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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.)

Objective: The prevalence of epilepsy is slightly higher in women than in men and sensitivity to seizure stimuli differs between sexes. Some evidence suggests sex differences in response to antiseizure medications exist mainly due to inconsistent pharmacokinetic differences; however, there is a lack of real-world evidence examining differences in response to antiseizure medications between men and women., Methods: This was a retrospective population-based cohort study in five large US healthcare databases. The population included adult patients with epilepsy, newly exposed to levetiracetam, and naive to antiseizure medication. The first exposure to levetiracetam was the index date. The requirement that all patients received the same medication was done to avoid potential confounding due to differences in index treatment. The outcome was the development of treatment resistant epilepsy (TRE), defined as having at least three distinct antiseizure medications in 1 year. The proportion of patients who developed TRE within 1 year following the index date was calculated. To compare the risk of developing TRE between sexes, relative risks (RR) and 95% confidence intervals (CI) were calculated, and estimates were pooled using meta-analytic techniques stratified by gender and age., Results: A total of 147 334 subjects were included in the databases, 50.8% were women, and 4.27% developed TRE. The comorbid profile differed greatly between men and women; however, the types of epilepsy syndromes observed during baseline were similar between the two groups. Across all databases, women were more likely to develop TRE than men (pooled RR 1.27, 95% CI 1.17-1.38). Results remained similar when stratified by age., Significance: This study assessed sex differences in response to antiseizure medications using the development of TRE as a proxy for effectiveness. Women newly exposed to levetiracetam were 27% more likely to develop TRE than men, independent of age., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Adverse cognitive effects are an important concern for drugs that influence the central nervous system. Carisbamate is a novel drug in development for treatment of seizures and neuropathic pain. Information on its cognitive effects is limited. Three controlled, multiple-dose, crossover studies with treatment durations of 5-9 days were designed to examine the cognitive effects of carisbamate on healthy volunteers. In one study, apparent dose-dependent effects on response, vigilance, and recognition speed were observed (1000 mg and 1500 mg/day). Carisbamate did not differ from placebo for most variables in the other two studies, but increased reaction time and reduced Sternberg memory were seen at higher dosages. Carisbamate did not produce clinically significant adverse effects on cognitive performance at doses <1000 mg/day. Effects were mild to modest at the higher doses tested., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

Objective: To evaluate the efficacy, safety, and tolerability of carisbamate (CRS), an investigational drug, as adjunctive treatment for partial-onset seizures in adults., Methods: A randomized, double-blind, placebo-controlled, multicenter, dose-ranging study was conducted in 12 countries. Patients counted seizures during an 8-week baseline period, and then, if eligible, entered a double-blind phase consisting of a 4-week dose-titration period (target CRS doses: 100, 300, 800, or 1,600 mg/d or placebo in two divided doses) and a 12-week maintenance period. The primary efficacy variable was percent reduction in partial-onset seizure frequency during the double-blind phase compared with pretreatment baseline. Safety data and responder rates were also assessed., Results: Five hundred thirty-seven patients were randomized, and 82% completed the study. In the intent-to-treat population (n = 533), CRS at doses of > or =300 mg/d (p < or = 0.006) reduced the frequency of partial-onset seizures vs placebo: 6% (placebo) vs 24% (300 mg/d), 21% (800 mg/d), and 29% (1,600 mg/d) for CRS. Adverse events consisted primarily of CNS effects, and led to discontinuation of drug in 8% of the placebo group vs 5% (100 mg/d), 6% (300 mg/d), 12% (800 mg/d), and 19% (1,600 mg/d) of the CRS groups., Conclusions: Carisbamate at doses of 300, 800, and 1,600 mg/d was effective as adjunctive therapy for reducing the frequency of partial-onset seizures.

Purpose: To evaluate the effect of age on the disposition of two different oral formulations of carisbamate (RWJ-333369), a novel neuromodulator under investigation., Methods: The disposition of carisbamate was studied in eight men and eight women in each of the three age groups: 18-55, 65-74, and >or= 75 years (N=48). Subjects received single (100mg immediate-release [IR] tablets or 250 mg controlled-release [CR] tablets) or repeated administration (up to 500 mg IR BID or 1250 mg CR QD) of carisbamate in a randomized, double-blind, placebo-controlled, parallel-group, single-center study., Results: After either single or repeated IR administration, no apparent differences were observed between the two elderly and the non-elderly groups. Following single-dose CR administration, the two elderly age groups had higher exposure compared with non-elderly subjects, but the difference decreased for all doses tested after repeated administration. There was no effect of age on plasma protein binding of carisbamate. Renal clearance decreased with age for both formulations, but this decrease had no effect on the total clearance of the drug because of its limited renal elimination., Conclusion: Age had no effect on pharmacokinetics of carisbamate IR formulation. The small effect observed after single-dose CR carisbamate diminished after repeated dosing. The drug was generally safe and well tolerated.

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.

We sought to identify factors associated with excessive weight gain in children treated with valproate, excluding patients fed by gastrostomy or treated with medications known to affect appetite (eg, stimulants). Weight and height were recorded before treatment and at the time of follow-up; a measure of adiposity, body mass index, was computed and expressed in kg/m2, and weight and height for age were converted to Z-score. Putative risk factors included sex, age at start of treatment, monotherapy at start of treatment, duration of follow-up, mental retardation, seizure type (generalized or partial), etiology (idiopathic or cryptogenic versus remote symptomatic), and dose of valproate. Fifty-five children (30 girls, 25 boys), ranging in age at the start of therapy from 1.8 to 16.9 years were followed for 8.6 to 33.8 months. Forty-three patients had primarily generalized seizures, 34 had idiopathic or cryptogenic epilepsy (including 30 with generalized idiopathic epilepsy), and 18 had mental retardation. Valproate was the first antiepileptic drug for 21 patients, and 43 were on monotherapy at the time of follow-up. Height Z-score decreased significantly in girls but was stable in boys. There was a significant increase in body mass index and in weight Z-score. Body mass index was greater than the 90th percentile for age in 14 patients at the start of treatment and in 20 patients at follow-up. Decrease in height Z-score was significantly correlated with female sex and duration of follow-up. Changes in weight Z-score and body mass index were significantly correlated with initial weight Z-score and initial body mass index, respectively, but not with age at start of therapy, duration of follow-up, sex, seizure type, etiology, dose of valproate, or monotherapy.

Objectives: To determine the association between subtherapeutic antiepileptic drug (AED) levels or AED withdrawal and status epilepticus (SE) in children with epilepsy., Methods: We studied the AED levels at the time of SE in 51 consecutive children with epilepsy. Information about prior AED levels, possible etiology of seizures, and acute precipitants was extracted from medical records., Results: The mean age at the time of SE was 5.7 years (range, 3 months through 18 years). Forty-three patients had history of remote insult, five had history of progressive encephalopathy, and three patients were classified as idiopathic. At the time of SE all AED levels were therapeutic in 34 (66%) patients and at least one level was therapeutic in 42 (82%) patients. All levels were subtherapeutic in 9 (18%) patients. Four patients had their AED reduced or discontinued less than 1 week before SE. Twelve patients with therapeutic AED levels on their most recent clinic visit had at least one subtherapeutic level at the time of SE. Eight (16%) patients were febrile and one was hyponatremic. Of the 51 patients, 31 (61%) had no obvious explanation for the development of SE, as all known AEDs were therapeutic and there were no known acute insults., Conclusions: Neurologically abnormal children with preexisting epilepsy are at high risk for development of SE despite having therapeutic AED levels at that time. Acute precipitants of SE, such as fever or AED withdrawal, may play a role in inducing SE only in a minority of patients.