Efficacy and tolerability of adjunctive lacosamide in patients aged <4 years with focal seizures.

OBJECTIVE: Primary objective was to evaluate efficacy of lacosamide administered concomitantly with 1-3 antiseizure medications in young children with uncontrolled focal (partial-onset) seizures. METHODS: Double-blind, parallel-group trial (SP0967: NCT02477839/2013-000717-20) conducted between June 2015 and May 2020 at hospitals and clinics in 25 countries. Patients (aged ≥1 month to <4 years) with uncontrolled focal seizures were randomized 1:1 to adjunctive lacosamide or placebo using an interactive voice/web response system and stratified by age. After a 20-day titration period, patients who reached target-dose range (8-12 mg/kg/day) entered a 7-day maintenance period. Region-specific primary efficacy variables were based on ≤72-h video-electroencephalograms: change in average daily frequency (ADF) of electrographic focal seizures as measured on end-of-maintenance video-electroencephalogram versus end-of-baseline video-electroencephalogram (United States); 50% responder rate (≥50% reduction in ADF of focal seizures) during maintenance (European Union). RESULTS: In total, 255 patients were randomized (lacosamide/placebo: 128/127) and received ≥1 trial medication dose. Percentage reduction in ADF of focal seizures for lacosamide (116 patients) versus placebo (120 patients) was 3.2% (95% confidence interval = -13.6 to 17.5, p = 0.69). 50% responder rate was 41.4% for lacosamide (116 patients), 37.5% for placebo (120 patients) (p = 0.58). Treatment-emergent adverse events were reported by 44.5% of lacosamide-treated patients (placebo 51.2%). INTERPRETATION: Adjunctive lacosamide did not show superior efficacy versus placebo in young children with focal seizures. However, efficacy variables were potentially affected by high variability and low reliability between readers in video-electroencephalogram interpretation. Lacosamide was generally well tolerated; safety profile was acceptable and consistent with that in adults and children aged ≥4 years.

Efficacy and safety of agomelatine in epilepsy patients with sleep and mood disorders: An observational, retrospective cohort study.

OBJECTIVE: To evaluate the therapeutic efficacy and safety of agomelatine for treating the sleep and mood disorders in epilepsy patients. METHODS: Retrospective data were derived from 113 epilepsy patients for at least 8 weeks. All the subjects were divided into two groups, one was treated with agomelatine, the other was treated with escitalopram. Their depression and anxiety states were assessed by Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) Scales. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The HAMA, HAMD and PSQI scores in both groups significantly declined after the treatments with agomelatine and escitalopram. However, the agomelatine group exhibited greater improvement in terms of HAMA and PSQI scores compared to the escitalopram group. No severe adverse events were observed in agomelatine group. SIGNIFICANCE: Agomelatine performed better in HAMA and PSQI scores compared to escitalopram, where no significant increase in seizure frequency or side effects were observed. Possibly, agomelatine presents a promising therapeutic option for treating the sleep or mood disorders in epilepsy patients.

Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.

BACKGROUND: Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. CASE REPORT: A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. CONCLUSIONS: LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.

Selexipag for the Treatment of Pediatric Pulmonary Hypertension: A Systematic Review.

PURPOSE: To systematically evaluate the safety, dosing regimen, and efficacy of selexipag for pediatric patients with pulmonary hypertension (PH). METHODS: A literature search of the electronic databases of PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar was performed from inception through February 28, 2023. Two reviewers independently searched and evaluated the quality of the studies and pooled data when appropriate. Full-text articles of studies of children diagnosed with PH and treated with selexipag were eligible. Pediatric patients with PH were classified into 2 groups: the add-on therapy group, in which selexipag was used as a third therapy in addition to the baseline treatment, and the transition therapy group, in which patients were switched from parenteral prostacyclin analogs to selexipag. FINDINGS: Fourteen studies involving 58 pediatric patients with PH were included. All studies were either case reports or case series. Overall, 30 and 28 patients were in the add-on and transition therapy groups, respectively. In both groups, selexipag was initially administered as 50-200 µg twice daily and titrated to a tolerated dosage of 200-1,600 µg twice daily. Prostacyclin analogs were simultaneously weaned for patients in the transition group. In the add-on therapy group, 16 patients (80.0%) were at low risk of the World Health Organization functional class (WHO FC I/II), 12 (76.9%) were at low risk of the 6-minute walk distance (6MWD; >350 m), and 21 (95.5%) were at low risk of the pulmonary vascular resistance index (PVRi; <20 WU/m2). Furthermore, N-terminal pro-brain natriuretic peptide and mean pulmonary arterial pressure were significantly improved. More than 70% of patients experienced common tolerable side effects, such as headache, nausea, and diarrhea. In the transition therapy group, 5 patients (55.6%) were at low risk according to WHO FC I/II, 6 (66.7%) were at low risk according to 6MWD, and 14 (87.5) were at low risk according to PVRi; however, selexipag had no significant effect on their hemodynamic parameters. Additionally, more than 80% of patients experienced no side effects. IMPLICATIONS: Selexipag as add-on therapy or for transition from prostacyclin analogs may have a favorable safety profile and potential efficacy for pediatric patients with PH. Further high-quality evidence of the efficacy and safety of selexipag for the treatment of pediatric PH is warranted.

Efficacy and safety of agomelatine in the treatment of patients with depressive disorder: A meta-analysis.

OBJECTIVE: To systematically assess the efficacy and safety of agomelatine in the treatment of patients with depressive disorder. METHODS: Randomized controlled trials (RCTs) related to agomelatine in the treatment of patients with depressive disorder published in PubMed, Web of Science, CNKI, VIP, and Wangfang were retrieved. Extracted data on the efficacy and safety of agomelatine and placebo in the treatment of depressive disorder, and the collected data were processed by RevMan5.4 software. RESULTS: A total of 10 RCTs were included. Meta-analysis showed that the HAMD-17 total scores of agomelatine group were statistically different from those of placebo group (odds ratio [OR]: 2.04, 95% confidence intervals [CIs]: 1.71-2.43, P < .001). High heterogeneity was found between agomelatine groups and placebo groups (P < .0001, and I2 = 78%), so a subgroup analysis was further performed, and the heterogeneity became insignificant (P = .33, and I2 = 14%) after excluding the studies, of which course of treatment was 24 weeks or the sample size was relatively small. The adverse events between agomelatine and placebo groups were not statistically significant (OR: 1.15, 95% CIs: 0.69-1.92; P = .05). CONCLUSION: Agomelatine was superior comparable to placebo in the treatment of patients with depressive disorder, and has fewer adverse events.

Agomelatine augmentation of sertraline in the treatment of moderate to severe obsessive-compulsive disorder: a randomized double-blinded placebo-controlled clinical trial.

BACKGROUND: As 40-60% of the patients with obsessive-compulsive disorder (OCD) do not adequately respond to the first-line treatment, finding an effective second-line treatment is required. Our aim was to assess the efficacy and safety of agomelatine (a selective melatonin receptor agonist and a 5-hydroxytryptamine (HT)2 C antagonist) augmentation of sertraline in the treatment of patients with moderate to severe OCD. METHODS: In this 12-week randomized, double-blinded, placebo-controlled, parallel-group clinical trial, 65 patients with moderate to severe OCD according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth edition (DSM-5) criteria and a Yale-Brown obsessive compulsive scale (Y-BOCS) score of over 21, were included. They were assigned with sertraline (100 mg/day for the first 4 weeks and 200 mg/day for the next 8 weeks) and either agomelatine (25 mg/day) or placebo. The primary outcome was OCD symptoms measured by the Y-BOCS. RESULTS: Fifty patients (24 in agomelatine group and 26 in placebo group) completed the trial. The Y-BOCS scores in total (MD (95% CI) = 12.25 (11.00, 13.49) (P < 0.001) vs. MD (95% CI) = 12.46 (6.65, 15.74) (P < 0.001)), the obsession subscale (MD (95% CI) = 5.04 (4.19, 5.88) (P < 0.001) vs. MD (95% CI) = 5.00 (3.84, 6.16) (P = 0.0001)), and compulsion subscale (MD (95% CI) = 7.21 (6.34, 8.07) (P < 0.001) vs. MD (95% CI) = 7.460 (6.50, 8.42) (P < 0.001)) significantly decreased in both groups. Although, at the end of the trial, no significant difference was observed between the scores of the two groups in total (MD (95% CI) = 0.480 (-1.23, 2.19) (P = 0.78)), the obsession subscale (MD (95% CI) = 1.020 (-0.15, 2.19) (P = 0.38)), and the compulsion subscale (MD (95% CI) = 0.540 (-0.34, 1.42) (P = 0.54)). No major adverse effects were recorded, and the frequency of side effects was not significantly different between the groups. CONCLUSION: Agomelatine in augmentation with sertraline is safe and tolerable in patients with moderate to severe OCD. However, our study does not support its efficacy in improving OCD symptoms, compared to placebo. TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials on 14/07/2020 ( www.irct.ir ; IRCT ID: IRCT20170123032145N5).

Changes of Serum C-Reactive Protein Level in Patients With Depressive Disorders After Treatment With Agomelatine Combined With Aerobic Exercise and Its Significance.

OBJECTIVE: Depressive disorders constitute a series of debilitating diseases. This study investigated the therapeutic effect of agomelatine (AG) combined with aerobic exercise (AE) on patients with moderate-severe depression (MSD) and the changes of the serum C-reactive protein (CRP) level in patients after treatment as well as its significance. METHODS: A total of 178 MSD patients were randomly assigned to the AG group (N = 90) and AG + AE group (N = 88). The severity of depressive disorders and anhedonia was assessed using the Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory, and Snaith-Hamilton Pleasure Scale scores. The serum CRP level in MSD patients was detected by turbidity assay. Patients were defined as remitters, responders, and nonresponders according to the HAM-D 17 score, and the treatment efficacy was analyzed, followed by evaluation of the serum CRP level in patients with different treatment responses. Finally, the adverse reactions of patients during treatment were statistically analyzed. RESULTS: After treatment, the HAM-D, Beck Depression Inventory, and Snaith-Hamilton Pleasure Scale scores and the serum CRP level of the 2 groups were reduced, and changes in the AG + AE group was more significant than that in the AG group. The clinical efficacy of the AG + AE group was better than that of the AG group. After treatment, the serum levels of CRP in remitters and responders were reduced, but not significantly in nonresponders. The incidence of adverse events in the AG + AE group was lower than that in the AG group. CONCLUSION: AG + AE reduced the serum level of CRP in MSD patients and had good therapeutic effects on MSD patients.

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.

Long-term effectiveness and safety of lacosamide as adjunctive therapy in children and adolescents with refractory epilepsy: a real-world study.

PURPOSE: The effectiveness and tolerability of lacosamide (LCM) among Chinese children and adolescents with refractory epilepsy has not yet been established. Therefore, the objective of this study was to assess the effectiveness and tolerability of LCM among children and adolescents with refractory epilepsy in Xinjiang, Northwest China. METHODS: Effectiveness was assessed by measuring changes in seizure frequency at 3, 6 and 12 months compared with baseline. Patients that achieved ≥ 50% reduction in the frequency of all seizures per month, relative to baseline, were considered to be responders. RESULTS: 105 children and adolescents with refractory epilepsy were enrolled in the study. The responder rates were 47.6%, 39.2%, and 31.9%, respectively at 3, 6, and 12 months. Seizure freedom rates were 32.4%, 28.9%, and 23.6% at 3, 6, and 12 months, respectively. The retention rates at 3, 6, and 12 months were 92.4%, 78.1%, and 69.5%, respectively. The maintenance dose of LCM within the responder group (8.2 ± 4.5 mg·kg- 1·d- 1) was significantly higher compared to the non-responder group (7.3 ± 2.3 mg·kg- 1·d- 1) (p < 0.05). At first follow-up, 44 patients (41.9%) reported experiencing at least one treatment-emergent adverse events. CONCLUSION: This real-world study of children and adolescents validated that LCM was both an effective and well-tolerated treatment option for the treatment of refractory epilepsy.

Tolerability and Safety of Lacosamide in Neonatal Population.

Lacosamide is a newer antiepileptic medication used in refractory neonatal seizures with limited safety and efficacy data. This case series spans 4 years and includes 38 neonates cared for in the neonatal, pediatric, and cardiovascular intensive care units, who received lacosamide for refractory seizures. Because lacosamide affects atrioventricular node function in adults, among other metrics, electrocardiogram (ECG) changes were monitored closely in these neonates. Within this cohort, 2 neonates were found to have atrial bigeminy on ECG and telemetry. Otherwise, lacosamide was generally well tolerated with sleepiness being the most common symptom noted. This case series reports data on the tolerability of lacosamide and emphasizes the importance of monitoring key cardiac intervals with ECG before and after the use of lacosamide in this population.

Safety and Tolerability of Intravenous Push Lacosamide and Levetiracetam.

Background: Lacosamide and levetiracetam are antiseizure medications (ASMs) commonly utilized in the treatment and prevention of seizures. Historically, these agents have been administered as slow IV infusions after further dilution. Recent literature suggests that rapid administration via undiluted IV push may be safe and may increase efficiency of administration. Objective: This study aimed to evaluate the safety and tolerability of undiluted IV push lacosamide and levetiracetam over 5 min. Methods: This study was conducted as a single-centered, retrospective, observational cohort that analyzed the rapid administration of undiluted lacosamide and levetiracetam. Adult patients admitted from September 1st, 2019, to May 31st, 2020, receiving at least one administration of IV push lacosamide at any dose or levetiracetam at doses ≤ 1500 mg were evaluated. The primary safety outcomes were the incidence of hypotension and bradycardia. Results: A total of 86 subjects were evaluated; 36 patients were administered lacosamide, and 50 patients were administered levetiracetam. Hypotension or bradycardia occurred in 6 patients in the lacosamide group (16.6%) and 6 patients in the levetiracetam group (12.0%). There were no reported infusion site reactions. Among the subjects who received lacosamide and had a 12-lead electrocardiogram (EKG), there were no reported incidences of a prolonged PR interval. Conclusions: In this safety-analysis cohort, undiluted lacosamide and levetiracetam were not associated with significant adverse events when administered via IV push over 5 min. This seems to be a safe alternative method of administration to intermittent infusion. A larger, prospective cohort is needed to confirm these findings.

Safety and tolerability of short-term infusions of intravenous lacosamide in pediatric patients with epilepsy: An open-label, phase 2/3 trial.

OBJECTIVE: The objective of this study is to evaluate the safety and tolerability of intravenous (IV) lacosamide infusion in patients aged ≥1 month to <17 years with epilepsy. METHODS: This Phase 2/3 open-label trial (EP0060; NCT02710890) enrolled patients in two age cohorts (cohort 1: ≥8 to <17 years; cohort 2: ≥1 month to <8 years). Eligible patients were receiving oral lacosamide as adjunctive treatment or monotherapy (in an open-label long-term trial or by prescription) or were not receiving lacosamide before enrolment. Patients initiated IV lacosamide (2-12 mg/kg/day or 100-600 mg/day; 15-60 minutes infusion) as a replacement for oral lacosamide or as adjunctive treatment. The primary outcomes were treatment-emergent adverse events (TEAEs) and discontinuations due to TEAEs. RESULTS: In total, 103 patients were enrolled and completed the trial; 55 patients were included in cohort 1 (≥8 to <17 years), 48 in cohort 2 (≥1 month to <8 years). During the 4 weeks before screening, 74 (71.8%) patients had focal seizures, 12 (11.7%) had generalized seizures, and two (1.9%) had unclassified seizures. Most patients (74 [71.8%]) initiated lacosamide as adjunctive IV treatment. The mean overall duration of exposure to IV lacosamide was 1.18 days. Seventy-nine (76.7%) patients had one IV lacosamide infusion, 20 (19.4%) had two, one (1.0%) had three, and three (2.9%) had 10 infusions. Overall, five (4.9%) patients had a total of seven TEAEs. The only TEAEs reported in two or more patients were increased blood triglycerides (two [1.9%]). No serious or severe TEAEs were reported, and no patients discontinued due to TEAEs. No TEAEs were considered drug-related by the investigator. No consistent or clinically relevant treatment-related changes from baseline were observed for hematology, clinical chemistry parameters, vital signs, or 12-lead electrocardiograms. SIGNIFICANCE: IV lacosamide was generally well tolerated in pediatric patients (≥1 month to <17 years) with epilepsy, and no new safety concerns were identified.

Dimethyl acetamide and dimethyl sulfoxide associated at glucose and egg yolk for cryopreservation of Pseudoplatystoma corruscans semen

This study aimed to develop a protocol for the cryopreservation of Pseudoplatystoma corruscans semen. For this, mature males were hormonally induced with a single dose of carp pituitary extract (5 mg/kg body weight). Semen was collected and evaluated. Two cryoprotectants were tested to compose the diluents: dimethyl acetamide (DMA) and dimethyl sulfoxide (Me2SO), in two concentrations (8% and 10%), + 5.0% glucose + 10% egg yolk. The semen was diluted in a 1: 4 ratio (semen: extender), packed in 0.5 mL straws and frozen in a dry shipper container in liquid nitrogen vapors. After thawing, sperm kinetics, sperm morphology and DNA integrity of cryopreserved sperm were evaluated. Pseudoplatystoma corruscans males produced semen with sperm motility > 80%. After thawing, all treatments provided semen with total sperm motility > 40%, with no significant difference (P < 0.05) between them, as well as between the other sperm kinetic parameters evaluated. The treatments with DMA provided a smaller fragmentation of the DNA of the gametes. Sperm malformations were identified in both fresh and cryopreserved semen, with a slight increase in these malformations being identified in sperm from thawed P. corruscans semen samples.(AU)

Este estudo teve como objetivo desenvolver um protocolo para a criopreservação do sêmen de Pseudoplatystoma corruscans. Para tal, machos maduros foram induzidos hormonalmente com uma dose única de extrato de hipófise de carpa (5 mg/kg de peso vivo). O sêmen foi coletado e avaliado. Sendo testados para compor os diluentes, dois crioprotetores: dimetil acetamida (DMA) e dimetil sulfóxido (Me2SO), em duas concentrações (8% e 10%), + 5,0% glicose + 10% gema de ovo. O sêmen foi diluído na proporção 1: 4 (sêmen: extensor), embalado em palhetas de 0,5 mL e congelado em container dryshipper em vapores de nitrogênio líquido. Após o descongelamento, foram avaliados os aspectos cinéticos espermáticos, a morfologia espermática e a integridade do DNA dos espermatozoides criopreservados. Os machos de P. corruscans produziram sêmen com motilidade espermática > 80%. Todos os tratamentos proporcionaram após o descongelamento sêmen com motilidade espermática total > 40%, sem diferença significativa (P < 0,05) entre eles, como também entre os demais parâmetros cinéticos espermáticos avaliados. Os tratamentos com DMA proporcionaram uma menor fragmentação do DNA dos gametas. Malformações espermáticas foram identificadas, tanto no sêmen fresco, como no criopreservado, sendo identificado um aumento discreto dessas malformações nos espermatozoides das amostras de sêmen descongeladas de P. corruscans.(AU)

Belumosudil with ROCK-2 inhibition: chemical and therapeutic development to FDA approval for the treatment of chronic graft-versus-host disease.

Belumosudil (BLM) is a ROCK inhibitor that has been firstly developed by Surface Logix, later acquired by Kadmon Pharmaceuticals for the treatment of chronic graft-versus-host disease (cGVHD), Psoriasis Vulgaris (PV), idiopathic pulmonary fibrosis (IPF), hepatic impairment (HI), diffuse cutaneous systemic sclerosis (dcSSc). BLM received a breakthrough therapy designation and priority review from the FDA, which reviewed the NDA under the real-time oncology review (RTOR) pilot programme and approved it six weeks ahead of the PDUFA deadline of August 30, 2021. On July 16th, 2021, The USFDA authorized BLM under the brand name REZUROCKTM for the treatment of cGVHD in adults and pediatric patients aged ≥ 12 years after the failure of at least two prior lines of systemic therapy. It has been granted orphan drug status by the FDA on August 9, 2020, for the treatment of systemic sclerosis. The European Union (EU) granted Quality Regulatory Clinical Ireland Limited, Ireland, orphan drug status for BLM (KD025) for the treatment of cGVHD on October 17, 2019. BLM is under regulatory assessment by Therapeutic Good Administration (TGA) Australia, Health Canada, MHRA (UK), and The Swiss Agency for Therapeutic Products (Swissmedic), Switzerland for cGVHD. A clinical trial is ongoing in the United States for cutaneous systemic sclerosis. This review article summarizes the milestones in the development of BLM chemistry, Chemical synthesis and development, mechanism of action, pharmacokinetics (PK), pharmacodynamics (PD), adverse effects, regulatory status, and ongoing clinical trials (CT) of BLM.

Clinical impact of the dose and blood concentration of lacosamide in Japanese pediatric patients with epilepsy: A cohort study.

PURPOSE: The relationship between treatment efficacy/tolerability and the dose/blood concentration of lacosamide (LCM) was investigated in a clinical cohort of Japanese pediatric patients with epilepsy. METHODS: This retrospective analysis reviewed the medical records of patients treated with LCM for >6 months at the Department of Pediatrics, Hiroshima University Hospital, from September 2017 to January 2021. The collected data included age, sex, epilepsy type, seizure type, seizure frequency before and after treatment initiation, adverse events leading to LCM discontinuation, dose at any evaluation point, serum concentration, and concomitant antiepileptic drugs (AEDs). RESULTS: The study included 51 patients (31 male patients) between the ages of 2 and 19 years. All patients were Japanese. Epilepsy was classified as focal in 44 patients, generalized in six patients, and combined generalized and focal in one patient. The 50% responder rate for LCM treatment was 56.9%. Seven patients experienced complete seizure control (absence of seizures for 6 months before the follow-up visit). A relationship between dose and blood concentration was identified. Although the blood LCM concentration was higher in the responders than in the nonresponders (7.86 vs. 6.16 µg/mL; p = 0.028), there was no significant difference in dose between the two groups. Lacosamide showed efficacy at a dose >5 mg/kg/day in more than half of the 50% responders. The treatment-emergent adverse events (TEAEs) included seizure aggravation in five patients, irritability in two patients, and somnolence and drug eruption in one patient each. In six patients with TEAEs, the TEAEs developed within 1 month after treatment initiation and led to LCM discontinuation. CONCLUSION: In Japanese pediatric patients with epilepsy, LCM treatment is effective, particularly at higher doses. The blood concentration may be related more to efficacy than to dose. Lacosamide is generally well-tolerated by pediatric patients, and should be used at the maximum tolerable dose (needed to be gradually increased) in patients with otherwise insufficient seizure control. As TEAEs leading to discontinue treatment likely occur in early phase, it is needed to monitor patients carefully if TEAEs would happen in that phase.

Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries.

BACKGROUND: Major depressive disorder is a severe illness that frequently manifests before the age of 18 years, often recurring later in life. Paediatric medical treatment options are scarce. The melatonin receptor agonist and 5-hydroxytryptamine2C receptor antagonist agomelatine is used to treat adults, and could offer a new therapeutic option for paediatric patients. Therefore, we aimed to investigate the short-term antidepressant efficacy and safety of agomelatine in children and adolescents with major depressive disorder. METHODS: We performed a 12 week, randomised, double-blind, parallel-group, multicentre, phase 3 trial in 46 specialist psychiatric units or centres in Bulgaria, Finland, Hungary, Poland, Romania, Russia, Serbia, South Africa, and Ukraine. Participants (aged 7-17 years) were eligible if they were unresponsive to psychosocial therapy during the 3-week run-in period (Children's Depression Rating Scale-revised [CDRS-R] score of ≥45). Ethnicity was not recorded. We investigated short-term antidepressant efficacy of agomelatine (10 mg or 25 mg per day) versus placebo with an active control (fluoxetine 10-20 mg depending on symptom severity) after 12 weeks of treatment in children (aged 7-11 years) and adolescents (12-17 years) with major depressive disorder. Patients were randomly assigned (1:1:1:1) to agomelatine 10 mg, agomelatine 25 mg, placebo, or fluoxetine via an interactive response system with permuted-block randomisation. Standardised manualised psychosocial counselling, developed for this trial, was initiated from selection and continued throughout the study, including the open-label extension. All people involved in the conduct of the clinical trial and patients were masked to treatment allocation. Study outcomes were measured using standardised interviews at each study visit. The primary endpoint was change in CDRS-R raw score from baseline to week 12. This study is registered with EudraCT, 2015-002181-23. FINDINGS: Between Feb 23, 2016, and Jan 14, 2020, 466 individuals were assessed for eligibility and of 400 included patients, 396 (247 [62%] girls, 149 [38%] boys; mean age 13·7 years [SD 2·7]) were analysed (full analysis set). The primary objective was met; 25 mg/day agomelatine (n=94, with n=102 receiving 10 mg/day) resulted in an improvement versus placebo (n=101) in CDRS-R raw score of 4·22 (95% CI 0·63-7·82; p=0·040) at 12 weeks, with a similar effect for fluoxetine (n=99), establishing assay sensitivity. The overall effect was confirmed in adolescents (n=317), but not in children (n=79). No unexpected safety signals were observed with agomelatine, with no significant weight gain or effect on suicidal behaviours. INTERPRETATION: This first study in a paediatric population supports the efficacy of 25 mg/day agomelatine, in addition to psychosocial counselling, in treating adolescent patients with major depressive disorder, with no unexpected safety signals. This medication could provide another option in the limited psychopharmaceutical repertoire for management of major depressive disorder. FUNDING: Servier. VIDEO ABSTRACT.

Phase 1 Maximal Use Pharmacokinetic Study of Tirbanibulin Ointment 1% in Subjects With Actinic Keratosis.

Tirbanibulin is a novel tubulin polymerization and Src kinase signaling inhibitor. This study was designed to fully characterize tirbanibulin pharmacokinetics (PK) when applied topically under maximal use conditions. This was an open-label, parallel-group PK safety study of tirbanibulin ointment 1% applied to 25 cm2 of the face or balding scalp in adults with actinic keratosis (AK). Eligible subjects self-applied tirbanibulin once-daily for 5 days. PK sampling occurred on days 1, 3 and 4 at 0 hour (before dosing), and on day 5 at prespecified time points up to 24 hours after application. Safety assessments included adverse events and local skin reactions were evaluated up to day 29. Eighteen subjects (face or scalp, n = 9 each) completed the study. Subjects were White (100%), of mean [range] age 66.4 [43-83] years, predominantly men (83.3%) with Fitzpatrick skin type I to III (94.4%); baseline AK lesion count, mean [range] 8.2 [6-14]. All subjects had quantifiable but low plasma concentrations of tirbanibulin. On day 5, overall mean (standard deviation) maximum concentration (Cmax ) was 0.26 (0.23) ng/mL (or 0.60 nM), median time to maximum concentration was 6.91 hours, and mean (standard deviation) area under the plasma concentration-time curve from time 0 to 24 hours was 4.09 (3.15) ng ∙ h/mL. Four subjects experienced a total of 5 treatment-emergent adverse events that resolved. Mild to moderate erythema, flaking, or scaling in the treatment area peaked around day 8 before resolving or returning to baseline by day 29. In conclusion, under maximal use conditions, tirbanibulin ointment 1% for 5 days in the treatment of AK on the face or scalp was well tolerated and resulted in low systemic exposure with subnanomolar plasma concentrations.

Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension.

INTRODUCTION: In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag. METHODS: Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019. RESULTS: Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively. CONCLUSIONS: These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306.