Safety of intravenous lacosamide in hospitalized children and neonates.

OBJECTIVE: Seizures are common in critically ill children and neonates, and these patients would benefit from intravenous (IV) antiseizure medications with few adverse effects. We aimed to assess the safety profile of IV lacosamide (LCM) among children and neonates. METHODS: This retrospective multicenter cohort study examined the safety of IV LCM use in 686 children and 28 neonates who received care between January 2009 and February 2020. RESULTS: Adverse events (AEs) were attributed to LCM in only 1.5% (10 of 686) of children, including rash (n = 3, .4%), somnolence (n = 2, .3%), and bradycardia, prolonged QT interval, pancreatitis, vomiting, and nystagmus (n = 1, .1% each). There were no AEs attributed to LCM in the neonates. Across all 714 pediatric patients, treatment-emergent AEs occurring in >1% of patients included rash, bradycardia, somnolence, tachycardia, vomiting, feeling agitated, cardiac arrest, tachyarrhythmia, low blood pressure, hypertension, decreased appetite, diarrhea, delirium, and gait disturbance. There were no reports of PR interval prolongation or severe cutaneous adverse reactions. When comparing children who received a recommended versus a higher than recommended initial dose of IV LCM, there was a twofold increase in the risk of rash in the higher dose cohort (adjusted incidence rate ratio = 2.11, 95% confidence interval = 1.02-4.38). SIGNIFICANCE: This large observational study provides novel evidence demonstrating the tolerability of IV LCM in children and neonates.

A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren's syndrome.

OBJECTIVES: This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren's syndrome (PSS). METHODS: Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies. RESULTS: Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: -2.59 (95% CI: -7.30, 2.11; P=0.266) and -1.55 (95% CI: -3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo. CONCLUSION: Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation. TRIAL REGISTRATION: https://clinicaltrials.gov, NCT02610543.

Efficacy and safety of adjunctive lacosamide in the treatment of primary generalised tonic-clonic seizures: a double-blind, randomised, placebo-controlled trial.

OBJECTIVE: To evaluate efficacy and safety of lacosamide (up to 12 mg/kg/day or 400 mg/day) as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients (≥4 years) with idiopathic generalised epilepsy (IGE). METHODS: Phase 3, double-blind, randomised, placebo-controlled trial (SP0982; NCT02408523) in patients with IGE and PGTCS taking 1-3 concomitant antiepileptic drugs. Primary outcome was time to second PGTCS during 24-week treatment. RESULTS: 242 patients were randomised and received ≥1 dose of trial medication (lacosamide/placebo: n=121/n=121). Patients (mean age: 27.7 years; 58.7% female) had a history of generalised-onset seizures (tonic-clonic 99.6%; myoclonic 38.8%; absence 37.2%). Median treatment duration with lacosamide/placebo was 143/65 days. Risk of developing a second PGTCS during 24-week treatment was significantly lower with lacosamide than placebo (Kaplan-Meier survival estimates 55.27%/33.37%; HR 0.540, 95% CI 0.377 to 0.774; p<0.001; n=118/n=121). Median time to second PGTCS could not be estimated for lacosamide (>50% of patients did not experience a second PGTCS) and was 77.0 days for placebo. Kaplan-Meier estimated freedom from PGTCS at end of the 24-week treatment period (day 166) for lacosamide/placebo was 31.3%/17.2% (difference 14.1%; p=0.011). More patients on lacosamide than placebo had ≥50% (68.1%/46.3%) or ≥75% (57.1%/36.4%) reduction from baseline in PGTCS frequency/28 days, or observed freedom from PGTCS during treatment (27.5%/13.2%) (n=119/n=121). 96/121 (79.3%) patients on lacosamide had treatment-emergent adverse events (placebo 79/121 (65.3%)), most commonly dizziness (23.1%), somnolence (16.5%), headache (14.0%). No patients died during the trial. CONCLUSIONS: Lacosamide was efficacious and generally safe as adjunctive treatment for uncontrolled PGTCS in patients with IGE.

Randomized open-label trial of intravenous brivaracetam versus lorazepam for acute treatment of increased seizure activity.

OBJECTIVE: The objective of the present trial was to assess efficacy and safety of intravenous (IV) brivaracetam (BRV) vs. lorazepam (LZP) in patients with epilepsy undergoing evaluation in an epilepsy monitoring unit (EMU) who experienced seizures requiring acute treatment. METHODS: This was a phase 2, open-label, randomized, active-control, proof-of-concept trial (EP0087; NCT03021018). Patients (18-70 years) admitted to EMU were randomized 1:1:1 to single-dose bolus IV LZP (dose per investigator's practice), IV BRV 100 mg, or IV BRV 200 mg. Trial medication had to be administered within 30 min of qualifying seizure. Primary efficacy outcome was time to next seizure (clinical observation with electroencephalogram [EEG] confirmation) or to rescue medication use within 12 h of trial medication administration. Secondary outcomes included seizure freedom and rescue medication use within 12 h of trial medication administration. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Overall, 46 patients were randomized, and 45 received trial medication for a qualifying seizure. Patients in the LZP arm had doses from 1 to 4 mg (median: 1 mg). Eleven of 45 patients had a seizure within 12 h of trial medication administration (LZP 5/15 [median time to next seizure: 5.55 h], BRV 100 mg 3/15 [5.97 h], BRV 200 mg 3/15 [3.60 h]). No patients received additional rescue medication to control their qualifying seizure. Most patients were seizure-free over 12 h (LZP 9/15 [60.0%], BRV 100 mg 12/15 [80.0%], BRV 200 mg 12/15 [80.0%]). Rescue medication use within 12 h was numerically higher for LZP (6/15 [40.0%]) vs. BRV 100 mg (1/15 [6.7%]) and vs. BRV 200 mg (2/15 [13.3%]). Treatment-emergent adverse events were reported by 5/16 (31.3%), 6/15 (40.0%), and 3/15 (20.0%) of LZP, BRV 100 mg, and BRV 200 mg patients; one LZP patient had a serious TEAE (seizure cluster). Most common TEAEs (≥10% of patients) were sedation and somnolence with LZP, and dizziness, headache, and nausea with BRV. SIGNIFICANCE: Intravenous LZP, IV BRV 100 mg, and IV BRV 200 mg showed similar efficacy in controlling acute seizure activity in the EMU. Treatment-emergent adverse events were as expected for each medication. Although this trial should be interpreted with caution because of small patient numbers, it suggests a possible role of BRV in the acute treatment of increased seizure activity.

Long-term exposure and safety of lacosamide monotherapy for the treatment of partial-onset (focal) seizures: Results from a multicenter, open-label trial.

OBJECTIVE: To assess long-term use and safety of lacosamide (LCM) ≤800 mg/day monotherapy in patients with partial-onset seizures (POS) enrolled previously in a historical-controlled, conversion-to-monotherapy study (SP902; NCT00520741). METHODS: Patients completing or exiting SP902 with LCM as monotherapy or as adjunctive therapy were eligible to enter this 2-year open-label extension (OLE) trial (SP904; NCT00530855) at a starting dose ±100 mg/day of their final SP902 dose. Investigators could adjust the LCM dose to 100-800 mg/day and add up to two antiepileptic drugs to optimize tolerability and seizure reduction. RESULTS: Three hundred twenty-two patients received LCM: 210 patients (65.2%) completed and 112 (34.8%) discontinued, most commonly owing to withdrawal of consent (9.3%). Two hundred fifty-eight patients (80.1%) had ≥1 year of and 216 (67.1%) had ≥2 years of LCM exposure, of whom 179/258 (69.4%) achieved LCM monotherapy lasting for any 12-month period, and 126/216 (58.3%) patients exposed for ≥24 months achieved LCM monotherapy for any 24-month period. Total exposure = 525.5 patient-years. The median modal dose was 500 mg/day. Two hundred ninety-two patients (90.7%) achieved LCM monotherapy at some point during the study. Sixty-five of 87 patients who exited and 193/235 who completed SP902 were exposed for ≥12 months, and 43.1% and 78.2%, respectively, achieved LCM monotherapy for ≥12 months. Median LCM monotherapy duration was 587.0 days (2-791 days); 91.0% of patients reported treatment-emergent adverse events, of which the most common were dizziness (27.3%), headache (17.1%), and nausea (14.3%). Compared with the SP902 study baseline, 74.2% of patients had a ≥50% seizure reduction and 5.6% were seizure-free at 24 months. SIGNIFICANCE: The majority of patients were receiving LCM monotherapy at 0, 12, and 24 months in this OLE. Lacosamide monotherapy (median dose of 500 mg/day) had a safety profile similar to that of adjunctive therapy studies. These results support the use of lacosamide as long-term monotherapy treatment for adults with POS.

Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study.

OBJECTIVE: To evaluate the efficacy and safety of conversion to lacosamide 400 mg/day monotherapy in adults with focal epilepsy. METHODS: This historical-controlled, double-blind study (NCT00520741) enrolled patients aged 16-70 years on stable doses of 1-2 antiepileptic drugs (AEDs) and experiencing 2-40 partial-onset seizures per 28 days during the 8-week prospective Baseline. Patients were randomized to lacosamide 400 or 300 mg/day (3:1 ratio), starting at 200 mg/day and titrated over 3 weeks to randomized dose. Patients then withdrew background AEDs over 6 weeks and entered a 10-week Monotherapy Phase. The primary assessment was the Kaplan-Meier-predicted percentage of patients on 400 mg/day in the full analysis set (FAS) meeting ≥ 1 predefined seizure-related exit criterion by day 112, compared with the historical-control threshold (65.3%). RESULTS: Four hundred twenty-five patients were enrolled and were eligible for safety analyses (400 mg/day, n = 319; 300 mg/day, n = 106). A total of 271 (63.8%) of 425 patients completed the Lacosamide Maintenance Phase (combined AED Withdrawal and Monotherapy Phases). Among 284 patients in the 400 mg/day group in the FAS, 82 (28.9%) met ≥ 1 exit criterion; the Kaplan-Meier-predicted exit percentage at day 112 for 400 mg/day (30.0%; 95% confidence interval [CI] 24.6-35.5%) was lower than the historical control. When exit events, withdrawal due to treatment-emergent adverse events (TEAEs), and withdrawal due to lack of efficacy were summed (n = 90), the predicted exit percentage (32.3%; 95% CI 26.8-37.8%) was also lower than the historical control. Most patients receiving 400 mg/day reported some improvement on the Clinical Global Impression of Change (75.4%) and Patient Global Impression of Change (74.3%). Overall, the most common (>10%) TEAEs were dizziness (24.0%), headache (14.4%), nausea (13.4%), convulsion (11.5%), somnolence (10.4%), and fatigue (10.1%); most (74.1%) were mild-to-moderate in intensity. Seventy-two patients (16.9%) discontinued due to TEAEs. Seventeen patients (4%, all receiving 400 mg/day) experienced serious AEs. SIGNIFICANCE: Lacosamide 400 mg/day monotherapy was effective, with a favorable safety profile in patients with focal epilepsy.

Certolizumab Pegol for the Treatment of Plaque Psoriasis in Routine Clinical Practice: One-Year Results from the CIMREAL Study.

INTRODUCTION: Certolizumab pegol (CZP) is an anti-tumor necrosis factor alpha (TNFα) approved for the treatment of moderate to severe plaque psoriasis (PSO). However, data on its real-world use is currently limited. The objective of this study was to describe the 1-year real-world effectiveness of CZP, its impact on health-related quality of life (HRQoL), and safety outcomes in patients with moderate to severe PSO in multi-country settings. METHODS: CIMREAL, a prospective, noninterventional study, was conducted across Europe and Canada from August 2019 to December 2022. Patients were followed for 1-year, receiving CZP 400 mg initial doses at weeks 0, 2, and 4, followed by CZP 200 mg every 2 weeks (Q2W) or CZP 400 mg Q2W maintenance dosing. Effectiveness was assessed using the Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI). Safety was also evaluated. RESULTS: Overall, 399 patients with moderate to severe PSO were included. Of these, 93.7% (374/399) and 77.9% (311/399) completed months 3 and 12, respectively. Mean age (± standard deviation) was 42.9 ± 13.5 years and body mass index was 28.5 ± 6.8 kg/m2, with the majority of patients being female (68.2%). At 12 months, CZP showed substantial effectiveness, achieving PASI 75 and PASI 90 response rates (≥ 75% and ≥ 90% improvement from baseline, respectively) of 77% and 56.5%, respectively. Patients with PASI score of ≤ 3 and ≤ 2 experienced improvement from 3 months (49.8% and 41.1%, respectively) to 12 months (82.0% and 75.3%, respectively). HRQoL considerably improved, with mean DLQI scores decreasing from 12.4 to 2.3 after 12 months of treatment, and the proportion of patients with DLQI 0/1 increased from 28.6% at 3 months to 59.4% at 12 months. The 1-year probability of persistence was approximately 85%. Overall, 30.6% of the patients experienced any adverse events and 9.3% had serious adverse events. CONCLUSION: In routine clinical practice, CZP exhibited consistent effectiveness, positively impacting both skin psoriasis activity and HRQoL. The 1-year persistence of CZP was high, and no new safety signals were identified. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04053881 https://www. CLINICALTRIALS: gov/study/NCT04053881 .

Assessment of the effects of lacosamide on sleep parameters in healthy subjects.

PURPOSE: Seizures and antiepileptic drugs (AED) may disrupt sleep patterns in patients with epilepsy, thus evaluation of lacosamide effects on objective and subjective sleep measures is warranted. METHODS: A multicenter, interventional, open-label study (NCT01530386) was conducted in healthy subjects without confounding effects of concomitant AED use, co-morbidities, or disease state to determine whether lacosamide impacts sleep parameters after 22 days of lacosamide exposure. After overnight polysomnography (PSG) to assess baseline parameters, lacosamide was initiated at 100mg/day (50mg twice daily) and increased by 100mg/day weekly to 300 mg/day (the mid-range maintenance dose for adjunctive therapy). The primary variable was change from baseline to post-treatment in wake after sleep onset (WASO). Secondary variables included additional objective sleep measures, subject-reported measures of sleep quality, daytime sleepiness, and tolerability. Change from baseline in WASO was analyzed using the Wilcoxon rank-sum test. RESULTS: A total of 27 subjects received ≥1 dose of lacosamide and 25 subjects completed the study. For WASO, median change from baseline was a 6-min reduction (95% confidence interval: -38, 77.5; p=0.1074) after lacosamide treatment; this was considered not clinically relevant. No clinically relevant changes were observed in any secondary variables. Thirteen subjects (48%) reported a treatment-emergent adverse event, none of which was severe or led to study discontinuation. CONCLUSION: Lacosamide 300 mg/day had no effect on objective or subjective sleep parameters in healthy subjects and was generally well tolerated.

Cognitive trauma therapy for battered women with PTSD (CTT-BW).

This article describes a second treatment-outcome study of cognitive trauma therapy for battered women with posttraumatic stress disorder (PTSD; CTT-BW). CTT-BW includes trauma history exploration: PTSD education; stress management; exposure to abuse and abuser reminders; self-monitoring of negative self-talk; cognitive therapy for guilt; and modules on self-advocacy, assertiveness, and how to identify perpetrators. One hundred twenty-five ethnically diverse women were randomly assigned to immediate or delayed CTT-BW. PTSD remitted in 87% of women who completed CTT-BW, with large reductions in depression and guilt and substantial increases in self-esteem. White and ethnic minority women benefited equally from CTT-BW. Similar treatment outcomes were obtained by male and female therapists and by therapists with different levels of education and training. Gains were maintained at 3- and 6-month follow-ups.

Effect of a blueberry nutritional supplement on macronutrients, food group intake, and plasma vitamin E and vitamin C in US athletes.

Antioxidants from a blueberry beverage may impact plasma vitamins. We examined vitamins/food selection in 12 college athletes during 30 days compared with placebo. Blood was collected before and after exercise at the beginning of the study (day 1) and then after a 30-day period of taking a daily supplemental beverage (day 30). The six trials involved blood that was drawn pre-beverage ingestion/pre-exercise (trials 1 and 4), post-beverage ingestion/pre-exercise (trials 2 and 5), and post-beverage ingestion/1 h post-exercise (trials 3 and 6), on day 1 (trials 1, 2, and 3) and day 30 (trials 4, 5, and 6). Analysis of variance revealed non-significant differences for macronutrient or gamma-tocopherol and vitamin C intakes by food frequency questionnaire or plasma vitamins by liquid chromatography. There was a trend (P = 0.083) in the group x time interaction for alpha-tocopherol intake by repeated-measures analysis of variance. Blueberry alpha-tocopherol (23.91 +/- 9.31 mg) was significantly (P < 0.05) higher than placebo alpha-tocopherol intake (7.59 +/- 0.95 mg) on day 1, but not on day 30 (blueberry, alpha-tocopherol = 9.04 +/- 2.35 mg, placebo, alpha-tocopherol = 11.46 +/- 3.65 mg) by pairwise comparisons. Blueberry supplementation did not affect plasma vitamin concentrations or gamma-tocopherol and vitamin C intakes, and may reduce alpha-tocopherol intake in those starting with a higher alpha-tocopherol intake, yet not altering athletes' eating habits.

Monoclonal antibody HCV-AbXTL68 in patients undergoing liver transplantation for HCV: results of a phase 2 randomized study.

A randomized, double-blind, dose-escalation study evaluated the safety and efficacy of hepatitis C virus (HCV)-Ab(XTL)68, a neutralizing, high-affinity, fully human, anti-E2 monoclonal antibody, in 24 HCV-positive patients undergoing liver transplantation. HCV-Ab(XTL)68 or placebo was administered at doses from 20-240 mg as 2-4 infusions during the first 24 hours after transplantation, followed by daily infusions for 6 days, weekly infusions for 3 weeks, and either 2 or 4 weekly infusions for 8 weeks. Serum concentrations of total anti-E2 obtained during daily infusions of 120-240 mg HCV-Ab(XTL)68 were 50-200 microg/mL above concentrations in the placebo group. Median serum concentration of HCV RNA dropped below baseline in all groups immediately after transplantation. On day 2, median change from baseline in HCV RNA was -1.8 and -2.4 log in the 120-mg and 240-mg groups, respectively, compared with -1.5 log with placebo. The difference was lost after day 7 when the dosing frequency was reduced. The coincidence of increases in anti-E2 with decreases in HCV RNA concentration indicate that the dose-related changes in HCV RNA concentration were a result of HCV-Ab(XTL)68 administration in the 120- and 240-mg groups. The overall incidence of nonfatal serious adverse events was higher with placebo (60%) vs. all active treatments combined (42%). In conclusion, HCV-Ab(XTL)68 may decrease serum concentrations of HCV RNA in patients after liver transplantation. Studies evaluating more frequent daily dosing at doses >120 mg are necessary to investigate sustained viral suppression in this population.