) 4(1.0)
Vertigo 0 1 (0.5) 2 (0.5) 3 (0.7)
Vomiting 1 (0.2) 2 (1.0) 3 (0.7) 2 (0.5)
Diplopia 0 3 (1.5) 1 (0.2) 2 (0.5)
Ataxia 0 3 (1.5) 3 (0.7) 1 (0.2)
Fall 2 (0.5) 2 (1.0) 2 (0.5) 1 (0.2)
Partial-onset seizures 0 2(1.0) 5(1.2) 0
TEAEs leading to discontinuationcj
Any TEAE 28 (6.6) 19 (9.7) 56 (13.5) 104(25.4)
Dizziness 2 (0.5) 2 (1.0) 23 (5.5) 37 (9.0)
Nausea 1 (0.2) 1 (0.5) 9 (2.2) 25 (6.1)
Vomiting 2 (0.5) 3 (1.5) 8 (1.9) 19 (4.6)
Ataxia 0 4 (2.0) 8 (1.9) 16 (3.9)
Diplopia 0 3 (1.5) 8 (1.9) 12 (2.9)
ESL, eslicarbazepine acetate; NA, not applicable; SAE, serious adverse event; TEAE, treatment-emergent adverse event. a According to ESL initiation dose and TEAE severity. b Data are number and percent of patients with TEAEs. c Patients with more than one event were counted only once. d n = 314. e n = 102. f n = 101. g n = 308.
h For TEAEs with an incidence >5% in any ESL treatment group. 1 For SAEs with an incidence >0.5% for ESL (all ESL doses combined).
j For TEAEs leading to treatment discontinuation in >2% of patients taking ESL (all doses combined).
-CBZ +CBZ
800 mg 1200 mg 800 mg 1200 mg 800 mg 1200 mg 800 mg 1200 mg 800 mg 1200 mg 800 mg 1200 mg Dizziness Diplopia Vomiting Nausea Somnolence Tremor
Fig. 1. Placebo-adjusted incidencea of TEAEs according to use of CBZ at baseline. Data are for TEAEs with absolute incidence >2% in any ESL dose group for either +CBZ or -CBZ, and >5% difference in incidence between +CBZ and - CBZ (for either ESL 800 mg or 1200 mg). aPlacebo-adjusted incidence = incidence in ESL group minus incidence in corresponding placebo group. CBZ, carbamazepine; ESL, eslicarbazepine acetate; TEAEs, treatment-emergent adverse events.
median time to onset of rash with ESL was 14 days (25% of events occurred within 9 days [i.e., during titration]; 75% occurred within 43 days). Severe rash was reported in one patient taking ESL 1200 mg. Rash leading to discontinuation occurred in 0.7% of patients taking ESL (all doses combined). Irrespective of titration schedule, incidence of rash was not clearly related to number of weeks on the ESL maintenance dose.
Two "allergic reaction" cases with ESL were described as "serious skin reactions" (Table 5). Analysis of the database indicated that one of these patients (ESL 1200 mg group) had combinations of AEs that potentially met RegiSCAR criteria for drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome; database analysis identified an additional potential case of DRESS in the ESL 400 mg group (Table 5).
3.7.2. Hyponatremia
TEAE reports of hyponatremia appeared to be dose-related (placebo, 0.2%; ESL400 mg, 0.5%; ESL800 mg, 1.7%; ESL 1200 mg, 2.2%) (Table 4). Low serum sodium concentration (minimum post-dose concentration < 125 mEq/L) occurred in 1.0% of patients taking ESL 800 mg and 1.5% of patients taking ESL 1200 mg, but in no patients taking placebo
(Table 4). In addition, a reduction from baseline in minimum postdose sodium > 10 mEq/L occurred in 4.7% and 6.5% of patients taking ESL 800 mg and 1200 mg, respectively, versus 0.7% of patients taking placebo (Table 4). Baseline CBZ use had no notable effect on the placebo-adjusted incidence of hyponatremia with ESL (all doses combined; CBZ, 1.5%; no CBZ, 1.4%). There were too few TEAE reports of hyponatremia in patients taking lamotrigine (2.9%), valproic acid (1.9%), or levetiracetam (1.5%) to allow conclusions about the individual effects of these AEDs. Hyponatremia leading to treatment discontinuation occurred in 0.4% of patients taking ESL (400 mg, 0%; 800 mg, 0.2%; 1200 mg, 0.7%). The hyponatremia-related TEAEs of somnolence, nausea and vomiting were more frequent in patients taking ESL who had minimum post-dose serum sodium levels < 125 mEq/L than in those with levels > 125 mEq/L.
3.7.3. Psychiatric events
The most frequently reported psychiatric TEAEs were depression and insomnia, the incidences of which were low and similar between placebo and ESL (2.1% versus 2.4%, and 1.2% versus 2.0%, respectively) (Table 4). The incidence of "depression and suicidality" events (identified by standardized MedDRA queries and questionnaire scores; Appendix 1) was numerically higher for ESL (8.9%) than for placebo (6.3%) (Table 4). "Suicidal ideation" was reported for one patient taking placebo (0.2%) and three patients in the ESL 800 mg group (0.7%) (Table 4), one of whom made an unsuccessful suicide attempt. There was one additional suicide attempt, during the baseline period.
3.7.4. Cognition-related TEAEs
The incidences of "cognition-related" TEAEs were greater for ESL (6.1%) than for placebo (3.8%) (Table 4). Memory impairment, and disturbance in attention were the most frequently reported cognition-related TEAEs (each reported for < 1.5% of patients taking ESL [all doses combined]). Cognition-related TEAEs leading to discontinuation occurred in 1.2% of patients taking ESL (400 mg, 0.5%; 800 mg, 1.0%; 1200 mg, 1.7%).
3.7.5. Changes in hepatic function
TEAEs potentially related to changes in hepatic function were reported infrequently (placebo, 0.5%; ESL, 1.2%) (Table 4). Increases
Adverse events of special interest.
Event, n (%) Placebo (n = 426) ESL400 mg (n = 196) ESL 800 mg (n = 415) ESL 1200 mg (n = 410)
Allergic reaction events
Category: Events related to "allergic reaction" 36 (8.5) 18 (9.2) 38 (9.2) 43 (10.5)
TEAE: Rash 4 (0.9) 1 (0.5) 5 (1.2) 13 (3.2)
Hyponatremia events
Assessment: Minimum post-dose serum sodium <125 mEq/L 0a 1 (0.5)b 4 (1.0)c 6 (1.5)d
Assessment: Reduction in minimum post-dose sodium >10 mEq/L 3 (0.7)a 6 (3.1)b 19 (4.7)c 26 (6.5)d
from baseline
TEAE: Hyponatremia 1 (0.2) 1 (0.5) 7 (1.7) 9 (2.2)
Psychiatric TEAEse
TEAE: Depression 9(2.1) 6(3.1) 6 (1.4) 12 (2.9)
TEAE: Insomnia 5 (1.2) 3(1.5) 9 (2.2) 8 (2.0)
Category: "Depression and suicidality" events 27 (6.3) 17(8.7) 31 (7.5) 43 (10.5)
TEAE: Suicidal ideation 1 (0.2) 0 3 (0.7) 0
Cognition-related TEAEs
Category: "Cognition-related" TEAEs 16 (3.8) 8(4.1) 21 (5.1) 33 (8.0)
TEAE: Memory impairment 1 (0.2) 2(1.0) 4(1.0) 7(1.7)
TEAE: Disturbance in attention 2 (0.5) 2(1.0) 3 (0.7) 6 (1.5)
Changes in hepatic function
Category: TEAEs potentially related to changes in hepatic function 2 (0.5) 3(1.5) 4(1.0) 5 (1.2)
Assessment: ALT levels >3 x ULN 1 (0.2) 1 (0.5) 1 (0.2) 1 (0.2)
ALT, alanine aminotransferase; ESL, eslicarbazepine acetate; TEAE, treatment-emergent adverse event; ULN, upper limit of normal. a n = 421. b n = 194. c n = 401. d n = 398.
e For TEAEs with an incidence >2% in patients taking ESL.
Table5
Serious skin reactions and potential cases of DRESS.
Study 301 ESL1200 mg • Rash (severe) • Fever
• Leucopenia • Increased AST/LDH/GGT
The patient was hospitalized; the AE was classified as serious Database analysis identified this event as a potential case of DRESS Study301 ESL 400 mg • Rash (moderate) • Fever
• Mildly elevated transaminases • Low platelet count
The patient was not hospitalized; the AE was not classified as serious Database analysis identified this event as a potential case of DRESS Study 304 ESL 800 mg • Exanthematous rash • Clinically diagnosed as leukocytoclastic vasculitis (no biopsy)
• Mildly elevated ALT (not clinically significant)
The Asian patient (Human Leukocyte Antigen-b [HLAb]*1502 negative) was hospitalized; the AE was classified as serious
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DRESS, drug reaction with eosinophilia and systemic symptoms; ESL, eslicarbazepine acetate; GGT, gamma-glutamyl transferase; LDH, lactate dehydrogenase.
in hepatic enzymes were rare. Alanine aminotransferase (ALT) levels >3 x the upper limit of normal (ULN) occurred infrequently (in <0.5% of patients) and at similar rates across treatment groups (Table 4). No patients with ALT or aspartate aminotransferase >3 x ULN had gastrointestinal TEAEs, and no patients taking ESL had bilirubin levels > 1.5 x ULN.
3.7.6. Cardiac rhythm and conduction disorders
EKGs were reviewed in a blinded fashion by external cardiologists; no clinically relevant EKG changes were identified. At study end/early-termination visit, no patients had a clinically relevant change in heart rate or prolongation of EKG interval (including PR and QT intervals).
3.8. Other safety assessments
Generally, changes in hematology and chemistry parameters appeared unrelated to ESL use. Decreases in free T3 and T4 from baseline were noted for some patients; mean (SD) changes from baseline to end of study/early termination (ng/dL) for free T3 were: placebo, 0.0014 (0.0688); ESL 400 mg, -0.0015 (0.0445); ESL 800 mg,
- 0.0169 (0.0495); ESL 1200 mg, - 0.0150 (0.0427); for freeT4, mean (SD) changes were: placebo, 0 (0.2); ESL 400 mg, 0 (0.2); ESL 800 mg,
- 0.1 (0.2); ESL 1200 mg, - 0.1 (0.2). These decreases in free T3 and T4 were not associated with other abnormal thyroid function test results suggestive of hypothyroidism. The incidence of hypothyroidism as a TEAE was <2% in all treatment groups. Overall, no clinically relevant changes in blood pressure, pulse rate, or body weight were identified.
4. Discussion
This post-hoc pooled analysis of data from ~ 1400 patients with refractory POS allowed estimation of treatment effects in key patient subgroups, including those taking different concomitant AEDs and those from different geographic regions. The large dataset also allowed a detailed assessment of safety topics of special interest for AEDs.
Addition of ESL (800 mg or 1200 mg QD) to existing AED therapy led to significant reductions in SSF versus placebo, whereas ESL 400 mg did not significantly separate from placebo on any measures of efficacy. The effect of ESL appeared to be dose related for most measures. Responder rates (50% and 75%) for ESL 1200 mg were approximately double those for placebo. Rates of seizure freedom were relatively low in all treatment groups; this was based on a conservative estimate (number of seizure-free patients completing the study/number of patients in the mITT population), and was not unanticipated (patient baseline characteristics indicated long epilepsy duration and frequent seizures, despite use of 1-3 AEDs; Table 1). These results corroborate those of the three individual phase III trials of adjunctive ESL (studies 301, 302, and 304), and are consistent with the previous pooled analysis conducted by Gil-Nagel et al. [8], whether or not study 303 was included (study 303 was not in accordance with GCP standards).
Demographics and age did not affect efficacy; there was no significant interaction between the effect of ESL treatment and age, race/ ethnicity, gender, concomitant AED use, duration of epilepsy, or geographic region, even though in study 304 (the first phase III ESL study to include North American patients) the effect of ESL on improvements in seizure frequency was found to be less marked in North American patients than in patients in the rest of the world [7]. This difference between regions may have been related to the use of a more rigorous daily entry diary system by the majority of patients in study 304, compared with the event entry diary system used by patients in studies 301 and 302. Also, differences in clinical practice, patient characteristics and placebo-response rate, as well as economic and cultural differences between regions, may have contributed towards these observed differences in seizure improvements. For all seizure types, the proportions of responders were numerically higher with ESL 800 and 1200 mg than with placebo.
Some evidence suggests that combinations of voltage-gated sodium-channel (VGSC) modulators may be less effective than combinations of drugs with different mechanisms of action (MoAs), which may produce additive or synergistic effects [10]. The effects of both CBZ and lamotrigine may involve inhibition ofVGSCs, and both were used by > 15% of patients in this study. CBZ (used by ~50% of patients in the current study) induces enzymes that metabolize eslicarbazepine, while eslicarbazepine is a moderate inducer of CYP3A4; potentially impacting exposure to eslicarbazepine and CBZ respectively (doses of ESL or CBZ may require adjustment, based on efficacy and tolerability) [11-13]. Despite this, there was no significant interaction between the effect of ESL treatment and use of carbamazepine, lamotrigine, valproic acid, or levetiracetam at baseline. However, improvements in seizure-related endpoints were somewhat greater among patients who were not taking concomitant CBZ versus those who were [9].
ESL in combination with existing AED therapy was well tolerated in adults with refractory POS. Reported TEAEs were consistent with the known side effects of VGSC modulators (diplopia, dizziness, headache, vertigo, and somnolence), and most were of mild or moderate severity. With ESL (all doses combined), most TEAEs began soon after the start of treatment and were of relatively short duration (median 7 days; interquartile range 2-29 days). Although the incidence of TEAEs appeared dose related, rates were substantially lower in patients who began taking ESL 400 mg versus 800 mg (regardless of maintenance dose). Nevertheless, initiating ESL at 800 mg appeared safe (although less well tolerated), and so could be considered if a more rapid effect is needed.
There is evidence that when the side effects of co-administered drugs are similar (e.g., VGSC-modulator-associated side effects), that pharmacodynamic interactions may increase the likelihood of these side effects occurring [10]. Indeed, the incidences of dizziness, diplopia, and nausea were greater for patients taking ESL plus CBZ than for those taking ESL without concomitant CBZ. Reducing the CBZ dose may improve tolerability for patients taking ESL and CBZ; indeed, in study 304, CBZ dose reduction was allowed if patients showed improved efficacy but had tolerability issues, providing an opportunity for these
patients to continue in the study. When drugs with a similar MoA are used in combination, a "threshold" of tolerability may be exceeded for a specific side effect; this may explain the pharmacodynamic interactions previously identified between lamotrigine and CBZ, and between CBZ and phenytoin (all putative VGSC modulators) [10], and may also explain the current findings. In practice, if the baseline therapies are deemed to have been ineffective, their doses could be tapered, potentially reducing pharmacodynamic interactions. There was little evidence of additive toxicity between ESL and other AEDs; concomitant lamotrigine (a putative VGSC modulator), levetiracetam, and valproic acid did not notably alter the TEAE profile of adjunctive ESL (data not shown).
The overall incidence of rash with ESL was 1.9%. In the current analysis, two patients taking ESL developed rash with systemic signs, which were later classified as potential DRESS via a database analysis (this type of analysis was not conducted for previously developed AEDs, or in previous analyses of ESL data). The low incidence of hyponatremia appeared to be dose related.
Individual psychiatric TEAE incidences with ESL were <2.5%. While AEs such as irritability, anxiety, and aggressive behavior have been associated with other AEDs [14,15], rates of aggression and agitation were comparable between ESL and placebo. Cognition-related side effects were also reported infrequently with ESL. Incidences of some cognition-related TEAEs, such as memory impairment, were dose-dependent; no single cognition-related TEAE had an incidence > 1.5%.
The incidence of SAEs with ESL was 5.3%, and the most frequently reported SAEs were generally consistent with the underlying illness, or with TEAEs commonly associated with AEDs in general (e.g., seizures, ataxia, nausea, and vomiting) [16-18].
A potential limitation of this analysis is that statistical comparisons of TEAE incidence were not prospectively planned. AE incidence was described using descriptive statistics only; the large number of possible comparisons reduces the power to determine statistical significance when corrections for multiplicity (e.g., Bonferroni) are applied. However, the large sample size allowed a more accurate estimation of the incidence of uncommon adverse events of special interest to epilepsy patients (e.g. rash). In post-hoc pooled analyses, findings of statistically significant differences in secondary efficacy endpoints should be interpreted with caution.
Other potential limitations relate to patient demographics and baseline characteristics. The inclusion criteria were slightly different between study 304 and studies 301 and 302. Study 304 randomized patients > 16 years, whereas studies 301 and 302 randomized patients > 18 years; this was a minor limitation as only a small number of randomized patients were aged 16-17 years. Baseline seizure frequency requirements differed slightly between studies but were all approximately equivalent to a baseline seizure frequency of >4 seizures per 4 weeks. A final point to note is that there is a potential under-representation of minorities (e.g., black, Hispanic), which may limit the generalizability of these results to the epilepsy population.
The results indicate that ESL (800 and 1200 mg QD) is an effective and well-tolerated option for adjunctive treatment of POS.
Sources of funding
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts, USA, and BIAL - Portela & Ca, S.A., Sao Mamede do Coronado, Portugal funded the clinical trials reported in this manuscript. The sponsors were involved in the study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. Medical writing support was funded by Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts, USA.
Disclosure of conflicts of interest
Dr Biton has received personal compensation for serving on a scientific advisory board for Upsher-Smith Laboratories Inc. Dr Biton has also
received research support from Eisai Inc., Accera Inc., Pfizer Inc., Sunovion Pharmaceuticals Inc., UCB Pharma Inc., Upsher-Smith Laboratories Inc., SK Life Science Inc., Marinus Pharmaceuticals Inc., Merck Research Laboratories, H. Lundbeck A/S, FORUM Pharmaceuticals Inc., Civitas Therapeutics Inc., Vertex Pharmaceuticals Inc., Schering-Plough Research Institute, and Wyeth Research.
Dr Rogin served on Sunovion and Eisai scientific advisory boards, received speakers' honoraria from Sunovion, Eisai and UCB, and received research support from Sunovion, UCB, Marinus, Eisai, SK Life Science and Pfizer.
Dr Krauss has received consultancy honoraria from Lundbeck and Sunovion and honoraria from Medscape Education (CME) for serving as an editor and writer. Dr Krauss has also received research funding from Sunovion, UCB Pharma, Upsher Smith, Eisai, SK Life Science and National Institutes of Health (NIH).
Dr Abou-Khalil received research support, paid to Vanderbilt University, from Sunovion, UCB, Upsher Smith, Cyberonics, SK Life Science, Pfizer, Human Epilepsy Project, NIH (Epilepsy Phenome/Genome Project), local Principal Investigator.
Drs Rocha, Moreira and Gama are full-time employees of BIAL -Portela & Ca, S.A.
Dr Trinka has acted as a paid consultant to Eisai, Ever Neuropharma, Biogen Idec, Bial and UCB, has received speakers' honoraria from Bial, Eisai, GL Pharma, GlaxoSmithKline, Boehringer, Viropharma, Actavis, Newbridge, Sunovion, Novartis, Takeda and UCB Pharma, and has received research funding from UCB Pharma, Biogen-Idec, Red Bull, Merck, the European Union, FWF Österreichischer Fond zur Wissenschaftsförderung, Bundesministerium für Wissenschaft und Forschung, and Jubiläumsfond der Österreichischen Nationalbank.
Dr Elger has received funding (honoraria or consultation fees) from UCB, Desitin, BIAL, Eisai, Pfizer, Medtronic, and Medichem-CNS, and has received federal funding from DFG (Deutsche Forschungsgemeinschaft).
Drs Cheng, Grinnell and Blum are full-time employees of Sunovion Pharmaceuticals Inc.
Acknowledgments
The authors would like to thank Dr Raymond Claus, formerly of Sunovion Pharmaceuticals Inc., who contributed to the statistical analysis, and Dr Rui Sousa, formerly of BIAL - Portela & Ca, S.A, for his advice and input during development of the article. Medical writing support was provided by Mallory Gough, PhD, of FireKite, an Ashfield Company, part of UDG Healthcare plc.
Appendix 2. Supplementary data
Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.yebeh.2017.04.019.
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