Lacosamide in patients with epilepsy of cerebrovascular etiology

Acta Neurologica ScandinavicaVolume 141, Issue 6 p. 473-482 ORIGINAL ARTICLEOpen Access Lacosamide in patients with epilepsy of cerebrovascular etiology Felix Rosenow, Corresponding Author Felix Rosenow rosenow@med.uni-frankfurt.de orcid.org/0000-0002-3989-7471 Epilepsy Center Frankfurt Rhine-Main, Neurocenter, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany Correspondence Felix Rosenow, Epilepsy Center Frankfurt Rhine-Main, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. Email: rosenow@med.uni-frankfurt.deSearch for more papers by this authorChristian Brandt, Christian Brandt Bethel Epilepsy Centre, Mara Hospital, Bielefeld, GermanySearch for more papers by this authorAli Bozorg, Ali Bozorg UCB Pharma, Raleigh, NC, USASearch for more papers by this authorSvetlana Dimova, Svetlana Dimova UCB Pharma, Brussels, BelgiumSearch for more papers by this authorBjörn Steiniger-Brach, Björn Steiniger-Brach UCB Pharma, Brussels, BelgiumSearch for more papers by this authorYing Zhang, Ying Zhang UCB Pharma, Raleigh, NC, USASearch for more papers by this authorBruno Ferrò, Bruno Ferrò UCB Pharma, Milan, ItalySearch for more papers by this authorGregory L. Holmes, Gregory L. Holmes University of Vermont College of Medicine, Burlington, VT, USASearch for more papers by this authorReetta Kälviäinen, Reetta Kälviäinen University of Eastern Finland and Kuopio Epilepsy Centre, Kuopio University Hospital, Kuopio, FinlandSearch for more papers by this author Felix Rosenow, Corresponding Author Felix Rosenow rosenow@med.uni-frankfurt.de orcid.org/0000-0002-3989-7471 Epilepsy Center Frankfurt Rhine-Main, Neurocenter, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany Correspondence Felix Rosenow, Epilepsy Center Frankfurt Rhine-Main, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. Email: rosenow@med.uni-frankfurt.deSearch for more papers by this authorChristian Brandt, Christian Brandt Bethel Epilepsy Centre, Mara Hospital, Bielefeld, GermanySearch for more papers by this authorAli Bozorg, Ali Bozorg UCB Pharma, Raleigh, NC, USASearch for more papers by this authorSvetlana Dimova, Svetlana Dimova UCB Pharma, Brussels, BelgiumSearch for more papers by this authorBjörn Steiniger-Brach, Björn Steiniger-Brach UCB Pharma, Brussels, BelgiumSearch for more papers by this authorYing Zhang, Ying Zhang UCB Pharma, Raleigh, NC, USASearch for more papers by this authorBruno Ferrò, Bruno Ferrò UCB Pharma, Milan, ItalySearch for more papers by this authorGregory L. Holmes, Gregory L. Holmes University of Vermont College of Medicine, Burlington, VT, USASearch for more papers by this authorReetta Kälviäinen, Reetta Kälviäinen University of Eastern Finland and Kuopio Epilepsy Centre, Kuopio University Hospital, Kuopio, FinlandSearch for more papers by this author First published: 18 February 2020 https://doi.org/10.1111/ane.13230Citations: 10AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Objectives To assess tolerability and efficacy of lacosamide in adults with cerebrovascular epilepsy etiology (CVEE). Materials and methods Exploratory post hoc analyses of a double-blind, initial monotherapy trial of lacosamide vs carbamazepine-controlled release (carbamazepine-CR) (SP0993; NCT01243177); a double-blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741); and an observational study of adjunctive lacosamide added to one antiepileptic drug (SP0973 VITOBA; NCT01098162). Patients with CVEE were identified based on epilepsy etiology recorded at baseline. Results In the initial monotherapy trial, 61 patients had CVEE (lacosamide: 27; carbamazepine-CR: 34). 20 (74.1%) patients on lacosamide (27 [79.4%] on carbamazepine-CR) reported treatment-emergent adverse events (TEAEs), most commonly (≥10%) headache, dizziness, and fatigue (carbamazepine-CR: headache, dizziness). A numerically higher proportion of patients on lacosamide than carbamazepine-CR completed 6 months (22 [81.5%]; 20 [58.8%]) and 12 months (18 [66.7%]; 17 [50.0%]) treatment without seizure at last evaluated dose. In the conversion to monotherapy trial, 26/30 (86.7%) patients with CVEE reported TEAEs, most commonly (≥4 patients) dizziness, convulsion, fatigue, headache, somnolence, and cognitive disorder. During lacosamide monotherapy, 17 (56.7%) patients were 50% responders and six (20.0%) were seizure-free. In the observational study, 36/83 (43.4%) patients with CVEE reported TEAEs, most commonly (≥5%) fatigue and dizziness. Effectiveness was assessed for 75 patients. During the last 3 months, 60 (80%) were 50% responders and 42 (56.0%) were seizure-free. Conclusions These exploratory post hoc analyses suggested lacosamide was generally well tolerated and effective in patients with CVEE, with data from the initial monotherapy trial suggesting numerically better efficacy than carbamazepine-CR. 1 INTRODUCTION Cerebrovascular disease, particularly stroke, is one of the most common causes of new-onset epilepsy among older adults with identified epilepsy etiology.1, 2 Considerations for the antiepileptic drug (AED) treatment of post-stroke epilepsy include the patient's susceptibility to age-related side effects and potential drug-drug interactions.3, 4 Treatment with non-enzyme-inducing AEDs may be preferable, as enzyme induction may interfere with secondary stroke prophylaxis and exacerbate vascular risk.3-5 Few studies have evaluated the tolerability and efficacy of AEDs in post-stroke epilepsy.6, 7 Lacosamide is a non-enzyme-inducing AED indicated for monotherapy and adjunctive therapy of focal (partial-onset) seizures in patients 4 years of age and older in the United States,8 the European Union,9 and several other countries (prescribing regulations vary). Preclinical in vitro10 and in vivo11, 12 models of ischemia or ischemic stroke have suggested neuroprotective effects of lacosamide. A small-scale pilot study (n = 16) indicated that intravenous lacosamide had a favorable tolerability and efficacy profile when used as initial treatment for post-stroke non-convulsive status epilepticus in elderly patients.13 These exploratory post hoc analyses were conducted to assess the tolerability and efficacy of oral lacosamide in adults with cerebrovascular epilepsy etiology (CVEE). 2 MATERIALS AND METHODS Post hoc analyses were conducted on data collected in three trials: a double-blind, non-inferiority, initial monotherapy trial of lacosamide vs carbamazepine-controlled release (carbamazepine-CR) (SP0993; NCT01243177)14; a historical-controlled double-blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741)15; and an observational study of adjunctive lacosamide added to one baseline AED (SP0973 VITOBA; NCT01098162).16 Patients with CVEE were selected based on epilepsy etiology data recorded by the investigators at baseline of each trial. Patients with an etiology category of “cerebrovascular accident” (initial monotherapy trial), “vascular causes” (conversion to lacosamide monotherapy trial), or “cerebrovascular etiology” (observational study) were included. Tolerability and efficacy/effectiveness outcomes were analyzed separately for each trial, as detailed below. The trials were conducted in accordance with Good Clinical Practice requirements, the Declaration of Helsinki and local laws. The protocols were reviewed by institutional and local ethics committees. All patients provided signed informed consent for their participation (double-blind trials) or use of medical data (observational study). 2.1 Initial monotherapy with lacosamide or carbamazepine-CR Eligible patients were aged ≥16 years with newly/recently diagnosed epilepsy and unprovoked focal or generalized tonic-clonic seizures (without signs of focal onset) (Table 1). Patients were randomized 1:1 to lacosamide or carbamazepine-CR, with strata defined by seizure-count (≤2 or >2 seizures) in the 3 months prior to screening. Doses were up-titrated over 2 weeks from initial dose (lacosamide, 100 mg/day; carbamazepine-CR: 200 mg/day) to the first target dose level (200 mg/day; 400 mg/day). Flexible up-titration to the second and third target dose levels (lacosamide: 400/600 mg/day; carbamazepine-CR: 800/1200 mg/day) was based on seizure control, an approach closely reflecting clinical practice. Following 1-week stabilization at the first target dose, patients entered a 6-month evaluation period. If a seizure occurred, the dose was escalated to the next target dose level (3-week titration and stabilization) and the 6-month evaluation began again. Patients who experienced a seizure at the third target dose were withdrawn from the trial. Upon completion of the evaluation period, patients continued to a 6-month maintenance period. During evaluation and maintenance, patients on the second and third target doses could undergo one dose reduction if required for tolerability reasons. Patients with a dose reduction could not return to their previous dose and were withdrawn if a new seizure occurred. Patients were eligible to participate in a double-blind extension trial (SP0994; NCT01465997) if they remained seizure-free during maintenance, or experienced a seizure during maintenance while on the first or second target dose levels. Table 1. Trials included in these exploratory post hoc analyses Initial monotherapy with LCM or CBZ-CR Conversion to LCM monotherapy LCM adjunctive to one baseline AED Study SP0993 SP0902 SP0973 CT.gov identifier NCT01243177 NCT00520741 NCT01098162 Phase Phase 3 Phase 3 Phase 4 Design Randomized, double-blind, non-inferiority trial Randomized, double-blind, historical-controlled Observational; physician's decision to add lacosamide had been reached prior to, and independently of, the decision to include the patient in the study. Treatment duration Up to 118 wk (2-wk titration; 1-wk stabilization; 6-mo evaluation; 6-mo maintenance)a Up to 19 wk (3-wk titration; 16-wk maintenance [6-wk Background AED withdrawal and 10-wk LCM monotherapy]) Up to 6 mo Starting dose LCM 100 mg/day CBZ-CR 200 mg/day LCM 200 mg/day Based on physician discretion Maintenance LCM 200-600 mg/day CBZ-CR 400-1200 mg/day LCM 300 and 400 mg/day Based on physician discretion Number of patients (SS) LCM: 444 CBZ-CR: 442 LCM 300 mg/day: 106 LCM 400 mg/day: 319 SS: 571 Main inclusion criteria Age ≥16 y 16-70 y ≥16 yb Seizure type Newly/recently diagnosed epilepsy with unprovoked partial-onset seizures (with clear focal origin) or generalized tonic-clonic seizures (without clear focal origin) Diagnosis of epilepsy with simple partial seizures (motor component) and/or complex partial seizures (with or without secondary generalization) Partial-onset seizures with or without secondary generalizationb Baseline seizure frequency 2 unprovoked seizures (separated by ≥48 h) in the previous 12 mo, of which at least one had occurred in the previous 3 mo At least 2 and ≤40 partial-onset seizures per 28 d during 8-wk prospective baseline period Physician discretion Background AEDs at LCM initiation Nonec 1 or 2 marketed AEDs at a stable dose for at least 28 d before Visit 1 and during baseline (dosage of second AED was ≤50% of minimum recommended maintenance dose per USA label) 1 AED Main exclusion criteria Criteria related to seizure type, disorders, and cardiac comorbidities Current/previous seizure clusters or status epilepticus Seizure types other than focal or generalized tonic-clonic seizures (without clear focal origin) Non-epileptic seizures, conversion disorders, or other non-epileptic events that could have been confused with seizures Sick sinus syndrome without a pacemaker, second- or third-degree atrioventricular block, or any other clinically significant electrocardiogram abnormalities Myocardial infarction in the previous 3 mo New York Heart Association Class III or IV heart failure History of status epilepticus within previous year, cluster seizures within 8 wk of study start History of primary generalized epilepsy or unclassified seizures Seizure disorder characterized primarily by isolated auras (ie, simple partial seizures without observable motor signs) Any seizure-free period lasting 28 d or longer during baseline Sick sinus syndrome without a pacemaker, or second- or third-degree atrioventricular block Myocardial infarction in the previous 3 mo New York Heart Association Class III or Class IV heart failure Conversion disorders or other non-epileptic ictal events Not applicable for this study Abbreviations: AED, antiepileptic drug; CBZ-CR, carbamazepine-controlled release; LCM, lacosamide. a In the SP0993 trial, 6 mo was equivalent to 26 wk. b Per therapeutic guidelines and approved indication at the time of the study (SmPC 2008). c Patients with AED treatment in the 6 mo before screening were excluded. Data were analyzed for the safety set (SS) and full analysis set (FAS); both analysis sets included all randomized patients who received at least one dose of trial medication. Tolerability outcomes included treatment-emergent adverse events (TEAEs) during treatment (titration, stabilization, evaluation, and maintenance) (summarized descriptively). Efficacy outcomes included the Kaplan-Meier estimated proportion of patients remaining seizure-free for 6 and 12 consecutive months following stabilization at last evaluated dose and for 12 consecutive months from the date of first trial dose. Patients who withdrew from the trial without a seizure were censored at the time of withdrawal. Kaplan-Meier estimates were adjusted for number of seizures (≤2 or >2) in the 3 months before screening. Additional efficacy outcomes included the observed proportion of patients who completed 6 and 12 consecutive months of treatment and were seizure-free following the last evaluated dose and from the date of first trial dose. 2.2 Conversion to lacosamide monotherapy Eligible patients were aged 16-70 years, on stable doses of one or two AEDs, and were experiencing between two and ≤40 partial-onset seizures/28 days during the 8-week prospective baseline (Table 1). If the patient was on two AEDs, the dosage of the second AED was required to be ≤50% of the minimum recommended maintenance dose per the United States label. Following baseline, patients were randomized 3:1 to 400 mg/day or 300 mg/day lacosamide. The 300 mg/day arm was included to allow blinding and ensure a trial design consistent with the historical-control studies. Lacosamide was initiated at 200 mg/day and up-titrated over 3 weeks. Upon reaching their randomized dose, patients entered the 16-week lacosamide maintenance period. Background AEDs were withdrawn over 6 weeks followed by a 10-week lacosamide monotherapy period. The primary background AED was tapered in approximately equal decrements every 2 weeks. If the patient was taking two background AEDs, the second AED was withdrawn on day 1 of the AED withdrawal period. A single reduction in lacosamide dose was permitted during maintenance, if required for tolerability reasons. Tolerability outcomes included TEAEs during treatment (titration and maintenance) and were summarized for the SS (all patients who received at least one lacosamide dose). Efficacy outcomes included 50% and 75% responders (patients with a ≥50% or ≥75% reduction in seizure frequency/28 days in comparison with baseline) and patients achieving seizure freedom during the 10-week lacosamide monotherapy period. Efficacy outcomes were summarized for the SS and completer set (patients who completed the monotherapy period). 2.3 Lacosamide as adjunctive therapy to one baseline AED Patients were consecutively enrolled from specialized epilepsy outpatient units, as well as from hospital-based and office-based neurologists in Germany. The decision to prescribe lacosamide was made by the physician prior to and independently of patient enrollment, according to the indication at the time of the study (adjunctive therapy of focal seizures in patients with epilepsy 16 years of age or older [2008 SmPC]). Eligible patients were receiving treatment with one AED at the time of initiation of lacosamide (Table 1). Dosing was at the physician's discretion, with lacosamide treatment recommended according to the 2008 SmPC. Upon enrollment, patients provided seizure frequency for the 3 months before the first lacosamide dose (retrospective baseline). Data were collected prospectively at routine visits over 6 months, or until discontinuation of lacosamide. A visit was planned for month 3, per usual clinical practice, with a final visit at month 6 or study termination. Seizures were reported per usual clinical practice (spontaneous reporting or patient diary). Tolerability outcomes included TEAEs. All patients who received at least one lacosamide dose (SS) were included in descriptive analyses of tolerability outcomes. Effectiveness outcomes were 50% and 75% responders (patients with a ≥50% or ≥75% reduction from baseline in seizure frequency/28 days) and seizure freedom at the final visit (seizure frequency during the 3 months prior to the visit was compared with 3-month retrospective baseline). Effectiveness was analyzed for the FAS (all SS patients with valid baseline and post-baseline seizure frequency data) and the modified FAS (mFAS; FAS patients treated with in-label lacosamide dosages only [up to 400 mg/day]). 3 RESULTS 3.1 Initial monotherapy with lacosamide or carbamazepine-CR Of 886 patients treated in the initial monotherapy trial, 61 (6.9%) had CVEE and were included in the SS/FAS for these analyses (Table 2). Twenty-seven patients were randomized to lacosamide and 34 to carbamazepine-CR. Eighteen (66.7%) patients on lacosamide and 17 (50.0%) on carbamazepine-CR completed the trial. The most common reasons for discontinuation (≥10% of patients) were adverse events (AEs) in patients on lacosamide, and AEs and lack of efficacy in patients on carbamazepine-CR (Table 2). A higher proportion of patients on lacosamide (19 [70.4%]) than carbamazepine-CR (15 [44.1%]) continued to the long-term extension trial. Table 2. Disposition of patients with cerebrovascular epilepsy etiology (SS) Initial monotherapy with LCM or CBZ-CR Conversion to LCM monotherapy LCM adjunctive to one baseline AED CBZ-CR LCM LCM LCM Received trial medication, n 34 27 30 83 Attended final visit: 82 (100) Completed, n (%) 17 (50.0) 18 (66.7) 22 (73.3) Continuing LCM at final visit: 69 (84.1)a Discontinued, n (%) 17 (50.0) 9 (33.3) 8 (26.7) 12 (14.6) Due to adverse event 7 (20.6) 3 (11.1) 5 (16.7) 7 (8.5) Protocol violation 2 (5.9) 2 (7.4) 0 0 Consent withdrawn/patient request 1 (2.9) 2 (7.4) 0 5 (6.1) Due to lack of efficacy 5 (14.7) 1 (3.7) 3 (10.0) 1 (1.2) Lost to follow-up 2 (5.9) 1 (3.7) 0 1 (1.2) Abbreviations: CBZ-CR, carbamazepine-controlled release; LCM, lacosamide; SS, safety set. a For one (1.2%) patient, the status of LCM therapy at the final visit (continuing/discontinued) was unknown. Baseline demographics were generally comparable between treatment groups, although patients on lacosamide were older (Table 3). Patients on lacosamide had a higher prevalence of comorbid conditions (median: 4.0) than those on carbamazepine-CR (3.0) (Table 3). Six (22.2%) patients on lacosamide and seven (20.6%) on carbamazepine-CR had an ongoing cardiac disorder, most commonly (≥2 patients) atrial fibrillation (lacosamide: three [11.1%]; carbamazepine-CR: one [2.9%]) and myocardial ischemia (none; three [8.8%]). Median (Q1, Q3) numbers of seizures in the previous 3 months (lacosamide: 3.0 [2.0, 5.0]; carbamazepine-CR: 3.0 [1.0, 5.0]) and in the past year (4.0 [3.0, 9.0]; 5.0 [2.0, 15.0]) were similar in both treatment groups. Table 3. Baseline demographic and epilepsy characteristics of patients with cerebrovascular epilepsy etiology (SS) Initial monotherapy with LCM or CBZ-CR Conversion to LCM monotherapy LCM adjunctive to one baseline AED CBZ-CR (n = 34) LCM (n = 27) LCM (n = 30) LCM (n = 83) Patient demographics Age, mean (SD), y 54.5 (16.5) 61.4 (11.8) 42.3 (14.5) 62.6 (14.6) <65, n (%) 22 (64.7) 13 (48.1) 28 (93.3) 36 (43.4) ≥65, n (%) 12 (35.3) 14 (51.9) 2 (6.7) 47 (56.6) Male, n (%) 23 (67.6) 20 (74.1) 11 (36.7) 41 (49.4) Epilepsy history Age at diagnosis, median (range), y 57.5 (23, 85) 64.0 (37, 79) 30.4 (0.7, 65.8) 58.0 (6, 84) Time since diagnosis, median (range), y 0.06 (<0.1, 0.9) 0.08 (<0.1, 0.9) 10.3 (0.6, 35.9) 3.0 (0, 54) Baseline seizure frequency/28 d, median (range) NA NA 6.6 (2.0, 30.0) 2.0 (0.0, 26.7) Classification of seizuresa Partial-onset seizures (focal), n (%) 34 (100) 26 (96.3) 30 (100) NA Simple partial (focal aware) 17 (50.0) 9 (33.3) 21 (70.0) NA Complex partial (focal impaired awareness) 14 (41.2) 16 (59.3) 28 (93.3) NA Partial evolving to secondarily generalized (focal to bilateral tonic-clonic) 16 (47.1) 11 (40.7) 22 (73.3) NA Generalized seizures, n (%) Tonic-clonic 0 1 (3.7) 0 NA Number of lifetime AEDs, n (%)b 0 NA NA 6 (20.0) 0 1 NA NA 6 (20.0) 51 (61.4) 2 NA NA 7 (23.3) 14 (16.9) 3+ NA NA 11 (36.7) 18 (21.7) Medical history (previous/ongoing medical conditions that occurred before trial entry) Any condition, n (%) 34 (100) 27 (100) 29 (96.7) 83 (100.0) Condition by System Organ Class reported in ≥40% of all patients in any of the three trials, n (%) (numbers meeting this criterion are bolded) Nervous system disorders 32 (94.1) 27 (100.0) 28 (93.3) 75 (90.4) Vascular disorders 23 (67.6) 19 (70.4) 13 (43.3) 43 (51.8) Metabolism and nutrition disorders 13 (38.2) 17 (63.0) 11 (36.7) 30 (36.1) Psychiatric disorders 9 (26.5) 7 (25.9) 15 (50.0) 22 (26.5) Musculoskeletal and connective tissue disorders 5 (14.7) 5 (18.5) 16 (53.3) 8 (9.6) Gastrointestinal disorders 3 (8.8) 6 (22.2) 12 (40.0) 10 (12.0) Immune system disorders 3 (8.8) 1 (3.7) 13 (43.3) 1 (1.2) Surgical and medical procedures 0 1 (3.7) 20 (66.7) 14 (16.9) Ongoing comorbid conditions at trial entry Any ongoing condition, n (%) 32 (94.1) 27 (100.0) 29 (96.7) 68 (81.9) Number of comorbid conditions per patient Mean (SD) 4.4 (4.6) 5.3 (4.3) 9.0 (6.7) 1.8 (1.6) Median (Q1, Q3) 3.0 (2.0, 5.0) 4.0 (2.0, 6.0) 8.0 (3.0, 11.0) 1.0 (1.0, 2.0) 0, n (%) 2 (5.9) 0 1 (3.3) 15 (18.1) 1-2, n (%) 12 (35.3) 8 (29.6) 4 (13.3) 49 (59.0) 3-4, n (%) 9 (26.5) 7 (25.9) 4 (13.3) 10 (12.0) 5+, n (%) 11 (32.4) 12 (44.4) 21 (70.0) 9 (10.8) Abbreviations: AED, antiepileptic drug; CBZ-CR, carbamazepine-controlled release; LCM, lacosamide; NA, not applicable; SD, standard deviation; SS, safety set. a For SP0993, classification of seizures in the 1 y before screening is reported. b AEDs that were taken and stopped before initiation of lacosamide (SP0902: AEDs stopped 28 d before Visit 1; SP0973: AEDs stopped before start date of lacosamide). During the treatment period, the median duration of exposure to trial medication was 385 (range: 12, 498) days in the lacosamide group and 381 (6, 574) days in the carbamazepine-CR group. Twenty (74.1%) patients on lacosamide and 19 (55.9%) on carbamazepine-CR had >364 days of treatment. A higher proportion of patients on lacosamide (24 [88.9%]) than carbamazepine-CR (23 [67.6%]) remained on the lowest target dose level. No patients on lacosamide and five (14.7%) on carbamazepine-CR escalated to the highest target dose. The overall incidence of TEAEs during the treatment period was similar in patients on lacosamide and carbamazepine-CR (Table 4). TEAEs were considered to be drug-related (opinion of the investigator) in eight (29.6%) patients on lacosamide and 17 (50.0%) on carbamazepine-CR. Headache, dizziness, and fatigue were the most common TEAEs (≥10%) with lacosamide, and headache and dizziness were most common TEAEs with carbamazepine-CR. Cardiac TEAEs were reported by one (3.7%) patient on lacosamide (first-degree atrioventricular block) and two (5.9%) on carbamazepine-CR (first-degree atrioventricular block and pericardial hemorrhage; one patient each). Fall was reported by two (7.4%) patients on lacosamide and one (2.9%) on carbamazepine-CR. Most TEAEs were mild or moderate in intensity; four (14.8%) patients on lacosamide and four (11.8%) on carbamazepine-CR had a severe TEAE. No specific TEAE (preferred term) was considered to be severe in >1 patient in either group (Table S1). Table 4. Treatment-emergent adverse events (TEAEs) in patients with cerebrovascular epilepsy etiology (SS) Initial monotherapy with LCM or CBZ-CR Conversion to LCM monotherapy LCM adjunctive to one baseline AED CBZ-CR (n = 34) LCM (n = 27) LCM (n = 30) LCM (n = 83) Any TEAE, n (%) 27 (79.4) 20 (74.1) 26 (86.7) 36 (43.4) Drug-related TEAEs, n (%) 17 (50.0) 8 (29.6) 20 (66.7) 21 (25.3) Serious TEAEs, n (%) 7 (20.6) 5 (18.5) 3 (10.0) 9 (10.8) Severe TEAEs, n (%) 4 (11.8) 4 (14.8) 8 (26.7) 10 (12.0) Discontinuation due to TEAEs, n (%) 7 (20.6) 3 (11.1) 5 (16.7) 8 (9.6) Deaths, n (%) 0 1 (3.7) 0 0 TEAEs reported by ≥10% patients in any group in any of the three trials, n (%) (numbers meeting this criterion are bolded) Headache 5 (14.7) 3 (11.1) 4 (13.3) 1 (1.2) Dizziness 4 (11.8) 3 (11.1) 8 (26.7) 6 (7.2) Fatigue 0 3 (11.1) 4 (13.3) 12 (14.5) Somnolence 3 (8.8) 0 4 (13.3) 2 (2.4) Cognitive disorder 1 (2.9) 1 (3.7) 4 (13.3) 1 (1.2) Tremor 1 (2.9) 1 (3.7) 3 (10.0) 4 (4.8) Convulsiona 1 (2.9) 0 5 (16.7) 2 (2.4) Dry mouth 0 0 3 (10.0) 0 Upper respiratory tract infection 0 1 (3.7) 3 (10.0) 0 Abbreviations: AED, antiepileptic drug; CBZ-CR, carbamazepine-controlled release; LCM, lacosamide; MedDRA, Medical Dictionary for Regulatory Activities; SS, safety set. a Preferred term “convulsion” captures both worsening of seizure conditions and improvements (emergence of less severe seizure types); therefore, the incidence of convulsion may be an overestimate of the number of patients with worsening seizures. Serious TEAEs were reported by five (18.5%) patients on lacosamide and seven (20.6%) on carbamazepine-CR (Table 4). No specific TEAE (preferred term) was considered to be serious in >1 patient on lacosamide; three (8.8) patients on carbamazepine-CR had serious TEAEs of partial seizures with secondary generalization. Three (11.1%) patients on lacosamide and seven (20.6%) on carbamazepine-CR had a TEAE leading to discontinuation. No TEAEs led to discontinuation in >1 patient in either group (Table S1). One patient in the lacosamide group died because of subarachnoid hemorrhage following a skull fracture (circumstances unknown); this death was not considered to be related to lacosamide. A numerically higher proportion of patients on lacosamide than carbamazepine-CR completed 6 months (22 [81.5%] vs 20 [58.8%]) and 12 months (18 [66.7%] vs 17 [50.0%]) of treatment without a seizure at the last evaluated dose level (Figure 1A). The stratified Kaplan-Meier estimates for 6- and 12-month seizure freedom at last evaluated dose were 95.5% and 91.1% on lacosamide, and 82.0% and 75.1% on carbamazepine-CR, respectively. Analyses performed from the first trial dose showed 6- and 12-month seizure freedom with lacosamide in 18 (66.7%) and 15 (55.6%) patients, respectively. In the carbamazepine-CR group, 6- and 12-month seizure freedom was observed in 16 (47.1%) and 13 (38.2%) patients, respectively. The stratified Kaplan-Meier estimates for 12-month seizure freedom from the first trial dose were 66.4% on lacosamide and 44.2% on carbamazepine-CR. Figure 1Open in figure viewerPowerPoint Efficacy/effectiveness outcomes in patients with cerebrovascular epilepsy etiology. A, Initial monotherapy with lacosamide or carbamazepine-CR: proportion of patients who completed 6 and 12 mo of treatment and were seizure free at the last evaluated dose (FAS; CBZ-CR, n = 34; LCM, n = 27). B, Conversion to lacosamide monotherapy: 50% and 75% responder rates and seizure freedom during the 10-wk lacosamide monotherapy period (SS; n = 30). C, Lacosamide as adjunctive therapy to one baseline AED: 50% and 75% responder rates and seizure freedom during the last 3 months of the 6-month observation period (FAS; n = 75). AED, antiepileptic drug; CBZ-CR, carbamazepine-controlled release; FAS, full analysis set; LCM, lacosamide; SS, safety set 3.2 Conversion to lacosamide monotherapy Of 425 patients treated with lacosamide in the conversion to monotherapy