Scholarly article on topic 'Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials'

Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Gregory Krauss, Victor Biton, Jay H. Harvey, Christian Elger, Eugen Trinka, et al.

Abstract Objective To examine the influence of titration schedule and maintenance dose on the incidence and type of treatment-emergent adverse events (TEAEs) associated with adjunctive eslicarbazepine acetate (ESL). Methods Data from three randomized, double-blind, placebo-controlled trials were analyzed. Patients with refractory partial-onset seizures were randomized to maintenance doses of ESL 400, 800, or 1200mg QD (dosing was initiated at 400 or 800mg QD) or placebo. The incidence of TEAEs was analyzed during the double-blind period (2‐week titration phase; 12-week maintenance phase), according to the randomized maintenance dose and the titration schedule. Results 1447 patients were included in the analysis. During the first week of treatment, 62% of patients taking ESL 800mg QD had ≥1 TEAE, vs 35% of those taking 400mg QD and 32% of the placebo group; dizziness, somnolence, nausea, and headache were numerically more frequent in patients taking ESL 800mg than those taking ESL 400mg QD. During the double-blind period, the incidences of common TEAEs were lower in patients who initiated ESL at 400mg vs 800mg QD. For the 800 and 1200mg QD maintenance doses, rates of TEAEs leading to discontinuation were lower in patients who began treatment with 400mg than in those who began taking ESL 800mg QD. Conclusions Initiation of ESL at 800mg QD is feasible. However, initiating treatment with ESL 400mg QD for 1 or 2 weeks is recommended, being associated with a lower incidence of TEAEs, and related discontinuations. For some patients, treatment may be initiated at 800mg QD, if the need for more immediate seizure reduction outweighs concerns about increased risk of adverse reactions during initiation.

Academic research paper on topic "Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials"

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Epilepsy Research

journal homepage: www.elsevier.com/locate/epilepsyres

Influence of titration schedule and maintenance dose on the tolerability of } adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials

CrossMark

Gregory KraussE

*, Victor Bitonb, Jay H. Harvey0, Christian Elgerd

Patricio Soares da Silvaf, Helena Gamaf, Hailong Chengg,

Eugen Trinkae, Todd Grinnellg, David Blumg

a The Johns Hopkins Hospital, Department of Neurology, Meyer 2-147, 600 N Wolfe St, Baltimore, MD 21287, USA b Arkansas Epilepsy Program, Clinical Trials Inc., 2 Lile Ct #100, Little Rock, AR 72205, USA c Texas Epilepsy Group, Neurological Clinic of Texas, 3 Forest Plaza, 12221 Merit Dr #350, Dallas, TX 75251, USA d Department of Epileptology, University of Bonn Medical Centre, Sigmund-Freud-Strafee 25, 53127 Bonn, Germany

e Department of Neurology, Christian Doppler Medical Centre, Paracelsus Medical University and Centre for Cognitive Neuroscience, Ignaz Harrerstrasse 79, 5020 Salzburg, Austria

f BIAL-Portela & Ca, S.A., Avenida da Siderurgia Nacional 4745-457 Sao Mamede do Coronado, Portugal g Sunovion Pharmaceuticals Inc., 84 Waterford Dr, Marlborough, MA 01752, USA

ARTICLE INFO

ABSTRACT

Keywords:

Eslicarbazepine acetate Titration schedule Tolerability Partial-onset seizures

Objective: To examine the influence of titration schedule and maintenance dose on the incidence and type of treatment-emergent adverse events (TEAEs) associated with adjunctive eslicarbazepine acetate (ESL). Methods: Data from three randomized, double-blind, placebo-controlled trials were analyzed. Patients with refractory partial-onset seizures were randomized to maintenance doses of ESL 400, 800, or 1200 mg QD (dosing was initiated at 400 or 800 mg QD) or placebo. The incidence of TEAEs was analyzed during the double-blind period (2-week titration phase; 12-week maintenance phase), according to the randomized maintenance dose and the titration schedule.

Results: 1447 patients were included in the analysis. During the first week of treatment, 62% of patients taking ESL 800 mg QD had > 1 TEAE, vs 35% of those taking 400 mg QD and 32% of the placebo group; dizziness, somnolence, nausea, and headache were numerically more frequent in patients taking ESL 800 mg than those taking ESL 400 mg QD. During the double-blind period, the incidences of common TEAEs were lower in patients who initiated ESL at 400 mg vs 800 mg QD. For the 800 and 1200 mg QD maintenance doses, rates of TEAEs leading to discontinuation were lower in patients who began treatment with 400 mg than in those who began taking ESL 800 mg QD.

Conclusions: Initiation of ESL at 800 mg QD is feasible. However, initiating treatment with ESL 400 mg QD for 1 or 2 weeks is recommended, being associated with a lower incidence of TEAEs, and related discontinuations. For some patients, treatment may be initiated at 800 mg QD, if the need for more immediate seizure reduction outweighs concerns about increased risk of adverse reactions during initiation.

1. Introduction

Efficacy limitations and poor tolerability contribute to incomplete seizure control in up to 40% of patients with epilepsy during monotherapy treatment with first- or second-line antiepileptic drugs (AEDs) (Stephen and Brodie, 2012). Adverse effects of AEDs can substantially

reduce patients' quality of life (QoL), and may limit their ability to tolerate effective doses of AEDs, which otherwise could be beneficial (French and Gazzola, 2011; Gilliam et al., 2004). To maximize therapeutic benefit and reduce the risk of adverse events (AEs), dosing of AEDs should be tailored to the needs of the individual (Perucca et al., 2001). Dose optimization can, however, be a complicated process that

Abbreviations: AE, adverse event; AED, antiepileptic drug; CNS, central nervous system; ESL, eslicarbazepine acetate; GCP, good clinical practice; MedDRA, medical dictionary for regulatory activities; NA, not applicable; OXC, oxcarbazepine; POS, partial-onset seizures; QoL, quality of life; SAE, serious adverse event; TEAE, treatment-emergent adverse event * Corresponding author at: Department of Neurology, The Johns Hopkins Hospital, 600 North Wolfe Street, Meyer 2-147, Baltimore, MD, 21287, USA. E-mail addresses: gkrauss@jhmi.edu (G. Krauss), vbiton@clinicaltrialsinc.com (V. Biton), dr.harvey@texasepilepsy.org (J.H. Harvey), Christian.Elger@ukb.uni-bonn.de (C. Elger), e.trinka@salk.at (E. Trinka), Psoares.silva@bial.com (P. Soares da Silva), Helena.Gama@bial.com (H. Gama), Hailong.Cheng@sunovion.com (H. Cheng), Todd.Grinnell@sunovion.com (T. Grinnell), David.Blum@sunovion.com (D. Blum).

http://dx.doi.org/10.10167j.eplepsyres.2017.10.021

Received 3 March 2017; Received in revised form 3 October 2017; Accepted 24 October 2017

Available online 04 November 2017 0920-1211/ © 2017 Published by Elsevier B.V.

requires skill and patience, and several studies have indicated that in routine clinical practice, dose individualization is often suboptimal (Perucca et al., 2001).

To reduce the risk of adverse effects when initiating AEDs, physicians often adopt a 'start low and go slow' dose titration approach (Schmidt and Schachter, 2008; Trinka, 2012), particularly in vulnerable groups such as the elderly, in which tolerability often determines the success of AED therapy (Rowan et al., 2005). While the rationale for this approach is widely accepted, supportive information is lacking for many AEDs, including newer agents. Most clinical trials are designed for regulatory purposes, and may therefore fail to answer questions of value to clinicians, such as what is the best starting dose and titration schedule (Faught, 2012). Regulatory trials tend to use fixed titration schedules, and consequently, fail to provide information relevant to the variety of titration schedules that tend to be used in day-to-day clinical practice. For many agents, only very limited information from controlled clinical trials is available on the effect of different titration schedules on treatment outcomes. Without such empirical information, clinicians are less able to make informed decisions on the appropriate starting dose and titration schedule for each patient, often having to resort to trial and error.

Eslicarbazepine acetate (ESL) is a once-daily oral AED, approved by the US Food and Drug Administration for the treatment of partial-onset seizures (POS) as monotherapy or adjunctive therapy. ESL is approved by the European Medicines Agency as adjunctive therapy of POS in adults, and by Health Canada as adjunctive therapy of POS in patients with epilepsy who are not satisfactorily controlled with conventional therapy. After oral administration, ESL is extensively converted to the primary active metabolite, eslicarbazepine, which is thought to act primarily by stabilizing the inactivated state of voltage-gated sodium channels (Almeida and Soares-da-Silva, 2007; Hebeisen et al., 2015). The efficacy and favorable safety profile of adjunctive ESL (800 mg and 1200 mg QD) have been demonstrated in three Phase III studies in patients with POS (Ben-Menachem et al., 2010; Elger et al., 2009; Sperling et al., 2015a), and are further supported by an analysis of pooled data from these three studies (Biton et al., 2017). The results suggest that most AEs began during the first few weeks of treatment (Sperling et al., 2012).

Patients who enrolled in the Phase III trials of ESL underwent one of six different titration schedules, with a variety of initiation doses, titration schedules, and maintenance doses. Taken together, the information generated by the three trials allowed us to evaluate the impact of ESL titration schedule (initiation, titration, and maintenance doses) on the incidence and type of treatment-emergent adverse events (TEAEs) during double-blind treatment with adjunctive ESL therapy. Understanding the influence of dose titration schedule on tolerability is important for newer AEDs; without this information, substantial clinical experience with these drugs may be needed before clinicians understand how best to initiate treatment, minimize tolerability issues, and optimize outcomes.

2. Methods

The efficacy and safety of ESL as adjunctive therapy in refractory POS were assessed in three multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase III studies: 2093-301 (ClinicalTrials.gov identifier: NCT00957684) (Elger et al., 2009); 2093302 (NCT00957047) (Ben-Menachem et al., 2010); and 2093-304 (NCT00988429) (Sperling et al., 2015a). A fourth multicenter, randomized, double-blind, placebo-controlled Phase III study (study 2093303) was not included in this pooled analysis.

This post-hoc analysis of individual patient data pooled from studies -301, -302, and -304 evaluated the effect of titration schedule (initiation dose and rate of dose escalation) and target (maintenance) dose on incidence rates of AEs. Pooling data from the three studies increased the size of the dataset, thereby permitting sub-analyses that

had not been feasible in the individual trials. As the three trials used various different titration schedules, AE incidence rates could be analyzed according to initiation dose, titration schedule, and maintenance dose. In most other respects, the three trials were of very similar design.

2.1. Study populations and design

Inclusion and exclusion criteria for the three studies have been reported elsewhere (see Table S1 for details) (Ben-Menachem et al., 2010; Elger et al., 2009; Sperling et al., 2015a). Patients were required to have had a diagnosis of epilepsy (POS) with or without secondary generalization, for at least 12 months, not adequately controlled with 1-3 AEDs.

Each study began with an 8-week baseline period (single-blind placebo or observational), at the end of which patients were randomized equally to receive placebo, ESL 400 mg (studies — 301 and — 302 only), 800 mg or 1200 mg QD (the randomization specified the dose received during the maintenance period, i.e., week 3 onward). Randomization was not stratified according to the baseline seizure frequency. The baseline period was followed by a 2-week double-blind titration period. Patients in the three trials underwent one of six different titration schedules, each comprising a starting dose of 400 or 800 mg QD, followed by weekly increments of 0 or 400 mg, to a maintenance dose of 400, 800 or 1200 mg QD. The titration period was followed by a 12-week double-blind, fixed-dose maintenance period. Dose reductions were not permitted during the maintenance period.

All patients gave written informed consent. All protocols were approved and all three studies were performed in accordance with Good Clinical Practice, the Code of Ethics of the World Medical Association (Declaration of Helsinki), and local laws and regulations.

2.2. Assessment of TEAEs

AEs reported spontaneously by patients during clinic visits were recorded by investigators, and coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 13.1. AEs were considered to be TEAEs if they began on or after the start of ESL treatment (or, if unknown or unclear, after the date of randomization) and up to 30 days after the last dose of ESL. The TEAE rates reported here include TEAEs recorded as such, plus additional events identified based on findings of audits of investigator records and case report forms, and from review of subject narratives and serious adverse event (SAE) reports (Council for International Organizations of Medical Sciences forms). Signs and symptoms associated with any reported diagnoses were also recorded as separate TEAEs.

2.3. Data analysis

All data presented are from the pooled safety population (any patient in the three trials who received at least one dose of study medication). Comparisons between groups were descriptive; formal statistical analysis and testing was not conducted, as the studies were not powered or designed to test for differences between dosing regimens/ titration schedules.

Baseline demographic and clinical characteristics were summarized descriptively for the randomized treatment groups.

Descriptive summaries were developed to explore whether the starting dose, the titration schedule, and the maintenance dose have an influence on the incidence of TEAEs with ESL. The incidence of TEAEs during the first week of treatment was summarized according to the dose received that week (the starting dose). The incidences of frequently reported TEAEs (and rates of TEAEs leading to discontinuation) during the double-blind period (titration and maintenance periods; weeks 1 -14) were summarized for six subgroups defined by ESL starting dose and titration schedule. For the same six subgroups, the cumulative incidence of treatment discontinuation due to TEAEs (% of

patients) over time was evaluated using Kaplan-Meier analysis. The frequency of rash during the double-blind period was evaluated according to ESL starting and maintenance dose.

Incidences of TEAEs, and TEAEs leading to discontinuation, during the double-blind period were summarized for patients who began treatment with ESL 400 mg QD and who remained on that dose for 1 or 2 weeks before the dose was increased to either 800 or 1200 mg QD (and for TEAEs leading to discontinuation, also for those who remained on ESL 400 mg QD throughout the study).

3. Results

3.1. Demographics and baseline characteristics

The pooled safety population comprised 1447 patients (placebo, n = 426; ESL, n = 1021). Baseline demographics and clinical characteristics per randomized treatment group were previously reported, and were similar between the randomized groups (see Table S2) (Sperling et al., 2015a). The median age was 37 years; there were approximately equal proportions of males and females, and the median duration of epilepsy was 20 years. During the study, 72% of ESL-treated patients used at least two background AEDs, the most common being carbamazepine (51%), lamotrigine (24%), levetiracetam (17%), and forms of valproic acid (sodium valproate, 12%; valproic acid, 9%; valproate semi-sodium, 1%). Other individual AEDs were used by < 15% of patients.

3.2. TEAEs occurring during week 1 of treatment, according to actual (starting) dose

During week 1 of treatment (the first week of the titration period), patients received either placebo (n = 426), or a starting dose of ESL 400 mg (n = 612) or 800 mg (n = 409) per day. Approximately 62% of patients taking ESL 800 mg QD had at least one TEAE, vs 35% of those taking ESL 400 mg QD and 32% of those taking placebo (Table 1). Dizziness, somnolence, nausea, and headache all occurred more frequently in patients taking ESL 800 mg QD than those taking ESL 400 mg QD (for these TEAEs only, the difference in incidence between doses was more than 5%). Rates of most TEAEs during the first week of treatment were not markedly different between the ESL 400 mg QD group and the placebo group; among the more frequently occurring TEAEs (that occurred in > 2% of either group) the difference between groups was greater than 1% for dizziness and somnolence only.

Table 1

TEAEsa occurring during week 1 of ESL treatment, according to actual (initial) dose.

Placebo ESL (initial) dose

(n = 426)

400 mg QD 800 mg QD

(n = 612) (n = 409)

Any TEAE, n (%) 134 (31.5) 215 (35.1) 253 (61.9)

Dizziness, n (%) 15 (3.5) 46 (7.5) 94 (23.0)

Somnolence, n (%) 19 (4.5) 34 (5.6) 60 (14.7)

Nausea, n (%) 12 (2.8) 18 (2.9) 47 (11.5)

Headache, n (%) 15 (3.5) 19 (3.1) 41 (10.0)

Diplopia, n (%) 1 (0.2) 11 (1.8) 26 (6.4)

Vomiting, n (%) 6 (1.4) 9 (1.5) 26 (6.4)

Fatigue, n (%) 5 (1.2) 5 (0.8) 19 (4.6)

Vertigo, n (%) 1 (0.2) 9 (1.5) 15 (3.7)

Blurred vision, n (%) 0 (0) 9 (1.5) 15 (3.7)

Ataxia, n (%) 1 (0.2) 2 (0.3) 21 (5.1)

Balance disorder, n 2 (0.5) 7(1.1) 12 (2.9)

Diarrhea, n (%) 7 (1.6) 4 (0.7) 9 (2.2)

ESL, eslicarbazepine acetate; TEAE, treatment-emergent adverse event. aData are for TEAEs reported in > 2% of patients in either ESL dose group (safety population).

3.3. ESL dosing regimen and incidence of TEAEs during the double-blind period

The incidences of TEAEs during the double-blind period (weeks 1-14) are shown in Table S3 for the groups defined by dose randomization. The three Phase III trials utilized six different ESL dosing regimens (different combinations of ESL starting dose, titration schedule, and maintenance dose). As shown in Table 2, patients in subgroups A and E remained on the starting dose throughout (400 and 800 mg QD, respectively), subgroups B, C, and D began taking 400 mg QD, with the dose being increased to 800 mg (groups B and C) or 1200 mg QD (group D) by week 3, while subgroup F began taking ESL 800 mg QD, the dose being increased to 1200 mg QD by week 3. Table 2 also shows the overall incidence of TEAEs in the six subgroups (A-F).

The incidences of common TEAEs appeared to be more affected by the starting dose than by the maintenance dose of ESL. Thus, the incidences of common TEAEs were notably higher in patients who began taking ESL 800 mg QD than in those who began taking ESL 400 mg QD, or placebo (Fig. 1). For groups of patients taking the same starting dose (400 or 800 mg QD), the incidences of TEAEs (overall and individual) did not differ markedly between those subsequently taking different maintenance doses (Table 2, Fig. 1). The overall incidence of TEAEs during the double-blind period was 57% for the placebo group. Among those who began taking ESL 400 mg QD, TEAE incidences were not notably different between maintenance doses of 400 mg (66%), 800 mg (59% when the dose was increased at the start of week 2; 69% when the increase was at the start of week 3) and 1200 mg QD (66%). Similarly, among patients who began taking 800 mg QD, the overall incidence of TEAEs was 85% in those who stayed on that dose, and 82% in those who increased to a maintenance dose of 1200 mg QD (Table 2).

With regard to central nervous system (CNS) TEAEs specifically, the overall incidence in patients assigned to a maintenance dose of ESL 800 mg QD was 39% for those who began taking 400 mg QD, compared with 61% in those who began on 800 mg QD. In patients assigned to a maintenance dose of 1200 mg QD, the incidence of CNS TEAEs was 37% in those who began on 400 mg QD, vs 61% in those who began on 800 mg QD. The incidence of CNS TEAEs in the placebo group was 31%.

The frequency of rash reported as a TEAE was 1.9% (19/1021) in patients taking ESL, versus 0.9% (4/426) in the placebo group. The incidence of rash was similar between patients who began taking ESL 400 mg QD (1.6%; 10/612) and those who began taking ESL 800 mg QD (2.2%; 9/409). The incidence of rash also appeared to be related to the ESL maintenance dose, at 0.5% (1/196), 1.2% (5/415), and 3.2% (13/410) in patients who took maintenance doses of 400, 800, and 1200 mg QD, respectively.

Analysis of the data according to both the maintenance dose and the titration schedule indicated that use of a lower starting dose or a more gradual titration schedule had no clear beneficial impact on the incidence of rash. Thus, among patients randomized to a maintenance dose of 800 mg QD, the incidence of rash was 1.9% for those who took 400 mg QD for the first two weeks, 0% for those who took 400 mg QD for the first week only (before increasing the dose to 800 mg QD), and 1.0% for those who began taking 800 mg QD from Week 1. Among patients randomized to a maintenance dose of 1200 mg QD, the incidence of rash was 4.9% for those who began taking 400 mg QD, versus 2.6% for those who began taking 800 mg QD.

The incidence of hyponatremia reported as a TEAE also appeared to be related to the ESL maintenance dose (ESL 400 mg QD, 0.5% [1/196]; ESL 800 mg QD, 1.7% [7/415]; ESL 1200 mg QD, 2.2% [9/410]). A separate analysis based on the starting dose revealed that the incidence of hyponatremia in patients who began taking ESL 400 mg QD to be 1.1% (7/612), versus 2.4% (10/409) in those who began taking ESL 800 mg QD.

In the placebo group, the incidence of TEAEs leading to discontinuation was 6.6%. In patients randomized to a maintenance dose

Table 2

Effect of ESL dosing regimen on the incidence of TEAEsa.

Group ESL titration scheme Study Titration period Maintenance period

Week 1 Week 2 Weeks 3-14

ESL (mg QD) ESL (mg QD) ESL (mg QD) n TEAEs (%)

Placebo NA 301, 302, 304 NA NA NA 426 57.3

A ESL 400 mg initiation and maintenance 301, 302 400 400 400 196 66.3

B ESL 400 mg initiation with titration to 800 mg 304 400 400 800 216 69.4

C ESL 400 mg initiation with titration to 800 mg 301 400 800 800 98 59.2

D ESL 400 mg initiation with titration to 1200 mg 301 400 800 1200 102 65.7

E ESL 800 mg initiation and maintenance 302 800 800 800 101 85.1

F ESL 800 mg initiation with titration to 1200 mg 302, 304 800 800 1200 308 82.1

ESL, eslicarbazepine acetate; NA, not applicable; TEAE, treatment-emergent adverse event. a During the double-blind period.

ESL dose (mg/day)

Week 1 Week 2 Week 3 n

■ PBO PBO PBO 426

■ 400 400 400 196

■ 400 400 800 216

■ 400 800 800 98

■ 400 800 1,200 1 02

■ 800 800 800 1 01

■ 800 800 1,200 308

400 Placebo

Week 1 Week 2 Week 3

Fig. 1. Most frequently reported TEAEsa during the double-blind periodb, by ESL maintenance dose and titration scheme.

The upper panels indicate the doses received during weeks 1-2 (titration period) and week 3 and thereafter (maintenance period), for patients enrolled in the three trials (analysis groups were defined retrospectively on the basis of the titration schedule). aData are TEAEs that occurred in >10% of patients in any titration scheme (safety population). bTitration and maintenance periods. ESL, eslicarbazepine acetate; PBO, placebo; TEAE, treatment-emergent adverse event.

Dizziness Somnolence Headache

Ataxia

Nausea Vomiting Diplopia

ESL dose (mg/day) Week 1 Week 2 Week 3

PBO PBO

400 400

400 400

400 800

400 800

800 800

800 800

PBO 426 400 196 800 216 800 98

1,200 102 800 1 01

1,200 308

Fig. 2. Incidence of treatment discontinuation due to TEAEs over time, by ESL titration scheme. The data shown are the cumulative incidence of discontinuation due to TEAEs (% of patients) over by time (days after the start of treatment). The symbols represent discontinuations by one or more patients. ESL, eslicarbazepine acetate; PBO, placebo; TEAE, treatment-emergent adverse event.

Days after start of treatment

of ESL 800 mg QD, the overall incidence of discontinuation due to TEAEs was 14%, but the rate was lower in those who began taking 400 mg QD (12%) than those who began on 800 mg QD immediately (20%). Similarly, among those randomized to a maintenance dose of ESL 1200 mg QD, the overall incidence of discontinuations due to

TEAEs was 25%, but was lower in those who began taking 400 mg (21%) than those who began on 800 mg QD (27%). Discontinuations due to TEAEs began earlier, and continued at a higher rate, among patients who began treatment with ESL 800 mg QD than those who began taking ESL 400 mg QD (Fig. 2). The difference in

Table 3

Incidence of TEAEsa in patients who began taking ESL 400 mg QD.

TEAE Placebo (n = 426) ESL (maintenance dose)

800 mg QD (n = 314)t 1200 mg QD (n = 102)

Vertigo (%) < 1 3 9

Diplopia (%) 2 7 12

Nausea (%) 5 8 8

Vomiting (%) 3 4 5

Dizziness (%) 9 17 14

Headache (%) 9 11 11

Somnolence (%) 8 9 10

f Groups B and C combined (see Table 2). ESL, eslicarbazepine acetate; TEAE, treatment-emergent adverse event.

a Data are TEAEs reported during the double-blind period in > 5% of patients in any group (safety population), among patients who took ESL 400 mg QD (for 1 or 2 weeks) before the dose was increased (in 400 mg increments) to 800f or 1200 mg QD.

discontinuations between the lower and higher starting dose groups was more marked for patients randomized to receive ESL 800 mg QD, versus 1200 mg QD (maintenance doses). Fig. 2 also shows that during the first four to five weeks, there were no notable increases in the rate of discontinuations due to TEAEs in any of the subgroups. Given that any dose increases had occurred by week 3, this demonstrates that the risk of discontinuation was not directly influenced by dose titration, i.e. patients were no more likely to discontinue treatment soon after a dose increase from 400 to 800 mg QD, or 800-1200 mg QD.

3.4. Incidence of TEAEs in patients who initiated dosing with ESL 400 mg QD

The incidences of TEAEs and of TEAEs leading to discontinuation are shown in Tables 3 and 4 for patients who began treatment with ESL 400 mg QD for 1 or 2 weeks before the dose was increased to the recommended maintenance dose of 800 or 1200mgQD. Overall rates of specific TEAEs were not substantially different between those who took 800 and 1200 mg QD during the maintenance period (Table 3). The incidence of TEAEs leading to discontinuation was dose dependent (10%, 12%, and 21% for maintenance doses of 400, 800, and 1200 mg QD, respectively, compared with 7% for the placebo group; Table 4). The incidence of most individual TEAEs leading to discontinuation also appeared to be related to the maintenance dose (Table 4).

4. Discussion

This post-hoc analysis of pooled patient-level data from Phase III

studies of adjunctive ESL in patients with POS demonstrates that initiating ESL at 400 mg QD for 1 or 2 weeks, followed by weekly 400 mg increments to the target dose, leads to a more favorable AE profile compared with initiation at 800 mg QD. After a starting dose of 400 mg QD, rates of most TEAEs during the first week of treatment were not markedly different from placebo, and most patients tolerated subsequent weekly increases of 400 mg, to effective maintenance doses of 800 or 1200 mg QD (88% and 79%, respectively, did not discontinue due to a TEAE). However, most patients who began taking the higher dose (800 mg QD) also tolerated the maintenance doses (i.e., 80% of the 800 mg QD maintenance dose group and 73% of the 1200 mg QD maintenance dose group).

The feasibility of using a low starting dose of ESL (400 mg QD during week 1) has previously been demonstrated in a randomized, double-blind, active-controlled 26-week study of ESL monotherapy in adults with newly-diagnosed POS. A preliminary report indicated that most patients achieved seizure freedom with a maintenance dose of ESL 800 mg QD (Trinka et al., 2016).

Optimizing titration schedules for AEDs is important, because AEs and related tolerability issues are potential causes of AED failure; tol-erability issues may restrict the range of doses that can be used, leading to inadequate efficacy and consequent discontinuation of treatment. Treatment-limiting adverse effects of AEDs are usually CNS-related symptoms such as dizziness, somnolence, blurred vision, and imbalance (Perucca and Gilliam, 2012), which are hypothesized to be due to the effects of AEDs on rapidly firing neurons in brainstem and cerebellar nuclei. Rates of AEs during AED therapy have been found to be closely associated with QoL (Quality of Life in Epilepsy Inventory [QOLIE-31] scores) (Gilliam et al., 2004). Indeed, QoL often appears to be more sensitive to the impact of AEs than the effectiveness of seizure control (Luoni et al., 2011). Therefore, in managing patients with POS, clinicians often have to balance the necessity of providing adequate seizure control against the need to minimize the risk of unwanted AEs. Optimizing AED tolerability by using appropriate titration schedules and maintenance doses is therefore critical for successful outcomes.

In the Phase III ESL adjunctive therapy trials, the most frequently reported TEAEs were CNS-related events such as dizziness, somnolence, and headache. The results suggest that in this challenging group of patients with drug-resistant epilepsy, the incidence of the most frequent TEAEs may be reduced by use of a lower starting dose, and that ESL may be titrated in order to minimize TEAEs in patients receiving polytherapy.

The total incidence of TEAEs during the double-blind treatment period increased with higher ESL maintenance doses, but this may also have been influenced by the patients' starting dose. In the pooled population, most patients randomized to 1200 mg QD (75%) began on the higher starting dose (800 mg QD), whereas most of those randomized to

Table 4

Incidence of TEAEs leading to discontinuation in patients who began taking ESL 400 mg QD, according to maintenance dose.

Placebo (n = 426) ESL maintenance dose

400 mg QD n = 196 800mgQDan = 314 1200 mg QDan = 102 ESL total n = 612

Any AE, n (%) 28 (6.6)

Dizziness, n (%) 2 (0.5)

Nausea, n (%) 1 (0.2)

Diplopia, n (%) 0 (0.0)

Somnolence, n (%) 2 (0.5)

Vomiting, n (%) 2 (0.5)

Vertigo, n (%) 1 (0.2)

Rash, n (%) 0 (0.0)

Partial seizures, n (%) 8 (1.9)

Ataxia, n (%) 0 (0.0)

19 (9.7) 36 (11.5)

2 (1.0) 15 (4.8)

1 (0.5) 5 (1.6)

3 (1.5) 3 (1.0)

1 (0.5) 4 (1.3)

3 (1.5) 1 (0.3)

1 (0.5) 2 (0.6)

0 (0.0) 1 (0.3)

1 (0.5) 0 (0.0)

4 (2.0) 1 (0.3)

21 (20.6) 76 (12.4)

4 (3.9) 21 (3.4)

4 (3.9) 10 (1.6)

4 (3.9) 10 (1.6)

4 (3.9) 9 (1.5)

4 (3.9) 8 (1.3)

4 (3.9) 7 (1.1)

2 (2.0) 3 (0.5)

2 (2.0) 3 (0.5)

1 (1.0) 6 (1.0)

Data are for TEAEs that led to discontinuation in >2% of patients in any treatment group (safety population).

a Data are for patients who took ESL 400 mg QD (for 1 or 2 weeks) before the dose was increased (in 400 mg increments) to 800 or 1200 mg QD AE, adverse event; ESL, eslicarbazepine acetate.

800 mg QD (76%) began on the lower starting dose (400 mg QD). Among those who began taking ESL 400 mg QD, there was no notable relationship between the maintenance dose and the incidence of TEAEs. Therefore, the overall incidence of TEAEs in patients randomized to 1200 mg QD may be driven by events of early onset, caused by exposure to the higher initiation dose.

The proportion of patients that discontinued treatment due to TEAEs was higher among those who began taking ESL 800 vs 400 mg QD. The more rapid dose titration was nevertheless tolerated by most patients (around 80-85% of those who started on 800 mg QD completed the 14-week treatment period), suggesting that it is feasible to initiate ESL at 800 mg QD in patients for whom a need for rapid seizure control outweighs concerns about the greater risk of AEs due to initiation at the higher dose. Among patients randomized to receive ESL 800 mg QD, the benefit of using the lower starting dose of 400 mg QD persisted throughout the trial. This is somewhat surprising, because the maintenance dose might be expected to have most influence on toler-ability (and discontinuation rate) from week 3 onwards.

While the tolerability of ESL may be improved by using a lower starting dose, discontinuations due to TEAEs were nevertheless more frequent among patients who received a maintenance dose of 1200 mg QD (approximately 20% discontinued due to an AED, compared with 6% of the placebo group). The starting dose and rate of dose increase are not the only factors that can affect discontinuation due to TEAEs; the maintenance dose clearly has an important influence, especially in studies using a forced titration protocol, and lacking the flexibility to reduce the dose or reduce the rate of titration for the sake of improvements in tolerability. This illustrates the importance of clinicians individualizing dosing schedules tailored to individual patient's seizure patterns and vulnerability to adverse medication effects. In the current analysis, use of the lower starting dose of 400 mg QD had only a limited impact on discontinuation due to TEAEs among patients randomized to 1200 mg QD. Importantly, patients' perceptions of the acceptability of treatment (and their motivation or willingness to persist with therapy) could be influenced by a range of factors, the impact of which may differ between treatment settings. Consequently, the impact of adverse events on treatment discontinuation may be very different between the clinical trial setting and clinical practice.

Importantly, these regulatory studies did not examine whether slower titration schedules (e.g. 400 mg increments every 2 weeks) could improve tolerability of a maintenance dose of 1200 mg QD. 'Fixed dose' regulatory trials are inflexible; it is likely that tolerability could be further improved by reducing doses of concomitant AEDs that previously failed to control patients' seizures. In two studies of ESL monotherapy, higher doses (1200 and 1600 mg QD) were shown to be tolerated by patients who converted to ESL (previous AEDs were withdrawn) (Jacobson et al., 2015; Sperling et al., 2015b).

Another factor that might have influenced the current findings is concomitant use of other 'background' AEDs. In particular, when drugs with a similar mechanism of action are combined, a "threshold" of tolerability may be exceeded for a specific side effect; this may explain the pharmacodynamic interactions previously reported between lamo-trigine and carbamazepine, and between carbamazepine and phenytoin (French and Faught, 2009). Concomitant use of carbamazepine has also been reported to lead to higher rates of adverse events in patients taking ESL, both in clinical trials (Gil-Nagel et al., 2013) and in real-world settings (Villanueva et al., 2014). Carbamazepine was the most commonly used concomitant AED in the pooled ESL study 301/302/304 population (being taken by 51% of patients), and incidences of dizziness, diplopia, and nausea were higher among patients taking ESL plus carbamazepine than in those not taking concomitant carbamazepine (Biton et al., 2017). Incidences of TEAEs in patients who began taking ESL 400 mg QD were generally lower than in those who began taking ESL 800 mg QD, whether or not they were also taking carbamazepine (data not shown). Therefore, the tolerability benefit of initiating ESL at a low dose is also apparent in patients taking concomitant

carbamazepine, although reducing the dose of carbamazepine may also improve the tolerability of the combination. Concomitant use of la-motrigine, levetiracetam, and valproic acid did not notably alter the TEAE profile of adjunctive ESL (Biton et al., 2017).

Only a small number of controlled studies have assessed the influence of titration schedule on the tolerability of AEDs, and most have examined AEDs with relatively long titration schedules. Slower titration schedules have been found to be effective in reducing symptoms of cognitive dysfunction associated with topiramate and lamotrigine (Albsoul-Younes et al., 2004; Biton et al., 2001; Lamictal (Lamictal), 2014; Korean Topiramate Study Group, 2002), and for reducing hy-persensitivity reactions associated with initially approved more rapid titration schedules. One double-blind study of topiramate found a lower incidence of withdrawal and dose adjustments after an initial dose of 50 mg/day followed by weekly 50 mg increments to a maximum of 400 mg/day, compared with an initial dose of 100 mg/day followed by weekly 100-200 mg increments (Biton et al., 2001). Use of gradual titration also led to favorable side effect profiles in two uncontrolled studies of topiramate (Albsoul-Younes et al., 2004; Korean Topiramate Study Group, 2002). In a placebo-controlled study, rapid and fixed titration to higher doses of oxcarbazepine (OXC) led to a high risk of adverse events (Barcs et al., 2000). Discontinuation due to TEAEs was reported to be less frequent after slower (7-week) vs more rapid (2-week) titration of ezogabine (Biton et al., 2013). Drug-resistant patients receiving high doses of multiple AEDs often report fewer AEs after consolidation of previously ineffective treatments (i.e., reductions in doses and numbers of AEDs) (Dash et al., 2015; Edwards et al., 2012). This supports the importance of carefully tailoring the dose regimen when adding or switching AEDs in patients with epilepsy, and demonstrates the relevance of the current analysis to clinical practice.

Rash is a recognized side effect of AEDs, with incidence rates being relatively high for phenytoin, lamotrigine and carbamazepine (Arif et al., 2007). Such allergic reactions are common and usually mild, but can progress to more severe cutaneous disorders, including StevensJohnson syndrome (Harden, 2000). In post-marketing studies, the risk of idiosyncratic dermatologic reactions to lamotrigine was found to be reduced by use of gradual titration (Lamictal (Lamictal), 2014). Consequently, as part of our evaluation of the impact of initial dose and titration schedule on the tolerability of ESL, we examined specifically whether the occurrence of rash was affected by use of a lower versus a higher starting dose. The incidence of rash with ESL was low, and appeared to be more clearly related to the maintenance dose than to the starting dose. This may be due to the short titration period of 2 weeks (maximum), which is similar to the median time to onset of rash with ESL (14 days). Among patients who began taking the lower starting dose (400 mg QD), the incidence of rash leading to discontinuation was also slightly higher in those randomized to the higher of the two maintenance doses. Only a small number of patients developed a rash, however, which limits the strength of any conclusions to be drawn on the relationship between rash and ESL dosing. Zaccara et al. reported that a history of rash with previous AEDs is an important predictor for subsequent rash (Zaccara et al., 2007). In the current analysis, although a large proportion of patients had previously been taking AEDs associated with rash (carbamazepine 51%; lamotrigine 24%; phenytoin 9%), relatively few had a history of rash (placebo 0.2%; ESL 0.3%).

We also examined whether the occurrence of hyponatremia was affected by use of a lower versus a higher starting dose. Overall, the incidence of reported hyponatremia was low (2.2% at the highest maintenance dose of 1200 mg QD). The incidence was similarly low (2.4%) among patients who began taking the higher starting dose of 800 mg QD, but also higher than the incidence in those who began taking 400 mg QD (1.1%). Thus, initiating treatment at the lower dose might also be beneficial with regard to hyponatremia, perhaps related to differences in renal adaptation during the titration period. However, as only a small number of patients were affected, this limits the strength of conclusions that may be drawn. Concomitant AEDs and concurrent

use of other medications may also have had an influence; diuretics and selective serotonin reuptake inhibitors in particular are known to contribute to hyponatremia, especially in older patients (Sachdeo and Karia, 2016).

One limitation of the current analysis is that although patients were randomized to receive maintenance doses of 400, 800 or 1200 mg QD, in the pooled safety data set, the starting dose was not randomized, but was dictated by the titration schedules used in the three Phase III studies. Nonetheless, all the studies had similar designs and inclusion criteria, and involved patients with similar demographic and clinical profiles, but as this was a post-hoc analysis and used subgroups identified retrospectively from the pooled data, it was not feasible to conduct a statistical analysis of the differences between subgroups. Another limitation is that relatively few patients in the controlled Phase III ESL epilepsy studies were older than 65 years, so a specific exploration of the impact of ESL titration schedule and maintenance dose in this age group was not possible. The safety of ESL as adjunctive therapy for POS in elderly patients has recently been evaluated (Costa et al., 2014); and previous studies have demonstrated the importance of slow AED titration in elderly patients (Rowan et al., 2005). Nevertheless, the pooled analysis made possible subgroup analyses that were not feasible in the original studies, including comparisons vs placebo and evaluation of the various titration schedules used in the three studies. It should be noted, however, that the studies were not designed to evaluate patient retention or discontinuation in a rigorous manner. A number of factors may influence treatment tolerability (as measured by discontinuation rates), including patients' and physicians' perceptions of the impact of treatment on symptoms and quality of life (e.g. patients experiencing greater symptomatic benefit may be more likely to tolerate the side effects of treatment than those experiencing lesser benefit). In treatment-resistant patients with high baseline seizure frequency, early efficacy achieved at 800 mg QD may have a beneficial impact on discontinuation, even among patients who are experiencing significant TEAEs. Being involved in a clinical trial may influence patients' and physicians' expectations and perceptions of the benefits and disadvantages of treatment. Even in patients with highly treatment-resistant disease, the flexibility to select an individualized maintenance dose and titration regimen in order to improve overall tolerability is likely to be very important. However, assessment of the potential influence of/interaction between such factors could not be investigated in the current post-hoc analysis.

In summary, initiation of treatment with ESL 400 mg QD for 1 or 2 weeks was associated with a relatively lower incidence of TEAEs and rates of discontinuation due to TEAEs in patients taking concomitant AEDs, even after dose titration to maintenance doses of 800 or 1200 mg QD. In some patients, ESL may be initiated at 800 mg QD, if the need for additional seizure control outweighs any concerns about the increased risk of AEs during initiation.

Disclosures

G. Krauss has received research support from Sunovion Pharmaceuticals Inc., Eisai, Upsher-Smith, UCB Pharma, and SK Life Science; and acted as a paid consultant for Otsuka Pharmaceutical. V. Biton has acted as a paid consultant for Merck, Pfizer, Jazz, Upsher-Smith, Lundbeck, Eisai, Avigen, GSK, Ortho-McNeil, Icagen, UCB Schwarz, and Valeant. J. H. Harvey has received research support from Sunovion Pharmaceuticals Inc., UCB Pharma, Pfizer, SK Life Science, Marinus, Acorda, Upsher-Smith, GW, Merck, and Sage; received lecture fees from Sunovion Pharmaceuticals Inc., and UCB Pharma; acted as a paid consultant for Sunovion Pharmaceuticals Inc.; and served as a Speakers Bureau member for Sunovion Pharmaceuticals Inc., and UCB Pharma. C. Elger has received research support from Deutsche Forschungsgemeinschaft; and acted as a paid consultant for BIAL, Desitin, Novartis, Eisai, and UCB Pharma. E. Trinka has received lecture fees from UCB Pharma, Biogen, Gerot-Lannach, BIAL, Eisai, Takeda, Newbridge, and Sunovion Pharmaceuticals Inc., Novartis; acted as a

paid consultant for UCB Pharma, Biogen, Gerot-Lannach, BIAL, Eisai, Takeda, Newbridge, Sunovion Pharmaceuticals Inc., and Novartis; and received grants from Biogen, Red Bull, Merck, UCB Pharma, European Union, and FWF Österreichischer Fond zur Wissenschaftsförderung, Bundesministerium für Wissenschaft und Forschung. P. Soares da Silva and H. Gama are paid employees of BIAL-Portela & Ca, S.A. H. Cheng, T. Grinnell, and D. Blum are employees of Sunovion Pharmaceuticals Inc.

Acknowledgements

The clinical studies were sponsored by Sunovion Pharmaceuticals Inc. and BIAL-Portela & Ca, S.A. The sponsors were involved in the design of the studies, in the collection, analysis and interpretation of data, in writing the report, and in the decision to submit this article for publication. The authors acknowledge the contributions of Dr Rui Sousa, formerly of BIAL-Portela & Ca, S.A, during development of this article. Medical writing support was funded by Sunovion Pharmaceuticals Inc., and was provided by Michael Simpson, PhD, CMPP of FireKite, an Ashfield company, part of UDG Healthcare plc.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.eplepsyres.2017.10.021.

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