A Phase 2 Randomized Controlled Trial of the Efficacy and Safety of Cannabidivarin as Add-on Therapy in Participants with Inadequately Controlled Focal Seizures

Antiepileptic drug; Cannabinoid; EpilepsyFármaco antiepiléptico; Cannabinoide; EpilepsiaFàrmac antiepilèptic; Cannabinoide; EpilèpsiaObjective: We assessed the efficacy, safety, and tolerability of cannabidivarin (CBDV) as add-on therapy in adults with inadequately controlled focal seizures. Materials and Methods: One hundred and sixty-two participants (CBDV n=81; placebo n=81) were enrolled. After a 4-week baseline, participants titrated from 400 to 800 mg CBDV twice daily (b.i.d.) (or placebo) over 2 weeks, followed by 6 weeks stable dosing (at 800 mg b.i.d.) and a 12-day taper period. The primary endpoint was the change from baseline in focal seizure frequency during the 8-week treatment period. Secondary endpoints included additional efficacy measures relating to seizures, physician- and participant-reported outcomes, change in the use of rescue medication, cognitive assessments, and safety. Results: Median baseline focal seizure frequencies were 17–18 per 28 days in both groups, and similar reductions in frequency were observed in the CBDV (40.5%) and placebo (37.7%) groups during the treatment period (treatment ratio [% reduction] CBDV/placebo: 0.95 [4.6]; confidence interval: 0.78–1.17 [−16.7 to 21.9]; p=0.648). There were no differences between the CBDV and placebo groups for any seizure subtype. There were no significant treatment differences between CBDV and placebo groups for any of the secondary efficacy outcome measures. Overall, 59 (72.8%) of participants in the CBDV group and 39 (48.1%) in the placebo group had ≥1 treatment-emergent adverse event (AE); the 3 most common were diarrhea, nausea, and somnolence. The incidence of serious AEs was low (3.7% in the CBDV group vs. 1.2% in the placebo group). There was little or no effect of CBDV on vital signs, physical examination, or electrocardiogram findings. Elevations in serum transaminases (alanine aminotransferase or aspartate aminotransferase) to levels >3×upper limit of normal occurred in three participants taking CBDV (two discontinued as a result) and one taking placebo; however, none met the criteria for potential Hy's Law cases. Conclusion: It is likely the 40.5% seizure reduction with CBDV represents an appropriate pharmacological response in this population with focal seizures. The placebo response was, however, high, which may reflect the participants' expectations of CBDV, and a treatment difference from placebo was not observed. CBDV was generally well tolerated.The trial was sponsored by GW Research Ltd

Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials

Antiepileptic drug; Antiseizure medication; TolerabilityFármaco antiepiléptico; Medicamento anticonvulsivo; TolerabilidadMedicament antiepilèptic; Medicament anticonvulsiu; TolerabilitatObjective To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug-resistant epilepsy in two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials. Methods The phase 2b dose-finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic–clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4-week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled. Results In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12-week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p-values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: −5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55). Significance In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified

Number needed to treat and associated cost analysis of cenobamate versus third-generation anti-seizure medications for the treatment of focal-onset seizures in patients with drug-resistant epilepsy in Spain

Medicamentos anticonvulsivos; Cenobamato; EficienciaMedicaments anticonvulsius; Cenobamat; EficiènciaAnti-seizure medications; Cenobamate; EfficiencyIntroduction Epilepsy is a serious neurological disease, ranking high in the top causes of disability. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, approximately 40% of patients suffer from Drug-Resistant Epilepsy (DRE) despite the availability of the latest options called third-generation Anti-Seizure Medications(ASMs). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. The introduction of a new drug increases the number of therapeutic options available, making it important to compare it with existing alternatives in terms of clinical benefit and efficiency. Purpose This study aimed to compare the clinical benefit, in terms of the Number Needed to Treat (NNT), and the efficiency, in terms of Cost per NNT (CNT), associated with cenobamate versus third-generation ASMs used in Spain for the adjunctive treatment of FOS in patients with DRE. Methods The Number Needed to Treat data was calculated based on the ≥50% responder rate and seizure freedom endpoints (defined as the percentage of patients achieving 50% and 100% reduction in seizure frequency, respectively), obtained from pivotal clinical trials performed with cenobamate, brivaracetam, perampanel, lacosamide, and eslicarbazepine acetate. The NNT was established as the inverse of the treatment responder rate minus the placebo responder rate and was calculated based on the minimum, mid-range Daily Defined Dose (DDD), and maximum doses studied in the pivotal clinical trials of each ASM. CNT was calculated by multiplying the annual treatment cost by NNT values for each treatment option. Results In terms of NNT, cenobamate was the ASM associated with the lowest values at all doses for both ≥50% responder rate and seizure freedom compared with the alternatives. In terms of CNT, for ≥50% responder rate, cenobamate was the ASM associated with the lowest CNT values at DDD and lacosamide and eslicarbazepine acetate at the minimum and maximum dose, respectively. For seizure freedom, cenobamate was associated with the lowest CNT value at DDD and the maximum dose and lacosamide at the minimum dose. Conclusions Cenobamate could represent the most effective ASM in all doses studied compared to the third-generation ASMs and the most efficient option at DDD for both ≥50% responder rate and seizure freedom. This study could represent an important contribution towards informed decision-making regarding the selection of the most appropriate therapy for FOS in adult patients with DRE from a clinical and economical perspective in Spain.This study was sponsored by Angelini Pharma España, S.L.U

Overnight switch from levetiracetam to brivaracetam: safety and tolerability

Brivaracetam; Epilepsy; TolerabilityBrivaracetam; Epilepsia; TolerabilidadBrivaracetam; Epilèpsia; TolerabilitatBrivaracetam is a newer antiseizure medication than levetiracetam. It has a more selective action on the synaptic vesicle glycoprotein 2A binding site, and it seems to provide a more favorable neuropsychiatric profile. The aim of this study was to assess the safety and tolerability of an overnight switch from levetiracetam to brivaracetam. This was a retrospective descriptive study including patients with epilepsy treated with levetiracetam, who switched due to inefficacy or previous adverse events (AEs). In total, forty-one patients were included (mean age 40.9 ± 17.8 years, women 48.8%). Focal epilepsy represented 75.6% (n = 31) of patients (structural cause [n = 25], unknown cause [n = 6]). Four patients had idiopathic generalized epilepsy, two had developmental and epileptic encephalopathy and four patients were unclassified. The reason to start brivaracetam was inefficacy in 53.7% (n = 22), AEs in 65.9% (25/27 neuropsychiatric) and both in 19.5% (n = 8). Brivaracetam-related AEs were reported in 24.4%. Neuropsychological AEs associated with the previous use of levetiracetam improved in 76% of patients. Treatment was discontinued in 19.5% patients. Patients’ reported seizure frequency improved, worsened and remained stable in 26.8%, 12.2%, and 61.0% of the cases, respectively. An overnight switching to brivaracetam is safe and well tolerated. This treatment can improve levetiracetam-related neuropsychiatric AEs

Epilepsy in Neurodegenerative Diseases: Related Drugs and Molecular Pathways

Alzheimer’s disease; Huntington’s disease; Parkinson’s diseaseEnfermedad de Alzheimer; Enfermedad de Huntington; Enfermedad de ParkinsonMalaltia d'Alzheimer; Malaltia de Huntington; Malaltia de ParkinsonEpilepsy is a chronic disease of the central nervous system characterized by an electrical imbalance in neurons. It is the second most prevalent neurological disease, with 50 million people affected around the world, and 30% of all epilepsies do not respond to available treatments. Currently, the main hypothesis about the molecular processes that trigger epileptic seizures and promote the neurotoxic effects that lead to cell death focuses on the exacerbation of the glutamate pathway and the massive influx of Ca2+ into neurons by different factors. However, other mechanisms have been proposed, and most of them have also been described in other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or multiple sclerosis. Interestingly, and mainly because of these common molecular links and the lack of effective treatments for these diseases, some antiseizure drugs have been investigated to evaluate their therapeutic potential in these pathologies. Therefore, in this review, we thoroughly investigate the common molecular pathways between epilepsy and the major neurodegenerative diseases, examine the incidence of epilepsy in these populations, and explore the use of current and innovative antiseizure drugs in the treatment of refractory epilepsy and other neurodegenerative diseases.A.C. acknowledges the support of the Spanish Ministry of Science, Innovation and Universities under the grant Juan de la Cierva (FJC2018-036012-I). Authors acknowledge the support of the Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated into the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER “Una manera de hacer Europa”) grant PI17/01474 awarded to M.B. Boada, grant PI19/00335 awarded to M.M. and the European Social Fund (ESF “Investing in your future”) for the Sara Borrell Contract (CD19/00232) to SA-L; M.E. acknowledges the support of the Spanish Ministry of Economy and Competitiveness under the project SAF2017-84283-R, and CIBERNED under project CB06/05/0024. E.B.S. acknowledges the support of the Portuguese Science and Technology Foundation (FCT) for the strategic fund (UIDB/04469/2020). A.R. acknowledges the support of CIBERNED (Instituto de Salud Carlos III (ISCIII)), the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, ADAPTED Grant Nº 115975, from EXIT project, EU Euronanomed3 Program JCT2017 Grant Nº AC17/00100, from PREADAPT project. Joint Program for Neurodegenerative Diseases (JPND) Grant No. AC19/00097, and from grants PI13/02434, PI16/01861 BA19/00020, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by Instituto de Salud Carlos III (ISCIII)- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de Hacer Europa”), by Fundación bancaria “La Caixa” and Grífols SA (GR@ACE project)

Determination of the economically justifiable price of cenobamate in the treatment of focal-onset seizures in adult patients with drug-resistant epilepsy in Spain

Anti-seizure medications; Cenobamate; Economically justifiable priceMedicamentos anticonvulsivos; Cenobamato; Precio económicamente justificableMedicaments anticonvulsius; Cenobamat; Preu econòmicament justificableObjective To determine the economically justifiable price (EJP) of cenobamate to become a cost-effective alternative compared with third-generation anti-seizure medications in the treatment of focal-onset seizures (FOS) in adult patients with drug-resistant epilepsy (DRE) in Spain. Methods Cost-effectiveness analysis compared cenobamate with brivaracetam, perampanel, eslicarbazepine acetate, and lacosamide. Markov model simulation of treatment pathway over a 60-year time horizon is presented. We determined the effectiveness and quality-adjusted life-years (QALYs) of health status and disutilities associated with treatment-related adverse events. Acquisition costs and use of medical resources were obtained from published literature and expert opinion. Base-case of cenobamate’s EJP calculated applying a willingness-to-pay (WTP) threshold of €21,000/QALY. Analyses were performed at different thresholds, including dominant price scenario. Result robustness was assessed through sensitivity analyses. Results Base-case shows that cenobamate’s daily EJP of €7.30 is cost-effective for a threshold of €21,000/QALY. At a daily price of €5.45, cenobamate becomes dominant over all treatment alternatives producing cost-savings for the national health system (NHS). Sensitivity analyses supported the robustness of base-case findings. Conclusions Treatment with cenobamate produces incremental clinical benefit over third-generation ASMs, and at the base-case, EJP could represent a cost-effective option for the adjunctive treatment of FOS in adult patients with DRE in Spain

Neuroimagen en epilepsia

El objetivo de este estudio es describir las alteraciones interictales de perfusión en RM por técnica de arterial spin labelled (ASL) y difusión, en pacientes con epilepsia focal y analizar su posible valor lateralizador/localizador del foco epileptógeno. Se trata de un estudio transversal de 53 pacientes adultos con epilepsia focal diagnosticados por semiología, RM y EEG. En todos ellos se realizó una RM de 3 TESLA con protocolo de epilepsia, que incluía secuencias de ASL. Las imágenes fueron sometidas a un análisis visual por un neurorradiólogo, clasificándolas en alteraciones de perfusión hemisféricas o focales. La muestra tenía un 51% de hombres y una edad media de 42.9 años (±16.5). El 60% tenían epilepsias sintomáticas. El 64% eran fármacorresistentes. Las etiologías más frecuentes fueron vascular (15%), malformaciones del desarrollo cortical (15%) y tumoral (13%). Un 45% se clasificaron como epilepsia temporal, 32% frontal y 13% temporal posterior, 8% occipital y 2% parietal. El 45% presentaban crisis parciales complejas, entre las que la semiología automotora era la más frecuente (36%). El ASL mostró, en un 74% de los pacientes, alteraciones de la perfusión interhemisféricas, observándose un valor lateralizador de éstas, especialmente cuando se observa hiperperfusión en la localización del foco y cuando se trata de epilepsia sintomática. Se observaron alteraciones focales en ASL que a pesar de encontrarse en un bajo porcentaje podrían tener valor localizador del área epileptógena

Effect of adjunctive perampanel on the quality of sleep and daytime somnolence in patients with epilepsy

Epilèpsia; Somnolència diürna; Fàrmacs antiepilèpticsEpilepsia; Somnolencia diurna; Fármacos antiepilépticosEpilepsy; Daytime somnolence; Antiepileptic drugsThis prospective uncontrolled study evaluated the effect of low-dose adjunctive perampanel therapy (4 mg/day for 3 months) on the sleep-wake cycle and daytime somnolence in adult patients (n = 10) with focal seizures. A > 50% reduction in the number of seizures was reported in 80% of the study patients; treatment had no significant effect on any sleep parameters as evident by the Maintenance of Wakefulness Test, Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale scores. Two patients reported dizziness with treatment. In conclusion, low-dose perampanel may improve seizure control without affecting the sleep characteristics or daytime somnolence in patients with epilepsy.This work was supported by Eisai Pharmaceuticals, Spain

Malaltia de Parkinson i epilèpsia: criteris d’indicació i tractament quirúrgic

Malaltia de Parkinson; Epilèpsia; TractamentEnfermedad de parkinson; Epilepsia; TratamientoParkinson Disease; Epilepsy; TreatmentInforme d'avaluació sobre el tractament quirúrgic per a la malaltia de Parkinson (MP) i l'epilèpsia. Objectiu general: formular recomanacions de pràctica clínica sobre criteris d’indicació del tractament quirúrgic d’MP i epilèpsia basades en l’evidència científica disponible. Objectius específics: 1. Determinar l’eficàcia, seguretat i eficiència de l’estimulació cerebral profunda (ECP) en el tractament d’MP idiopàtica en pacients amb malaltia de llarga evolució. 2. Determinar l’eficàcia, seguretat i eficiència de les diferents tècniques quirúrgiques en el tractament de l’epilèpsia refractària a tractament farmacològic. 3. Determinar el nombre mínim d’intervencions a realitzar per cada equip multidisciplinari per garantir-ne l’eficiència de la creació de l’equip i la qualitat de la intervenció. 4. Estimar la demanda potencial d’intervencions a realitzar a Catalunya.Report regarding the surgical treatment of Parkinson´s disease (PD) and epilepsy. General objective: to issue clinical practice recommendations regarding criteria for the indication of surgical treatment in PD and epilepsy based on the available scientific evidence. Specific objectives: 1. To determine the efficacy, safety and efficiency of deep brain stimulation (DBS) in the treatment of idiopathic PD in patients with long-lasting disease. 2. To determine the efficacy, safety and efficiency of different surgical techniques in the treatment of epilepsy refractory to drug therapy. 3. To determine the minimum number of interventions to be performed by each multidisciplinary team to ensure the efficiency of the creation of the team and the quality of the intervention. 4. To estimate the potential demand for interventions to be performed in Catalonia.Informe de evaluación sobre el tratamiento quirúrgico para la enfermedad de Parkinson (EP) y la epilepsia. Objetivo general: formular recomendaciones de práctica clínica sobre criterios de indicación del tratamiento quirúrgico de EP y epilepsia basadas en la evidencia científica disponible. Objetivos específicos: 1. Determinar la eficacia, seguridad y eficiencia de la estimulación cerebral profunda (ECP) en el tratamiento de EP idiopática en pacientes con enfermedad de larga evolución. 2. Determinar la eficacia, seguridad y eficiencia de las diferentes técnicas quirúrgicas en el tratamiento de la epilepsia refractaria a tratamiento farmacológico. 3. Determinar el número mínimo de intervenciones a realizar por cada equipo multidisciplinario para garantizar la eficiencia de la creación del equipo y la calidad de la intervención. 4. Estimar la demanda potencial de intervenciones a realizar en Cataluña

Perampanel: A therapeutic alternative in refractory status epilepticus associated with MELAS syndrome

MELAS; Perampanel; Status epilepticusMELAS; Perampanel; Estatus epilèpticMELAS; Perampanel; Status epilépticoTo our knowledge, there are no reports of status epilepticus (SE) associated with mitochondrial diseases and treated with perampanel (PER). We present three cases of patients with refractory SE associated with MELAS syndrome who responded favorably to PER. All cases were diagnosed as non-convulsive SE (focal without impairment of level of consciousness). After an initial treatment with other anti-seizure drugs, PER was added in all cases (8, 16 and 12 mg) and cessation of SE was observed within the next 4-8 hours. All the cases involved a stroke-like lesion present on brain MRI. In our patients, PER was an effective option in SE associated with MELAS syndrome