Epilepsy & Behavior 41 (2014) 164–170

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Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years William Rosenfeld a,⁎, Nathan B. Fountain b, Gintaras Kaubrys c, Elinor Ben-Menachem d, Cindy McShea e, Jouko Isojarvi e,1, Pamela Doty e, the SP615 Study Investigators a

Comprehensive Epilepsy Care Center for Children and Adults, Chesterfield, MO 63017, USA University of Virginia School of Medicine, Charlottesville, VA 22908, USA c Faculty of Medicine, Clinic of Neurology and Neurosurgery, Vilnius University, Vilnius, Lithuania d Institute of Clinical Neurosciences, Division of Neurology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden e UCB Pharma, Raleigh, NC 27617, USA b

a r t i c l e

i n f o

Article history: Received 2 July 2014 Revised 24 September 2014 Accepted 26 September 2014 Available online xxxx Keywords: Epilepsy Partial-onset seizures Antiepileptic drug Lacosamide

a b s t r a c t Long-term (up to 8 years of exposure) safety and efficacy of the antiepileptic drug lacosamide was evaluated in this open-label extension trial (SP615 [ClinicalTrials.gov identifier: NCT00552305]). Patients were enrolled following participation in a double-blind trial or one of two open-label trials of adjunctive lacosamide for partialonset seizures. Dosage adjustments of lacosamide (100–800 mg/day) and/or concomitant antiepileptic drugs were allowed to optimize tolerability and seizure reduction. Of the 370 enrolled patients, 77%, 51%, and 39% had N1, N 3, or N5 years of lacosamide exposure, respectively. Median lacosamide modal dose was 400 mg/day. Common treatment-emergent adverse events (TEAEs) were dizziness (39.7%), headache (20.8%), nausea (17.3%), diplopia (17.0%), fatigue (16.5%), upper respiratory tract infection (16.5%), nasopharyngitis (16.2%), and contusion (15.4%). Dizziness (2.2%) was the only TEAE that led to discontinuation in N 2% of patients. Ranges for median percent reductions in seizure frequency were 47–65%, and those for ≥50% responder rates were 49–63% for 1-, 3-, and 5-year completer cohorts. Exposure to lacosamide for up to 8 years was generally well tolerated, with a safety profile similar to previous double-blind trials, and efficacy was maintained. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Epilepsy is a chronic disease requiring long-term pharmacological management. While the evaluation of antiepileptic drugs (AEDs) in blinded placebo-controlled trials usually occurs over a comparatively short period of time (e.g., up to 1 year), longer-term open-label extension (OLE) trials can help determine whether medication side effects increase in frequency or severity with time or become apparent in a notable number of patients only after prolonged treatment. However, OLE trials have inherent limitations in that they can be prone to patient selection bias, which can inflate estimates of efficacy and tolerability [1,2]. Abbreviations: AED, antiepileptic drug; ECG, electrocardiogram; FAS, Full Analysis Set; OLE, open-label extension; POS, partial-onset seizures; SAE, serious adverse event; SGS, secondarily generalized seizures; SS, Safety Set; TEAE, treatment-emergent adverse event. ⁎ Corresponding author at: Comprehensive Epilepsy Care Center for Children and Adults, 222 South Woods Mill Road, Suite 610-N, Chesterfield, MO 63017, USA. Tel.: +1 314 453 9300x45; fax: +1 314 453 0163. E-mail address: [email protected] (W. Rosenfeld). 1 Current affiliation: Lundbeck LLC, Deerfield, IL 60015, USA.

http://dx.doi.org/10.1016/j.yebeh.2014.09.074 1525-5050/© 2014 Elsevier Inc. All rights reserved.

Lacosamide is approved in the United States for monotherapy and adjunctive therapy in the treatment of partial-onset seizures (POS) in patients with epilepsy aged 17 years and older [3] and in the European Union for adjunctive therapy in the treatment of POS for patients aged 16 years and older [4]. Three pivotal, multicenter, randomized, double-blind, placebo-controlled trials (SP667; SP754 [ClinicalTrials.gov identifier: NCT00136019]; SP755 [ClinicalTrials.gov identifier: NCT00220415]) demonstrated the safety and efficacy of oral lacosamide tablets in patients with uncontrolled POS despite treatment with up to 3 concomitant AEDs [5–7]; approximately half of all trial participants across these studies had failed ≥7 AEDs in their lifetime. Even with this population with difficult-to-treat seizures, these pivotal trials demonstrated reduced seizure frequency with 12 weeks of adjunctive lacosamide 200–600-mg/day therapy. The most common treatment-emergent adverse event (TEAE) across these trials was dizziness, which was dose-related and occurred most frequently during dose titration. A pooled analysis of these three trials that examined the clinical utility of lacosamide reported findings similar to those observed in each individual trial and overall superior efficacy relative to placebo across the 200–600-mg/day dose range [8].

W. Rosenfeld et al. / Epilepsy & Behavior 41 (2014) 164–170

To evaluate longer-term safety and efficacy of oral lacosamide therapy in patients with POS, three similarly designed OLE trials were conducted. Two of the trials (SP756 [ClinicalTrials.gov identifier: NCT00522275] and SP774 [ClinicalTrials.gov identifier: NCT00515619]) have been published [9,10]. Presented here are results of the longest of the three lacosamide OLE trials, evaluating up to 8 years of exposure to lacosamide in the adjunctive treatment of patients with POS (SP615 [ClinicalTrials.gov identifier: NCT00552305]). 2. Material and methods 2.1. Trial design SP615 was a prospective, multicenter, multinational, phase II OLE trial in patients with POS (with or without secondary generalization) who were previously enrolled in one of two open-label trials (SP598 [11], SP607 [12]) or a double-blind placebo-controlled trial (SP667 [5]) of lacosamide. This trial was conducted from August 30, 2001 to February 24, 2010 at 69 sites across Germany, Hungary, Lithuania, Poland, Sweden, Switzerland, the United Kingdom, and the United States. Written informed consent was obtained from each patient. Trial protocol and patient informed consent documentation were reviewed by a national, regional, or independent ethics committee or institutional review board. The trial was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice requirements and with the local laws of the countries involved. 2.2. Patient population Patients eligible for participation in the OLE trial included those who had completed a previous phase II trial of lacosamide for the adjunctive treatment of POS (SP598, SP607, or SP667) and, in the opinion of the investigator, were expected to benefit from continued participation. To qualify for those initial trials, patients were required to have uncontrolled POS (SP598, average of ≥2 POS/week; SP607 and SP667, average of ≥4 POS/28 days) with or without secondary generalization and had to be on a stable regimen of 1–2 AEDs (SP598), or on a stable regimen of 1–2 AEDs with or without vagal nerve stimulation (SP607, SP667). Patients were excluded from this trial if they used any investigational drug or experimental device in addition to lacosamide. Patients who had a major protocol violation (defined as having met withdrawal criteria) in a previous lacosamide trial or who had an ongoing serious adverse event (SAE) were also excluded from enrolling in the OLE trial. 2.3. Treatment schedule Patients who enrolled in this trial were receiving lacosamide doses ranging from 100 to 600 mg/day at completion of the previous trials. For patients who enrolled following completion of an OLE trial (SP598 or SP607), the initial dose of lacosamide at entry to this trial was the same as the last dose received during the previous trial. Patients who completed the maintenance phase of the double-blind placebocontrolled trial (SP667) underwent a 2-week double-blind transition to lacosamide 200 mg/day before entry to the OLE trial. The clinic visit schedule varied across years in the trial with visits every 4–8 weeks in year 1, every 3 months in year 2, and every 6 months thereafter. Telephone contact occurred between visits. During the OLE trial, lacosamide was administered orally twice daily in equally divided doses (at ~ 12-hour intervals given in the morning and evening). Lacosamide dose could be increased or decreased at the discretion of the investigator to optimize seizure control and tolerability, using an up-titration schedule of 100 mg/day/week to a maximum dose of 800 mg/day. If a patient discontinued from the trial, lacosamide was to be tapered off at a rate of 200 mg/day/week unless safety concerns required a more rapid withdrawal. Investigators were allowed to increase or decrease the dose of concomitant AEDs alongside

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lacosamide titration to optimize tolerability and seizure control or to achieve lacosamide monotherapy. New commercially available AEDs could be introduced only if the patients' seizures had not adequately responded to the maximum tolerated dose of lacosamide. 2.4. Safety and efficacy outcomes The primary outcomes pertained to long-term safety, specifically the following: TEAEs reported spontaneously by the patient or caregiver, recorded in a patient diary or observed by the investigator; treatmentemergent SAEs; withdrawals due to TEAEs; and changes in 12-lead ECG (recorded at each clinic visit). Electrocardiograms were reviewed locally and also evaluated by a qualified cardiologist at a central ECG laboratory. Treatment-emergent adverse events were defined as events that started or worsened on or after the first lacosamide dose received during this trial and within 30 days following the last dose of lacosamide given during the trial. Treatment-emergent adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA®) version 9.1. Ongoing AEs from the previous lacosamide trials were not considered treatment-emergent unless they worsened during this trial. Other safety variables considered in the evaluation of long-term safety included changes in hematology, blood chemistry, urinalysis, vital signs, body weight, and physical or neurological examination findings (assessed at each clinic visit). Efficacy parameters were assessed descriptively and included percent change from the baseline of the respective previous trial in 28-day seizure frequency and percentage of patients with ≥50% reduction in seizure frequency compared with the baseline of the respective previous trials (i.e., ≥50% responder rate). Seizure freedom was evaluated post hoc using the following parameters: maximum duration of continuous seizure freedom, percentage of patients seizure-free, and percentage of patients free from secondarily generalized seizures (SGS). 2.5. Analysis Descriptive statistics were generated for outcome variables using SAS® version 9.1 (Cary, NC, USA) or higher. Data for safety parameters evaluated at clinic visits (i.e., laboratory values, ECG, vital signs, body weight, physical and neurological exams) were summarized for each visit. Data for efficacy parameters based on seizure diary data were summarized for the treatment period or by time interval. For all safety and efficacy analyses, only reported data were used in each analysis time interval. Lacosamide exposure was summarized by lacosamide modal dose (100, 200, 300, 400, 500, 600, and N 600 mg/day). Modal dose was defined as the daily lacosamide dose the patient received for the longest duration during the treatment period. Retention rates were estimated using a Kaplan–Meier analysis. Analyses of safety data were based on the Safety Set (SS), defined as all enrolled patients who received at least one dose of lacosamide. Assessment of efficacy was based on the Full Analysis Set (FAS), defined as all patients from the SS who had at least one postbaseline seizure diary day with available data during the trial. The subset of patients in the FAS who were treated with lacosamide and had seizure diary data for a specified duration of time during the OLE trial constituted a completer cohort. For example, a 1-year completer cohort comprised patients treated with lacosamide for ≥ 1 year and had seizure diary data during the OLE trial (where 1 year was defined as 12 months; 1 month = 28 days). 3. Results 3.1. Patient baseline demographics and characteristics Patients enrolled in the OLE trial had completed SP598 (n = 2), SP607 (n = 66), or SP667 (n = 302; Table 1). All 370 enrolled patients

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Table 1 Disposition of patients from phase II lacosamide trials who enrolled in the trial. Phase II lacosamide trials leading into this trial

Patients enrolled in this trial (n = 370) Patients included in this Safety Set (n = 370) Patients included in this Full Analysis Set (n = 369)

SP598

SP607 (MTD trial)

SP667 (double-blind pivotal trial)

Lacosamide

Lacosamide ≤600 mg/day

Placebo

Lacosamide 200 mg/day

Lacosamide 400 mg/day

Lacosamide 600 mg/day

Total from SP667

2 2 2

66 66 66

84 84 84

83 83 82

76 76 76

59 59 59

302 302 301

MTD = maximum tolerated dose.

received ≥1 dose of lacosamide during the OLE trial and constituted the SS. Of these, 369 (99.7%) patients had ≥1 postbaseline efficacy assessment and constituted the FAS. Patients in the FAS who were exposed to lacosamide and had seizure diary data for ≥ 1 year (n = 283), ≥3 years (n = 187), and ≥5 years (n = 142) constituted the 1-year, 3-year, and 5-year completer cohorts, respectively. Baseline demographics and patient characteristics (taken from the baseline of previous trials) are shown in Table 2. At entry to the OLE trial, patient mean age was 40.8 ± 11.0 years, and 51.9% of the patients were female. Mean time since diagnosis was 25.3 ± 12.6 years. More than half (51.9%) of the participants had tried ≥ 7 lifetime AEDs and most (81.9%) were taking 2 concomitant AEDs at the baseline of their respective previous trial. Levetiracetam was the most commonly prescribed concomitant AED during the OLE trial (Fig. 1).

3.2. Patient disposition (SS) A total of 120 (32.4%) patients completed the OLE trial, and 250 (67.6%) discontinued during the treatment period (Table 3). The three most common reasons for discontinuation were lack of efficacy (33.8%), AEs (13.2%), and consent withdrawal (13.0%). Of the 120 patients who completed the OLE trial, 115 (95.8%) continued taking commercially available lacosamide after trial completion. Table 2 Patient demographics and characteristics (Safety Set).a Parameter

N = 370

Age at trial entry, mean (SD), yearsa Female, n (%) Weight, mean (SD), kg Body mass index, mean (SD), kg/m2 Race, n (%) White Black Asian Other Time since first diagnosis, mean (SD), years Number of lifetime AEDs, n (%) 1–3 4–6 ≥7 Missing Number of concomitant AEDs, n (%) 1 2 3 Active VNS, n (%)b Yes No Missing Median (minimum, maximum) seizure frequency per 28 days Median (minimum, maximum) duration of continuous seizure freedom, days

40.8 (11.01) 192 (51.9) 81.8 (21.26) 27.1 (6.02) 345 (93.2) 13 (3.5) 3 (0.8) 9 (2.4) 25.3 (12.55)

3.3. Lacosamide exposure (SS) Patients were exposed to lacosamide for up to 8 years, and all patients had the opportunity to complete ~ 64 months of open-label treatment. The median lacosamide treatment duration was 1029.5 days (~2.8 years) with a total of 1225 patient-years of exposure (year defined as 365.25 days). Estimated retention rates (Kaplan–Meier analysis with a month defined as 28 days) were 76.8% at 12 months, 50.8% at 36 months, and 38.7% at 60 months (Fig. 2). The median modal dose was 400 mg/day; 262 (70.8%) patients had a lacosamide modal dose of ≥ 400 mg/day, and 121 (32.7%) patients had a modal dose of 600–800 mg/day (Fig. 3). The numbers of patient-years of lacosamide exposure for each modal dose were 13.9 (100 mg/day), 104.7 (200 mg/day), 164.6 (300 mg/day), 246.6 (400 mg/day), 179.1 (500 mg/day), 327.9 (600 mg/day), and 187.9 (N600 mg/day). Eight (2.8%) patients maintained lacosamide monotherapy for ≥ 1 year. The modal dose for patients during the treatment period was N600 mg/day (2 patients), 600 mg/day (3 patients), 500 mg/day (1 patient), 400 mg/day (1 patient), and 300 mg/day (1 patient).

3.4. Safety outcomes (SS) 3.4.1. Treatment-emergent adverse events Treatment-emergent adverse events related to the nervous system were most frequently reported (264/370 [71.4%] patients) in the SS. The most common TEAEs (with an incidence of ≥15%) were dizziness, headache, nausea, diplopia, fatigue, upper respiratory tract infection, nasopharyngitis, and contusion (Table 4). Most TEAEs were of mild or moderate intensity (22.4% and 46.8% of patients, respectively). A number of TEAEs that were reported with a low incidence are of particular relevance to patients with POS. Memory impairment was reported by 27 patients (7.3%), cognitive disorder by 16 patients (4.3%), increased weight by 21 patients (5.7%), decreased weight by 13 patients (3.5%),

66 (17.8) 110 (29.7) 192 (51.9) 2 (0.5) 66 (17.8) 303 (81.9) 1 (0.3) 49 (13.2) 253 (68.4) 68 (18.4) 12.0 (2.5, 567.9) 9.0 (0.0, 26.0)

AED = antiepileptic drug; VNS = vagal nerve stimulation. a Data presented are from the baseline period of the previous trials except for age at trial entry, which was based on the patient's visit 1 value in the open-label extension trial. b Data were collected only for patients originating from trial SP667 (n = 302).

Fig. 1. Most commonly used concomitant antiepileptic drugs during the open-label extension trials (prescribed to ≥10% of patients in the Safety Set; N = 370). Valproate includes valproic acid, divalproex sodium, valproate sodium, and valpromide. Phenytoin includes phenytoin, phenytoin sodium, ethotoin, fosphenytoin, and fosphenytoin sodium. Lorazepam was used as a rescue medication and was not administered chronically.

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Table 3 Summary of patient disposition during the open-label extension trial (Safety Set). Disposition

n (%)

Treated Completed Continued to commercial lacosamide Tapered off lacosamide Discontinued trial prematurely Reason for discontinuationb Lack of efficacy Adverse event Consent withdrawal Other Unsatisfactory compliance Lost to follow-up Protocol deviation

370 120 (32.4) 115 (95.8a) 5 (4.2a) 250 (67.6) 125 (33.8) 49 (13.2) 48 (13.0) 18 (4.9) 12 (3.2) 5 (1.4) 3 (0.8)

a

Percentages of patients who tapered off or continued to commercial lacosamide are based on the number of patients who completed the trial. All other percentages are based on the number of patients treated. b Nine patients had two or more reasons for discontinuing, and 2 patients discontinued because of an ongoing adverse event from their previous trial.

and depression by 35 patients (9.5%). The most common cardiac- or ECG-related TEAE was chest pain (15 patients [4.1%]). Three patients (0.8%) discontinued from the trial because of TEAEs related to cardiac or ECG abnormalities. Three patients (0.8%) reported suicidal ideation, and 1 of these patients had a TEAE of intentional overdose. One (0.3%) additional patient had a treatment-emergent SAE of suicide attempt (unsuccessful). Five patient pregnancies were reported during the trial; 3 were terminated, 1 resulted in a healthy newborn, and no follow-up information was available for 1 of the pregnancies. Two partner pregnancies were reported during the trial, but follow-up information was not available. 3.4.2. Serious adverse events Overall, 125 patients (33.8%) experienced treatment-emergent SAEs during the treatment period of up to 8 years. The only treatment-emergent SAE that occurred in ≥2% of patients was convulsion (23 patients [6.2%]). Other SAEs that occurred with an incidence ≥1% were status epilepticus (7 patients [1.9%]); chest pain (5 patients [1.4%]); and noncardiac chest pain, transient ischemic attack, elective hospitalization for EEG monitoring, and confusional state (4 patients each [1.1%]). Twenty-seven (21.6%) of the 125 patients had treatmentemergent SAEs that were considered related to lacosamide treatment by the investigator. Among treatment-related SAEs, the most frequently reported were convulsion (6 patients [1.6%]) and chest pain, dizziness, dyspnea, ECG prolonged QRS complex, headache, sinus bradycardia, status epilepticus, and vomiting (2 patients each [0.5%]). The only SAE that occurred with an incidence ≥ 2% was convulsion (6.2%). Treatment-

Fig. 3. Lacosamide exposure by modal dose (Safety Set; N = 370). Modal dose was the dose used most often by the patient during the treatment period. Modal doses calculated as 50 mg/day were grouped with the 100 mg/day group. For any modal dose N100 mg/day falling between 2 consecutive categories, the modal dose with the lower of the consecutive categories was presented.

related SAEs were reversible or resolved in all except 3 patients (cerebral hemorrhage [severe, not resolved], cardiomyopathy [mild, resolved with sequelae], urinary casts/proteinuria/hematuria [mild, ongoing when patient discontinued and dropped out of the trial]) whose events were considered possibly related to lacosamide treatment. Five patients died during the trial because of status epilepticus, glioblastoma multiforme, seizure-related asphyxia, injury, and road traffic accident (1 patient each). Each of the SAEs leading to death was considered by the investigator to be unrelated or unlikely related to lacosamide treatment. 3.4.3. Discontinuations due to TEAEs A total of 47 (12.7%) patients discontinued because of TEAEs. Treatment-emergent adverse events leading to discontinuation in more than 1 patient were dizziness (n = 8; 2.2%); convulsion (n = 4; 1.1%); abnormal coordination (n = 3; 0.8%); and fatigue, depression, status epilepticus, and intentional overdose (n = 2 for each; 0.5%). Two additional patients had AEs that were ongoing at the time of entry into the OLE trial (and therefore were not treatment-emergent during this trial) but did lead to discontinuation; 1 patient had sedation, nausea, and dizziness, and 1 patient had diplopia. 3.4.4. 12-lead ECGs, laboratory findings, and vital signs Chronic lacosamide treatment was not associated with changes in heart rate or prolongation of the corrected QT (QTc) interval. A small increase in mean PR interval as well as a slight increase in QRS duration across all patients (all modal dose groups) were observed.. From a mean baseline PR interval of 161.1 ms, changes recorded at weeks 24, 48, 168, and 264 were + 5.0 ms (SD 15.3), + 5.3 ms (SD 14.6), + 6.7 ms (SD 15.9), and +9.3 ms (SD 16.5), respectively. From a mean QRS duration at baseline of 90.4 ms, changes recorded at weeks 24, 48, 168, and 264 Table 4 Incidence of most common treatment-emergent adverse events (≥15% of the Safety Set). N = 370 Adverse event

Fig. 2. Estimated retention on lacosamide: Kaplan–Meier analysis (Safety Set; N = 370). All patients had an opportunity to complete approximately 64 months of open-label lacosamide treatment (beyond 64 months, lacosamide became commercially available at different time points in different countries). Patients who did not prematurely discontinue were censored on the date of the last lacosamide dose; open circles represent ≥1 censored event.

a

Dizziness Headache Nausea Diplopia Fatigue Upper respiratory tract infection Nasopharyngitis Contusion a b

n (%)b 147 (39.7) 77 (20.8) 64 (17.3) 63 (17.0) 61 (16.5) 61 (16.5) 60 (16.2) 57 (15.4)

Medical Dictionary for Regulatory Activities (MedDRA), version 9.1 preferred term. Percentage of patients who reported ≥1 event during treatment.

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were + 1.4 ms (SD 6.4), + 1.6 ms (SD 6.2), + 1.7 ms (SD 6.1), and + 3.0 ms (SD 6.8), respectively. Six patients (1.6%) had a treatmentemergent PR interval of N 250 ms; these patients had baseline PR intervals ranging from 191 to 231 ms. One (0.3%) of these patients also experienced a QRS duration of N140 ms while receiving lacosamide 100 mg/ day (baseline value from the previous trial was 103 ms). No other patient had QRS duration recorded N140 ms. Two further patients had a SAE of prolonged QRS complex while receiving lacosamide 300 mg/ day; for 1 patient, the SAE continued after lacosamide treatment was stopped, and the patient discontinued early. Long-term (up to 8 years) treatment with lacosamide was not associated with changes in measurements of hematology, clinical chemistry, urinalysis, vital signs, body weight, or physical and neurological examinations that were considered as clinically relevant. 3.5. Efficacy assessments (FAS) 3.5.1. Percent change from baseline in seizure frequency Median percent reduction from baseline in 28-day seizure frequency across the treatment period for 369 patients in the FAS was 50.8%. Median percent reductions from baseline in 28-day seizure frequency by lacosamide exposure were 42.9% (N0–6 months), 48.2% (N 6–12 months), 55.7% (N12–18 months), 60.7% (N 18– 24 months), 65.7% (N24–36 months), and 66.1% (N 36–48 months). Median percent reductions from baseline in seizure frequency over each yearly interval for the 1-, 3-, and 5-year completer cohorts were 47.3%, 56.8%, and 65.2%, respectively, and seizure reduction appeared to be sustained over time (Fig. 4). Within each completer cohort, reductions from baseline in seizure frequency of 45.1% (1-year completer cohort), 46.1% (3-year completer cohort), and 49.4% (5-year completer cohort) were seen initially within the first 3 months of lacosamide treatment. 3.5.2. Response to treatment (≥50% responder rates) Over the entire treatment period for the FAS, 51.2% of patients (189/369) had a ≥ 50% reduction in seizure frequency from baseline. The ≥50% reduction in seizure frequency for N0–6 months of lacosamide exposure was 43.9% (162/369 patients), N6–12 months was 48.5% (158/326 patients), N12–18 months was 56.4% (159/282 patients), N18–24 months was 60.6% (149/246 patients), N 24–36 months was 66.7% (146/219 patients), and N 36–48 months was 64.5% (120/186 patients). For the 1-, 3-, and 5-year completer cohorts, the ≥ 50% responder rates were 48.8%, 57.2%, and 63.4%, respectively. Within each completer

Fig. 5. ≥50% responders over time by yearly completer cohorts. Responders were defined as patients with ≥50% reduction from the baseline of the previous trials in seizure frequency during the time interval specified. Percentages are based on the number of patients in the completer cohort group with an evaluable responder status during the specified time interval.

cohort, there was an initial response to treatment within 0–6 months that was maintained over time for patients completing each time period (Fig. 5).

Fig. 4. Median percent reduction from baseline in seizure frequency over time by yearly completer cohort. Baseline is defined as the baseline from the previous trial. Percent change from baseline = 100 × ([seizure frequency during the time interval − baseline seizure frequency] / baseline seizure frequency). Median reduction from baseline is presented as a positive number. Completer cohorts include patients in the Full Analysis Set exposed to lacosamide with available seizure diary data for the duration of the interval.

3.5.3. Lacosamide monotherapy Eight patients (2.8%) were maintained on lacosamide monotherapy for ≥ 1 year. One patient, who entered the OLE trial and remained on lacosamide monotherapy (modal dose of 300 mg/day) throughout the trial, was seizure-free for 6 years. Another patient, who entered the OLE trial on lacosamide monotherapy, remained on monotherapy for 456 days during the trial and discontinued because of lack of efficacy. Of the 8 patients who were on lacosamide monotherapy for ≥ 1 year at some point during the trial, 5 were deemed ≥ 50% responders over the entire treatment period and had median percent reductions from baseline in 28-day seizure frequency of 51–100%; the 3 patients who did not meet 50% responder criteria for the entire treatment period

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experienced median percent reductions from baseline in 28-day seizure frequency of 14.9–27.0%. 3.5.4. Seizure freedom In the post hoc analysis of seizure freedom by completer cohort, 21.2% (60/283), 29.4% (55/187), and 35.9% (51/142) of patients were seizure-free for ≥6 months during open-label treatment in the 1-, 3-, and 5-year completer cohorts, respectively (Fig. 6a). The longest median duration of continuous seizure freedom during open-label treatment for the 1-, 3-, and 5-year completer cohorts was 58.0 days, 72.0 days, and 88.0 days, respectively. For patients with SGS at the baseline and postbaseline of the previous trials, freedom from SGS for ≥ 6 months during open-label treatment was observed in 54.7% (47/86), 66.1% (41/62), and 76.7% (33/ 43) of patients in the 1-, 3-, and 5-year completer cohorts, respectively (Fig. 6b). 4. Discussion Long-term (up to 8 years) treatment with adjunctive lacosamide in patients with POS receiving up to 3 approved concomitant AEDs was generally well tolerated, with a safety profile similar to that observed in shorter phase II/III placebo-controlled clinical trials and open-label extension studies [5–7,9,13]. No new types of TEAEs of note emerged during this OLE trial, which evaluated patients over a prolonged period beyond any previous lacosamide trial. Consistent with the known profile of adjunctive lacosamide for POS, the most commonly reported TEAEs were generally related to the nervous system (e.g., dizziness, headache) and the gastrointestinal tract (e.g., nausea, vomiting) or were infections (e.g., nasopharyngitis,

Fig. 6. (a) Overall seizure freedom and (b) freedom from secondarily generalized partial seizures during open-label lacosamide therapy by yearly completer cohorts. A patient was counted as seizure-free if the patient had no seizures during the specified period of consecutive days (≥3, ≥6, and ≥12 months) at any time during open-label treatment.

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upper respiratory tract infection). The majority of TEAEs were mild to moderate in intensity. Incidence of TEAEs commonly attributed to AEDs, such as change in weight or cognitive disorder/memory impairment, was low (b10%). This trial had no comparator group or an epidemiologically similar patient population for direct comparison. However, an analysis of lacosamide 200 and 400 mg/day from the pivotal trials found that lacosamide treatment was weight neutral [14], and a second analysis indicated that the odds of experiencing TEAEs related to cognition (including memory impairment and cognitive disorder) were similar between placebo and lacosamide [15]. Suicidal ideation and attempts are TEAEs also reported for AEDs as a drug class, although the underlying mechanism of this risk is unknown. In this OLE trial, the low (b 1%) incidence of suicidal ideation or behaviors provides longer-term data in this patient population for a TEAE of interest. The lacosamide dose range evaluated in this trial (100–800 mg/day) was wider than the dose range evaluated in the pivotal trials (200–600 mg/day) [5–8] and included doses higher than the approved dose range of up to 400 mg/day [3]. One-third of patients had a lacosamide modal dose of 600–800 mg/day during the treatment period, and the modal dose for 71% of patients was the same or higher than the maximum approved dose of 400 mg/day. In contrast to the pivotal trials [5–8], the lacosamide dose in this OLE trial could be optimized for tolerability and seizure control, and the dose of concomitant AEDs could be adjusted and/or new AEDs added as required. As a result of this flexibility of dose and concomitant AEDs, it is not possible to determine which AEDs may be differentially contributing to the observed TEAEs. Despite the longer exposure for lacosamide and concomitant AEDs, the profile of TEAEs was generally similar to that observed in other OLE trials, of lacosamide, as well as from doubleblind placebo-controlled lacosamide trials [5–8]. The only SAE that occurred with an incidence of ≥2% was convulsion (6.2%), which was not unexpected in this patient population with difficult-to-treat seizures, more than half of whom had tried ≥7 lifetime AEDs. The 5 deaths during the trial were not considered by the investigators in each case to be related to lacosamide. Lacosamide was well tolerated during this 8-year OLE trial, with 12.7% of patients discontinuing because of TEAEs, which lies within the range observed for other OLE studies of AEDs between 1 and 8 years of duration [9,10,16–23]. Overall, the types of SAEs and TEAEs leading to discontinuation during this trial were similar to those observed in the other lacosamide OLE trials, as well as in pivotal double-blind placebo-controlled lacosamide trials [5,7,8], suggesting that long-term treatment with lacosamide was not associated with a different safety profile from that established in the pivotal trials. No clinically relevant changes were observed in the median or mean hematology or clinical chemistry values or vital signs with the increased duration of exposure to lacosamide. A review of ECG data suggested that long-term lacosamide treatment was not associated with changes in heart rate or with prolongation of QTc interval. The small increase in mean PR interval observed in this trial was consistent with other lacosamide trials [3,5–7,9]. There was a slight increase in mean QRS interval observed in the trial that was not considered to be clinically relevant. Lacosamide should continue to be used with caution in patients with known conduction problems, sodium channelopathies, on drugs known to induce PR interval prolongation, or those with severe cardiac disease such as myocardial ischemia or heart failure, or structural heart disease; in such patients, obtaining an ECG before beginning lacosamide and after lacosamide is titrated to steady-state maintenance dose, is recommended [3,4]. Patients entering the OLE trial had completed a lacosamide clinical trial for which entry criteria specified uncontrolled POS despite treatment with up to 2 AEDs. Given this patient population with difficultto-treat seizures, the efficacy observations of this long-term trial are encouraging as 51% (189/369) of patients experienced ≥ 50% reduction from baseline in seizure frequency over the course of the trial. However, because treatment was not blinded, flexible dosing of lacosamide and

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concomitant AEDs was permitted to optimize seizure control, and because patients could withdraw over time due to lack of efficacy, all efficacy results should be viewed as descriptive in nature. To counteract potential selection for increasing efficacy over time from patients discontinuing because of lack of response, efficacy was also assessed by yearly completer cohorts (evaluating only patients remaining in the trial at the respective time points). In these completer analyses, seizure reduction was generally maintained over time. In addition, meaningful durations of seizure freedom were attained. Between 21% and 36% of patients in the 1–5-year completer cohorts had no seizures of any type for ≥ 6 months, and most patients with SGS at baseline and during the previous trial experienced freedom from SGS for ≥6 months during the OLE trial. These observations are encouraging, given that the 6-month benchmark for seizure freedom may represent tangible quality-of-life benefits to patients [24]. In conclusion, adjunctive lacosamide (up to 800 mg/day) treatment for up to 8 years among patients with POS taking up to 3 concomitant AEDs was generally well tolerated and had a similar safety profile to that seen in shorter-term adjunctive lacosamide trials [5–8]. No new safety concerns were identified with longer-term exposure. Although the open-label trial design limits the analysis of efficacy, long-term maintenance of seizure reduction was observed. Acknowledgments This trial was funded by UCB Pharma. Writing and editorial support was provided by Merrilee R. Johnstone, PhD, of Prescott Medical Communications Group (Chicago, IL, USA) and was funded by UCB Pharma. Editorial support was also provided by Beth Sesler, PhD, CMPP, of Evidence Scientific Solutions (Southport, CT) and was funded by UCB Pharma. The authors would like to thank the UCB trial team of Tony Daniels and Lien Heinzen (Clinical Project Managers) and Tori Hartsfield (Associate Clinical Project Manager) and the SP615 trial investigators (Bassel Abou-Khalil, MD; Mark Agostini, MD; Jorge Juan Asconape, MD; Gregory Barkley, MD; Danny Bartel, MD; Elinor Ben-Menachem, MD; Donna C. Bergen, MD; Victor Biton, MD; Martin J. Brodie, graduate degrees; Deborah Cantrell, MD; Derek Chong, MD; Steve Chung, MD; Bhupesh Dihenia, MD, PA; Dudley Dinner, MD; Filippo Donati, MD; Keith Edwards, MD; Christian E. Elger, graduate degrees; Milda Endziniene, MD; Toufic Fakhoury, MD; Raymond Edward Faught, MD; Nathan Fountain, MD; Jacqueline French, MD; Frank Gilliam, MD, MPH; Paul Ginsberg, MD; Peter Halasz, MD; Cynthia Harden, MD; Richard Hull, MD; Aatif Husain, MD; Peter Kaplan, MB, BS, FRCP; Gintaras Kaubrys, MD, PhD; David Ko, MD; Mohamad Koubeissi, MD; Wojciech Kozubski, graduate degrees; Gunter Kraemer, MD; Gregory Krauss, MD; Kaarkuzhali Babu Krishnamurthy, MD; Douglas Labar, MD; Robert F. Leroy, MD; Per Lindstrom, MD; Kore Liow, MD; Anthony Guy Marson, MD; Geert Mayer, MD; Klaus Meyer, MD; Daniela Minecan, MD; J. Layne Moore, MD; George Morris, MD; Dean Naritoku, MD; Janos Nikl, MD; Patricia Penovich, MD; J. Todd Perkins, MD; Barbara Phillips, MD; Michael Privitera, MD; Marc Raphaelson, MD; William Rosenfeld, MD; Rajesh Sachdeo, MD; Josemir Wanderley Alves Sander, graduate degrees; Evan Sandok MD; Andras Solyom, MD; Michael Sperling, MD; Erik St. Louis, MD; Hermann Stefan, MD; Bernhard Steinhoff, graduate degrees; William Tatum, DO; Anthony Turel Jr, MD; Basim M. Uthman, MD; Blanca R. Vazquez, MD; Jeanette Wendt, MD; and Mary Ann Werz, MD; PhD). Publication coordination was provided by Azita Tofighy, PhD, an employee of UCB Pharma. Conflicts of interest disclosure W. Rosenfeld receives grants/research support from Artemis, Eisai, GlaxoSmithKline, King Pharmaceuticals, Lundbeck, Medtronic, Pfizer Inc., SK Life Sciences, Sunovion, UCB Pharma, Upsher-Smith, and Valeant Pharmaceuticals. He is also a consultant and serves on the Speakers Bureau for Lundbeck and UCB Pharma. N.B. Fountain received research

grants from Lundbeck, SK Life Sciences, UCB Pharma, and Vertex during the study period. E. Ben-Menachem has received consultancy fees and/ or research grants from UCB, Eisai, ElectroCore, Bial, and Wiley Press during the past 18 months. C. McShea and P. Doty are employees of UCB Biosciences Inc. J. Isojarvi was an employee of UCB Biosciences Inc. during the conduct of the trial. G. Kaubrys declares no conflicts of interest.

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