Efficacy, safety, and tolerability of adjunctive brivaracetam in adult Asian patients with uncontrolled focal-onset seizures: A phase III randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Evaluate efficacy, safety, and tolerability of adjunctive brivaracetam (BRV) in adult Asian patients with focal-onset seizures (FOS). METHODS: Phase III, randomized, double-blind, placebo-controlled study (EP0083; NCT03083665) evaluating BRV 50 mg/day and 200 mg/day in patients (≥16-80 years) with FOS with/without secondary generalization (focal to bilateral tonic-clonic seizures) despite current treatment with 1 or 2 concomitant antiseizure medications. Following an 8-week baseline, patients were randomized 1:1:1 to placebo, BRV 50 mg/day, or BRV 200 mg/day, and entered a 12-week treatment period. Efficacy outcomes: percent reduction over placebo in 28-day FOS frequency (primary); 50% responder rate in FOS frequency; median percent reduction in FOS frequency from baseline; seizure freedom during treatment period (secondary). Primary safety endpoints: incidences of treatment-emergent adverse events (TEAEs); TEAEs leading to discontinuation; serious TEAEs. RESULTS: In this study, 448/449 randomized patients (mean age, 34.5 years; 53.8% female) received ≥1 dose of study medication (placebo/BRV 50 mg/BRV 200 mg/day: n = 149/151/148). Percent reduction over placebo in 28-day adjusted FOS frequency was 24.5% (p = 0.0005) and 33.4% (p < 0.0001) with BRV 50 mg/day and 200 mg/day, respectively, 50% responder rate was 19.0%, 41.1%, and 49.3% with placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p < 0.0001 for both BRV groups vs. placebo). Median percent reduction in FOS frequency from baseline was 21.3%/38.9%/46.7% in patients on placebo/BRV 50 mg/BRV 200 mg/day, respectively. Overall, 0, 7 (4.6%), and 10 (6.8%) patients were classified as seizure-free during the treatment period on placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p = 0.0146/p = 0.0017 for BRV 50 mg/200 mg/day vs. placebo, respectively). TEAE incidences were similar between patients on placebo (58.4%) and all patients receiving BRV (58.5%); TEAE incidences for BRV 50 mg/day and BRV 200 mg/day were 57.0% and 60.1%, respectively. Overall, 0.7% of patients on placebo and 2.0% of all patients on BRV reported serious TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 1.3% and 2.7%, respectively), 20.1% of patients on placebo and 33.1% of all patients on BRV reported drug-related TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 26.5% and 39.9%, respectively), and 4.7% of patients on placebo and 3.0% of all patients on BRV discontinued due to TEAEs (discontinuation incidences for BRV 50 mg/day and BRV 200 mg/day were 2.6% and 3.4%, respectively). SIGNIFICANCE: Adjunctive BRV was efficacious and well tolerated in adult Asian patients with FOS. Efficacy and safety profiles were consistent with BRV studies in predominantly non-Asian populations. PLAIN LANGUAGE SUMMARY: Brivaracetam is used to treat partial or focal seizures in people with epilepsy. Most studies with brivaracetam tablets have involved people from non-Asian racial backgrounds. In this study, 449 Asian adults with epilepsy took part. One third took 50 mg of brivaracetam, one third took 200 mg of brivaracetam, and one third took a placebo each day for 12 weeks. On average, those who took brivaracetam had fewer seizures than those given the placebo. Most of the side effects were mild and the number and type of side effects seen were as expected for this medication.

Sorption of Cs+ and Eu3+ ions onto sedimentary rock in the presence of gamma-irradiated humic acid.

The influence of humic acid (HA) and its radiological degradation on the sorption of Cs+ and Eu3+ by sedimentary rock (obtained from the Horonobe Underground Research Laboratory in Japan) was investigated to understand the sorption process of metal ions and humic substances. Aldrich HA solution was gamma-irradiated assuming a strong radiation from a highly radioactive waste to be disposed of in deep geological formations. Batch sorption experiments were performed to evaluate the effect of gamma-irradiated HA on the sorption of Cs+ and Eu3+ ions. The addition of non-irradiated HA weakened the Eu sorption because of the lower sorption of the negatively charged Eu-HA complexes compared with free Eu ions. The sorption of Cs ions was barely affected by the presence of HA and its gamma irradiation. The concentration ratio of metal complexed and non-complexed species in the solid and liquid phases was evaluated by sequential filtration and chemical equilibrium calculations. The ratios were low in both phases for Cs and supported the minimal contribution of HA to Cs sorption. However, the concentration ratio for Eu3+ in the liquid phase was high, indicating that the complexing ability of HA to Eu3+ was higher than that of HA to Cs+.

Safety and efficacy of adjunctive lacosamide in Chinese and Japanese adults with epilepsy and focal seizures: A long-term, open-label extension of a randomized, controlled trial.

This Phase III, long-term, open-label extension (OLE) trial (EP0009; NCT01832038) was conducted to evaluate the long-term safety, tolerability, and efficacy of adjunctive lacosamide (100-400 mg/day) in Chinese and Japanese people with epilepsy (PWE) (16-70 years) who had completed a double-blind, randomized, placebo-controlled trial of adjunctive lacosamide (EP0008; NCT01710657). PWE entered the OLE trial on 200 mg/day lacosamide and up to 3 concomitant antiseizure medications. Dose adjustments were permitted to optimize tolerability and seizure reduction. Safety variables were treatment-emergent adverse events (TEAEs) and discontinuations due to TEAEs. Efficacy variables were percent change in focal seizure frequency per 28 days from Baseline of the double-blind trial, ≥50 % and ≥75 % responder rates, seizure-freedom, and proportion of PWE on lacosamide monotherapy. Overall, 473 PWE (74.0 % Chinese and 26.0 % Japanese) were enrolled; 238 (50.3 %) PWE completed the trial and 235 (49.7 %) discontinued, most commonly due to lack of efficacy (81 [17.1 %]), adverse events (55 [11.6 %]), and consent withdrawn (49 [10.4 %]). During the trial, PWE received lacosamide for a median of 1016.0 days (∼3 years), with a total exposure of 1454.8 person-years; 321 (67.9 %) PWE received lacosamide for >24 months, and 246 (52.0 %) for >36 months. The median modal dose of lacosamide was 300 mg/day. Overall, 410/473 (86.7 %) PWE reported TEAEs, 244 (51.6 %) had a TEAE that was considered drug-related, and 49 (10.4 %) discontinued due to a TEAE. The most common TEAEs (≥20 % of PWE) were nasopharyngitis, dizziness, and upper respiratory tract infection. The median reduction in focal seizure frequency per 28 days from Baseline was 57.1 %, and the ≥50 % and ≥75 % responder rates were 57.1 % (269/471) and 29.7 % (140/471), respectively. Among PWE who completed 12, 24, and 36 months of treatment, the 12-, 24-, and 36-month seizure-freedom rates were 3.5 % (13/375), 3.4 % (11/321), and 2.0 % (5/247), respectively. Among PWE exposed to lacosamide for ≥6 months and ≥12 months, the proportions of PWE that maintained continuous monotherapy for ≥6 months and ≥12 months were 5.0 % (21/421) and 5.0 % (19/378), respectively. Overall, lacosamide was well-tolerated as long-term adjunctive therapy in Chinese and Japanese PWE and uncontrolled focal seizures, with improvements in seizure reduction maintained over 36 months of treatment.