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Well-designed placebo-controlled clinical trials are critical to the development of novel treatments for epilepsy, but their design has not changed for decades. Patients, clinicians, regulators, and innovators all have concerns that recruiting for trials is challenging, in part, due to the static design of maintaining participants for long periods on add-on placebo when there are an increasing number of options for therapy. A traditional trial maintains participants on blinded treatment for a static period (e.g., 12 weeks of maintenance), during which participants on placebo have an elevated risk of sudden unexpected death in epilepsy compared to patients on an active treatment. Time-to-event trials observe participants on blinded treatment until a key event occurs (e.g., post-randomization seizure count matches pre-randomization monthly seizure count). In this article, we review the evidence for these designs based on re-analysis of prior trials, one published trial that used a time-to-second seizure design, and experience from an ongoing blinded trial. We also discuss remaining concerns regarding time-to-event trials. We conclude that, despite potential limitations, time-to-event trials are a potential promising mechanism to make trials more patient friendly and reduce placebo exposure, which are urgent needs to improve safety and increase recruitment to trials., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose: To assess the efficacy, safety, and tolerability of adjunctive carisbamate treatment at 800 mg/day and 1,200 mg/day in patients with partial-onset seizures (POS)., Methods: Patients ≥ 16 years of age with an established diagnosis of POS for ≥ 1 year and uncontrolled on one to three antiepileptic drugs were enrolled. Eligible patients remained on stable doses of prescribed antiepileptic drugs for an 8-week pretreatment baseline phase and were then randomized (1:1:1) to receive carisbamate (800 mg/day or 1,200 mg/day), or placebo, for a 14-week double-blind phase. Primary efficacy endpoints were percentage reduction in POS frequency and responder rate (patients with ≥ 50% reduction in POS frequency) during the double-blind versus baseline phase., Key Findings: Five hundred forty-seven patients were randomized; 540 composed the intent-to-treat (ITT) analysis. Four hundred thirty-four patients (79%) completed the study. The median percent reduction from baseline to treatment phase in POS frequency was: 21% (placebo); 30% (carisbamate 800 mg); 36% (carisbamate 1,200 mg), and 32% (combined carisbamate doses). The combined carisbamate dose group was not significantly different from placebo for the median percent reduction of POS frequency (p = 0.20) or responder rate (p = 0.18). Therefore, the difference from placebo for the individual carisbamate dose groups was also considered nonsignificant, based on a prespecified step-down analysis. Dizziness was the most common treatment-emergent adverse event, with a higher incidence (≥ 5% difference) in the combined carisbamate group (31%) than placebo (9%); the incidence was higher with carisbamate 1,200 mg (32%, n = 58) than with carisbamate 800 mg (30%, n = 53)., Significance: Adjunctive carisbamate therapy in patients with POS did not demonstrate efficacy across the dose range assessed versus placebo. No new safety findings were observed., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial-onset seizures (POS)., Methods: Two identical, randomized, placebo-controlled, double-blind studies were conducted in adults with POS uncontrolled for >or=1 year. Therapy-refractory epilepsy patients (>or=16 years) remained on stable doses of prescribed antiepileptic drugs (or=50% reduction in POS frequency) during the double-blind phase compared with the prospective baseline phase., Results: Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16-75 years) and 36 years (study 2, range 16-74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment-emergent adverse events (>or=5% in any group), those with an incidence exceeding placebo (>or=3%) were dizziness (400 mg/day group) and somnolence., Conclusions: Carisbamate 400 mg/day was effective in patients with refractory partial-onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well-tolerated in both studies.

Purpose: To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations., Methods: An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5-8; subsequently, 500 mg on days 9-12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry., Results: Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80-125% limits, which are considered not to be of clinical significance. With dose-body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80-125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1-41.4 ml/h/kg and 11.5-12.8 h., Discussion: Carisbamate plasma exposure (AUC) and C(max) in Japanese subjects is approximately 20-25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality.

Purpose: To characterize possible pharmacokinetic interactions between the new antiepileptic drug carisbamate (RWJ-333369) and valproic acid (VPA) or lamotrigine (LTG) following multiple dosing in healthy subjects., Methods: Two open-label, sequential-design studies were conducted in 24 healthy adults. In Study 1, subjects received carisbamate alone (5 days 250 mg q12h; 5 days 500 mg q12h), then VPA alone (7 days 300 mg q12h; 7 days 500 mg q12h), and then a combination of VPA (500 mg q12h) and carisbamate (5 days 250 mg q12h; 5 days 500 mg q12h). In Study 2, subjects received carisbamate alone as in Study 1, then LTG alone (14 days 25 mg q12h; 14 days 50 mg q12h), and then combination of LTG (50 mg q12h) and carisbamate (3 days 250 mg q12h; 14 days 500 mg q12h)., Results: Coadministration of VPA or LTG had minimal effect on carisbamate mean C(max) and AUC(ss) values. Mean VPA-C(max) and AUC(ss) values were approximately 15% lower when given concomitantly with carisbamate. However, the 90% confidence intervals (CIs) for the C(max) and AUC(ss) ratio with/without carisbamate were within the 80-125% equivalence range, C(max) 82-89%; AUC(ss) 81-88%. Mean LTG C(max) and AUC(ss) values were approximately 20% lower when given concomitantly with carisbamate. The 90% CIs with and without carisbamate for LTG C(max) and AUC(ss) were 79-86% and 75-81%, respectively. This modest change is not considered clinically significant., Conclusions: There were no clinically significant interactions between carisbamate and VPA or LTG. Concomitant administration of carisbamate with VPA or LTG was generally safe and well tolerated.

Purpose: To characterize the possible pharmacokinetic interaction between the new antiepileptic and CNS drug RWJ-333369 and carbamazepine (CBZ) following multiple dosing in healthy subjects., Methods: In an 8-week, open-label, sequential design study, 24 healthy adults received multiple-dose RWJ-333369 alone (5 days 250 mg q12h; 5 days 500 mg q12h), then after a 4-day washout, multiple-dose CBZ alone (3 days 100 mg q12h; 3 days 200 mg q12h; 22 days 300 mg q12h), and then combination of CBZ (300 mg q12h), and RWJ-333369 (5 days 250 mg q12h; 5 days 500 mg q12h)., Results: At steady-state following multiple dosing, RWJ-333369 peak plasma concentration (C(max)) and area under the concentration-time-curve within the dosing interval (AUCss) increased in proportion to dose. The C(max) and AUCss of CBZ were similar when given alone or concomitantly with RWJ-333369. The 90% confidence intervals for the ratio of CBZ C(max) and AUCss with/without RWJ-333369 were: 94-104% and 95-104%, respectively (well within the equivalence range of 80-125%). When RWJ-333369 was administered with CBZ, its mean (SD) oral clearance increased from 3.2 L/h to 4.9 L/h and consequently its mean half-life was shortened from 10.4 (1.9) h to 7.4 (1.2) h, and mean AUCss and C(max) were reduced by 37% and 30%, respectively., Conclusions: There was no effect of multiple-dose RWJ-333369 on CBZ pharmacokinetics. CBZ induced RWJ-333369 clearance, resulting in shortened half-life and decreased exposure (AUCss) and C(max). Concomitant administration of RWJ-333369 with CBZ was generally safe and tolerated.

Purpose: To characterize the pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369 following single and multiple oral doses to healthy subjects, including the effect of food on bioavailability., Method: Two studies were conducted. The first study had a randomized, double-blind, placebo-controlled, sequential, ascending-dose crossover design. Subjects were divided into four dose groups (100, 250, 500, and 750 mg) of 10 to 11 subjects each. RWJ-333369 or placebo was administered for two 7-day periods, separated by a 14-day washout. In the second study RWJ-333369 (750 mg) was administered to 12 healthy subjects under fasted and fed conditions. Plasma and urine samples were analyzed for RWJ-333369 by liquid chromatography-mass spectroscopy. Safety was assessed throughout the studies., Results: Mean (range) pharmacokinetic parameters in the above studies were: oral clearance (CL/F) 3.4-4.2 L/h, half-life (t(1/2)) 10.6-12.8 h, and renal clearance (CLr) 0.042-0.094 L/h, indicating that RWJ-333369 is eliminated primarily by metabolism. These parameters were not significantly different (p > 0.05) for the four dose groups and for single and multiple dosing. C(max) and AUC increased proportionally with dose and decreased with food by 11% and 5%, respectively., Conclusions: Following single and repetitive (q12h) doses of 100-750 mg, RWJ-333369 had linear pharmacokinetics; food did not alter pharmacokinetics to a clinically relevant extent. RWJ-333369 is extensively metabolized and has a low CL/F that equals < 5% of the liver blood flow. Thus, orally administered RWJ-333369 has no hepatic first-pass effect. The 12-h half-life will enable bid dosing with an immediate-release oral formulation.

Background: The purpose of neuroimaging of a patient with new onset of seizures is to demonstrate cause and explore the prognosis. It was recently recommended that emergency brain computed tomography (CT) be performed only in adult seizure patients with an increased likelihood of life-threatening lesions, i.e., those with new focal deficits, persistent altered mental status, fever, recent trauma, persistent headaches, history of cancer, history of anticoagulation, or suspicion of acquired immunodeficiency syndrome. The objective of this study was to determine the diagnostic utility of emergency brain CT in children who present to the emergency department with new onset of seizures., Methods: A 1-year retrospective chart review of all children who presented to the emergency department of the Schneider Children's Hospital with a new onset of seizures and who underwent CT of the brain, excluding children with simple febrile seizures., Results: Sixty-six patients, 34 boys and 32 girls with a mean age of 4.9 years, qualified for inclusion in the study. Fifty-two patients (78.8%) had normal CT results and 14 patients (21.2%) had abnormal CT results. Seizure cause was considered cryptogenic in 33 patients, of whom 2 (6%) had abnormal CT results; neither patient required intervention. Seizure cause was considered symptomatic in 20 patients, of whom 12 (60%) had abnormal CT results (p < 0.0001). In two patients with abnormal CT scans (both acute symptomatic), the imaging findings were of immediate therapeutic significance and were predictable from the clinical history and the physical examination. None of the 13 patients with complex febrile seizure cause had an abnormal CT scan. Patients with partial convulsive seizures were more likely to have abnormal CT scans than patients with generalized convulsive seizures, but the difference was not statistically significant., Conclusions: The routine practice in many pediatric emergency departments of obtaining brain CT scans for all patients with new onset of nonfebrile seizures is unjustified. History and physical examination are sufficient to identify those patients for whom such studies are likely to be appropriate. Emergent CT is not indicated for patients with no known seizure risk factors, normal neurological examinations, no acute symptomatic cause other than fever, and reliable neurological follow-up. For these patients, referral to a pediatric neurologist for further workup, including electroencephalography and the more diagnostically valuable magnetic resonance imaging, would be more appropriate.

Purpose: We assessed rates of symptoms of anxiety and depression among pediatric patients with epilepsy., Methods: We administered the Revised Child Manifest Anxiety Scale (RCMAS), and Child Depression Inventory (CDI) to 44 epilepsy patients aged 7-18 years (mean age 12.4 years). Demographic, socioeconomic, and epilepsy-related information was examined in relation to depression and anxiety scores., Results: No patients had been previously identified to have depression or anxiety. However, 26% had significantly increased depression scores and 16% met criteria for significant anxiety symptomatology., Conclusions: Symptoms of depression and anxiety are common among pediatric patients with epilepsy and appear to be overlooked by care providers.