RESUMEN
OBJECTIVES: To evaluate long-term efficacy, safety, and tolerability, including behavior and executive functioning, during adjunctive lacosamide (LCM) treatment in pediatric patients (≥1 month to <18 years of age) with focal-onset or generalized seizures enrolled in 2 open-label, long-term follow-up trials. METHODS: Two open-label extension trials (SP848: NCT00938912; EP0034: NCT01964560) were conducted in pediatric patients who had participated in previous trials of adjunctive LCM (SP0847/NCT00938431; SP0966/NCT01969851; EP0060/NCT02710890; SP0967/NCT02477839; SP0969/NCT01921205); SP848 also directly enrolled eligible pediatric patients who had not previously participated in a clinical trial of LCM. Outcomes included retention, efficacy, and safety/tolerability. Patient improvement was assessed with Clinician's and Caregiver's Global Impression of Change scale. Behavior and emotional function was assessed with Achenbach Child Behavior Checklist (CBCL) and executive functioning was assessed with Behavior Rating Inventory of Executive Function® (BRIEF). RESULTS: The pooled dataset from both trials included 905 patients (851 in the focal-onset seizure population and 47 in the generalized seizure population). In the overall population, Kaplan-Meier-estimated 1-year retention was 80 %. From baseline to the end of the treatment period, patients in the focal-onset seizure population had a median percent reduction in focal-onset seizure frequency per 28 days of 60.4 %, 55.4 % of patients were 50 % responders, and 40.8 % of patients were 75 % responders. In patients with ≥12 months of LCM treatment, ≥12 month seizure freedom during the LCM treatment period was achieved by 29.9 % of patients in the focal-onset seizure population (median duration of first ≥12-month seizure-free interval: 641 days) and 24.4 % of patients in the generalized seizure population (median duration of first ≥12-month seizure-free interval: 665 days). Improvement during LCM treatment was reported in >75 % of patients by both physicians and caregivers. Treatment-emergent adverse events (TEAEs) were reported by 749 (82.8 %) patients, most commonly pyrexia (18.9 %), upper respiratory tract infection (18.6 %), nasopharyngitis (16.2 %), vomiting (15.7 %), and somnolence (11.8 %). The most common drug-related TEAEs were somnolence (8.5 %), dizziness (7.6 %), and vomiting (5.4 %). Behavioral and emotional function was generally stable in patients 1.5-5 years of age and slightly improved in patients ≥6 years of age, and executive functioning was stable in patients <5 years of age and generally slightly improved in patients 5-18 years of age. CONCLUSIONS: In this analysis of a large patient pool from 2 open-label trials, long-term adjunctive LCM was efficacious and generally well tolerated in children with epilepsy and focal-onset or generalized seizures. Behavior and executive functioning were generally stable without observable worsening during long-term adjunctive LCM treatment.
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Anticonvulsivantes , Función Ejecutiva , Lacosamida , Humanos , Lacosamida/administración & dosificación , Lacosamida/uso terapéutico , Lacosamida/efectos adversos , Niño , Femenino , Masculino , Función Ejecutiva/efectos de los fármacos , Función Ejecutiva/fisiología , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/administración & dosificación , Adolescente , Preescolar , Resultado del Tratamiento , Lactante , Epilepsia/tratamiento farmacológico , Epilepsia/psicología , Acetamidas/efectos adversos , Acetamidas/administración & dosificación , Acetamidas/uso terapéutico , Estudios de SeguimientoRESUMEN
OBJECTIVE: We previously analyzed data from three phase lll trials of adjunctive brivaracetam (BRV) in adults showing that the incidence and prevalence of drug-related central nervous system treatment-emergent adverse events (TEAEs) quickly peaked and decreased over several weeks following BRV treatment initiation. However, that analysis did not assess psychiatric and behavioral side effects which can occur with antiseizure medication (ASM) treatment. Here, we investigate the time-course of psychiatric and behavioral TEAEs by week of BRV treatment and how these TEAEs were managed. METHODS: Data were pooled from three trials (N01252 [NCT00490035]; N01253 [NCT00464269]; N01358 [NCT01261325]) in adult patients (≥16 years of age) with focal-onset seizures receiving BRV adjunctive therapy. This post hoc analysis reports data on the incidence and prevalence of drug-related psychiatric or behavioral TEAEs over time in patients who received BRV doses of 50-200 mg/day (without titration) or placebo (PBO) during the 12-week treatment period. A logistic regression model was used to determine if psychiatric or behavioral comorbid conditions were predictors for drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. RESULTS: A total of 803 patients received BRV 50-200 mg/day, and 459 patients received PBO. Drug-related psychiatric or behavioral TEAEs were reported by 11.0 % of patients during adjunctive BRV treatment (PBO: 4.8 %) with onset early after BRV initiation (median time to onset of first drug-related psychiatric or behavioral TEAE: 15 days). Incidence peaked at week 1 and decreased over the first 4 weeks following BRV initiation. Prevalence peaked at week 4 and then remained stable between weeks 5-12. In an analysis excluding patients on concomitant levetiracetam (BRV: n = 744; PBO: n = 422), the incidence of drug-related psychiatric or behavioral TEAEs was similar to the incidence in the overall population. The most common drug-related psychiatric or behavioral TEAEs were irritability, insomnia, depression, and anxiety. Only 2 % of patients discontinued BRV due to psychiatric or behavioral TEAEs (PBO: 1.3 %), while most patients on BRV who reported drug-related psychiatric or behavioral TEAEs did not require a change in dose (84.1 %; PBO: 63.6 %). A history of psychiatric or behavioral comorbid conditions (not ongoing at BRV initiation) was not associated with an increased likelihood of drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. Ongoing psychiatric or behavioral comorbid conditions at BRV initiation increased the likelihood of drug-related psychiatric or behavioral TEAEs, but not the likelihood of BRV discontinuation due to psychiatric or behavioral TEAEs. CONCLUSIONS: Drug-related psychiatric and behavioral TEAEs occurred early during BRV treatment, and most patients did not require a change in BRV dose. These data can help guide clinician monitoring and patient expectations after starting BRV.
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Anticonvulsivantes , Pirrolidinonas , Convulsiones , Humanos , Masculino , Adulto , Femenino , Anticonvulsivantes/efectos adversos , Pirrolidinonas/efectos adversos , Pirrolidinonas/administración & dosificación , Pirrolidinonas/uso terapéutico , Persona de Mediana Edad , Convulsiones/inducido químicamente , Convulsiones/epidemiología , Trastornos Mentales/epidemiología , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/inducido químicamente , Factores de Tiempo , Adulto Joven , Método Doble Ciego , Epilepsias Parciales/tratamiento farmacológico , Anciano , AdolescenteRESUMEN
INTRODUCTION: This article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure medications (ASMs) taken as part of their treatment regimen. METHODS: This was a post hoc analysis of pooled data from double-blind, placebo-controlled trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in patients with uncontrolled focal-onset seizures randomized to BRV (50-200 mg/day) or placebo on the most common concomitant ASMs at trial initiation. RESULTS: Nine concomitant ASMs were analyzed: carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), oxcarbazepine (OXC), topiramate (TPM), phenytoin (PHT), lacosamide (LCM), clobazam (CLB), and phenobarbital (PHB). Reduction over placebo in focal-onset seizure frequency per 28 days with BRV ranged from 11.7% (concomitant OXC) to 33.5% (concomitant PHB). The median percentage reduction from baseline in focal-onset seizure frequency per 28 days ranged from 25.5% to 42.8% in patients on BRV (placebo 4.4-21.2%); 50% responder rates ranged from 31.9% to 44.9% in patients on BRV (placebo 11.4-25.2%). In patients on BRV, seizure freedom ranged from 1.4% (concomitant PHT) to 12.5% (concomitant LCM); seizure freedom ranged from 0% to 1.2% in patients on placebo. All efficacy endpoints analyzed were consistently numerically higher in patients on BRV versus placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was generally similar across subgroups by specific concomitant ASMs in patients on BRV (range 60.8-74.5%) or placebo (range 53.8-66.7%). Drug-related TEAEs were numerically higher across all subgroups by concomitant ASM in patients on BRV (range 35.2-48.3%) versus placebo (range 23.9-37.1%). Discontinuations due to TEAEs ranged from 2.9% to 13.3% in patients on BRV and was 0-5.7% for patients taking placebo across subgroups. CONCLUSION: BRV was efficacious and well tolerated regardless of the specific concomitant ASMs used as part of their treatment regimen. These data show that in patients with focal-onset seizures, BRV provides additional efficacy to a broad range of ASMs.
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Anticonvulsivantes , Pirrolidinonas , Convulsiones , Adulto , Humanos , Resultado del Tratamiento , Quimioterapia Combinada , Convulsiones/tratamiento farmacológico , Convulsiones/inducido químicamente , Anticonvulsivantes/efectos adversos , Lacosamida/uso terapéutico , Método Doble CiegoRESUMEN
PURPOSE: Temporal lobe epilepsy (TLE) is often associated with drug-resistant seizures. We evaluated the efficacy and tolerability of lacosamide (LCM) versus controlled-release carbamazepine (CBZ-CR) monotherapy in adults with newly diagnosed TLE. METHODS: Exploratory post hoc analysis of patients with temporal focus of localization (indicated as the only localization focus) in a double-blind, noninferiority, phase 3 trial (SP0993; NCT01243177) in patients aged ≥ 16 years with newly diagnosed epilepsy randomized 1:1 to LCM or CBZ-CR monotherapy. RESULTS: Of 886 treated patients in this trial, temporal lobe focus of localization (TLE) was reported as the single focus for 287 (32.4%) patients (LCM 134, CBZ-CR 153). A similar proportion of patients with TLE on LCM (82 [61.2%]) and CBZ-CR (99 [64.7%]) completed the trial. Kaplan-Meier estimates for 6- and 12-month seizure freedom at the last evaluated dose level (stratified by number of seizures in the 3 months before screening [≤2 or >2 seizures]) were similar with LCM and CBZ-CR (6 months overall: 88.7% and 89.7%; 12 months overall: 78.3% and 81.7%). Treatment-emergent adverse events (TEAEs) were reported by fewer patients on LCM (73.9%) than CBZ-CR (81.0%). Drug-related TEAEs (assessed by the investigator) were reported in 41.8% of patients on LCM and 52.3% of patients on CBZ-CR; 11.2% of patients on LCM and 15.0% on CBZ-CR discontinued due to TEAEs. CONCLUSION: Lacosamide was efficacious and generally well tolerated as monotherapy in patients with TLE with efficacy outcomes comparable with CBZ-CR, and fewer patients on LCM reported any TEAEs, drug-related TEAEs, or discontinued due to TEAEs.
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Anticonvulsivantes , Epilepsia del Lóbulo Temporal , Adulto , Humanos , Anticonvulsivantes/efectos adversos , Benzodiazepinas , Carbamazepina/efectos adversos , Preparaciones de Acción Retardada/efectos adversos , Método Doble Ciego , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Lacosamida , Convulsiones/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate long-term retention, reasons for discontinuation, efficacy, tolerability, and health-related quality of life (HRQOL) during adjunctive brivaracetam (BRV) treatment in adults with focal seizures by number of lifetime antiseizure medications (ASMs). METHODS: Post hoc analyses of a randomized, double-blind, placebo-controlled trial (N01358; NCT01261325) and corresponding open-label extension (OLE) (N01379; NCT01339559) of adjunctive BRV in adults (16-80 years of age) with focal seizures. Outcomes were assessed from the first day of BRV treatment in the double-blind (patients randomized to BRV) or open-label trial (patients randomized to placebo) by number of lifetime ASMs (1-2, 3-4, 5-6, or ≥ 7). Lifetime ASMs were defined as previous (stopped before BRV initiation) and concomitant ASMs at BRV initiation. RESULTS: Seven hundred and forty patients received adjunctive BRV (safety set [SS]; median modal dose: 200 mg/day [N = 737]; median treatment duration: 2.67 years), of whom 13.8 % had 1-2, 20.8 % had 3-4, 21.1 % had 5-6 and 44.3 % had ≥7 lifetime ASMs. Patients with a higher number of lifetime ASMs had a younger age at epilepsy onset, longer epilepsy duration, and higher baseline seizure frequency. Kaplan-Meier estimated retention on BRV at 12 (83.2-65.9 %) and 36 months (63.0-44.1 %) was highest in patients with 1-2 lifetime ASMs and decreased with the number of lifetime ASMs. The estimated proportions of patients who discontinued BRV due to lack of efficacy or treatment-emergent adverse events (TEAEs) increased with the number of lifetime ASMs. Efficacy analyses included seven hundred and thirty eight patients (intention-to-treat set [ITT]). Median percentage reductions from baseline in focal seizure frequency/28 days (76.3-39.6 %), 50 % responder rates (66.7-39.8 %), 75 % responder rates (51.0-19.6 %), and continuous seizure freedom for ≥12 months at any time during BRV treatment (35.3-6.1 %) were highest in patients with 1-2 lifetime ASMs and decreased by the number of lifetime ASMs. The overall incidence of TEAEs (SS) was generally similar in each lifetime ASM subgroup (84.4-90.5 %). Discontinuations due to TEAEs increased with the number of lifetime ASMs (7.8-20.1 %). The greatest improvements in QOLIE-31-P scores occurred in the Seizure Worry and Daily Activities/Social Function subscales, with no clear pattern by the number of lifetime ASMs at 12 months and with the highest improvement in patients with 1-2 lifetime ASMs at 24 months. At 24 months, the Hospital Anxiety and Depression Scale (HADS) Anxiety subscale scores improved in patients (SS) with 1-2 and 3-4 lifetime ASMs. HADS Depression subscale scores were generally stable independent of the number of lifetime ASMs. CONCLUSIONS: The balance between efficacy, tolerability, and HRQOL was most favorable in patients with focal seizures who had been exposed to one or two ASMs before BRV initiation. However, patients exposed to ≥7 ASMs before BRV initiation also benefitted from long-term adjunctive BRV treatment.
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Anticonvulsivantes , Epilepsia , Adulto , Humanos , Anticonvulsivantes/efectos adversos , Método Doble Ciego , Epilepsia/tratamiento farmacológico , Epilepsia/inducido químicamente , Pirrolidinonas/efectos adversos , Calidad de Vida , Convulsiones/tratamiento farmacológico , Convulsiones/inducido químicamente , Resultado del TratamientoRESUMEN
OBJECTIVE: This study was undertaken to evaluate safety/tolerability and efficacy of adjunctive brivaracetam (BRV) in patients on one or two concomitant antiseizure medications (ASMs) and in patients on one specific concomitant ASM. METHODS: Post hoc analysis was made of double-blind trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in adults with focal seizures randomized to BRV (50-200 mg/day; approved therapeutic dose range for adults) or placebo with concomitant ASM regimen unchanged throughout a 12-week evaluation period. Outcomes were analyzed in patients on one or two concomitant ASMs, and those on concomitant carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), or valproate (VPA) only. RESULTS: Patients randomized to BRV with one or two concomitant ASMs, respectively (n = 181/557), reported similar incidences of treatment-emergent adverse events (TEAEs; 68.0%/66.4%), drug-related TEAEs (41.4%/41.5%), and TEAEs leading to discontinuation (6.6%/5.4%). Respective values for patients randomized to placebo with one or two concomitant ASMs (n = 95/331) were 60.0%/60.7% (TEAEs), 32.6%/30.2% (drug-related TEAEs), and 2.1%/4.5% (TEAEs leading to discontinuation). The incidences of TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation by specific concomitant ASM (CBZ, LTG, OXC, VPA) were similar to the overall incidences in patients taking one concomitant ASM. In patients on one or two concomitant ASMs, respectively, 50% responder rates were numerically higher on BRV (42.3%/36.8% [n = 175/511]) versus placebo (18.3%/19.5% [n = 93/298]). Patients with one or two ASMs on BRV (n = 175/509) versus placebo (n = 92/298) also had numerically higher 100% responder rates (BRV, 9.1%/4.5%; placebo, 1.1%/.3%) and seizure freedom (6.9%/3.7%; 1.1%/0). For patients taking concomitant CBZ, LTG, OXC, or VPA, efficacy was numerically higher with BRV (n = 54/30/27/27) versus placebo (n = 34/13/10/14-15; 50% responder rates: BRV, 31.5%/30.0%/40.7%/70.4%; placebo, 17.6%/7.7%/20.0%/33.3%; 100% responder rates: BRV, 5.6%/10.0%/11.1%/11.1%; placebo, 0 for all; seizure freedom: BRV, 3.7%/6.7%/7.4%/11.1%; placebo, 0 for all). SIGNIFICANCE: Therapeutic doses of BRV were efficacious and well tolerated regardless of the number of concomitant ASMs (one or two) or specific concomitant ASM (CBZ, LTG, OXC, VPA).
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Pirrolidinonas , Convulsiones , Adulto , Anticonvulsivantes/efectos adversos , Carbamazepina/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Humanos , Lamotrigina/uso terapéutico , Oxcarbazepina/uso terapéutico , Pirrolidinonas/efectos adversos , Convulsiones/tratamiento farmacológico , Resultado del TratamientoRESUMEN
This post hoc analysis was conducted to evaluate the efficacy, tolerability, and health-related quality of life during long-term adjunctive brivaracetam (BRV) treatment in adult patients with focal to bilateral tonic-clonic seizures (FBTCS). Patients (≥ 16 years) were included in this post hoc analysis if they were randomized to BRV or placebo in double-blind, placebo-controlled (N01252 [NCT00490035], N01253 [NCT00464269], N01358 [NCT01261325]; core) trials, and received adjunctive BRV in the corresponding long-term follow-up (N01125 [NCT00175916], N01199 [NCT00150800], N01379 [NCT01339559]) trials, and reported FBTCS during the 8-week prospective baseline (core trial). Efficacy (concomitant levetiracetam excluded) and tolerability (concomitant levetiracetam included) were assessed from the first day of BRV in patients who initiated BRV at 50-200 mg/day. Two hundred and eighty-four patients reported FBTCS during baseline (core trials) and were included in the Efficacy Set. Patients (mean age of 37.0 years; 51.8% male; mean epilepsy duration of 22.4 years; median baseline frequency of 2.8 FBTCS per 28 days) received BRV for a median treatment duration of 2.5 years (range< 0.1-11.3) at a median modal dose of 150 mg/day. BRV was discontinued by 175 (61.6%) patients, most commonly (≥ 10% of patients) due to adverse event (18.3%), lack of efficacy (18.3%), and consent withdrawn (11.6%); the median time to discontinuation of BRV due to any reason was 358.5 days. The Kaplan-Meier (KM)-estimated retention on BRV at 1, 3, and 5 years, were 69.3%, 48.2%, and 37.3%, respectively. The KM-estimated proportion of patients not discontinuing BRV due to lack of efficacy or adverse event were 80.0%, 63.9%, and 57.2% at 1, 3, and 5 years, respectively. Overall, the median percentage reduction in FBTCS frequency from baseline was 76.2%, and the 50% and 75% responder rates for FBTCS were 68.7% and 50.7%, respectively, which were sustained over time across completer cohorts. Sustained 50%, 75%, and 100% response in FBTCS from day 1 of adjunctive BRV treatment during the entire first year was estimated for 32.5%, 21.1%, and 15.0% of patients, respectively (KM analysis), and showed maintenance or improvement in the response to BRV over time. For patients with ≥ 1 year of BRV exposure, 51.3% were free from FBTCS for ≥ 1 year during any time of the treatment period, and 22.8% of patients did not report FBTCS during the first year from the first day of treatment. Clinically meaningful improvements in total Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score were reported by 43.6% and 46.4% of patients after 1 and 2 years of treatment, respectively. The largest improvements in the QOLIE-31-P score, with > 50% of patients reporting a clinically meaningful improvement, were observed in the seizure worry and daily activities/social functioning subscales after 1 and 2 years of BRV treatment. Overall, 278/313 (88.8%; Safety Set) patients reported at least one treatment-emergent adverse event (TEAE), 170 (54.3%) had a drug-related TEAE, 88 (28.1%) had a serious TEAE, and 55 (17.6%) discontinued BRV due to a TEAE. Overall, long-term adjunctive BRV was generally well tolerated and reduced the frequency of FBTCS in adults, with 22.8% of patients (who completed ≥ 1 year of treatment) not reporting any FBTCS during the first year from the first day of BRV treatment.
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Anticonvulsivantes , Calidad de Vida , Adulto , Anticonvulsivantes/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Estudios Prospectivos , Pirrolidinonas/efectos adversos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVE: The effects of anticonvulsants on lipids are the subject of considerable concern and investigation, but there are almost no data on this issue from randomized trials. We evaluated serum lipid profiles in adults with newly diagnosed epilepsy, following randomization to lacosamide (LCM) or carbamazepine (CBZ) monotherapy. METHODS: We analyzed data from a Phase 3, international, randomized, double-blind trial of LCM vs CBZ for the initial treatment of focal epilepsy. Serum lipid profiles in patients not taking lipid-lowering agents and providing blood samples under fasting conditions before treatment, and following 3 or 12 months of treatment with LCM or CBZ at various doses were analyzed. RESULTS: At 12 months, 271 patients satisfied the inclusion criteria for the analysis. No change was observed in LCM-treated patients for total cholesterol, cholesterol fractions, or triglycerides. CBZ-treated patients showed an increase of 21.1 mg/dL in total cholesterol, 12.6 mg/dL in low-density lipoprotein (LDL) cholesterol, 12.5 mg/dL in non-high density lipoprotein (non-HDL) cholesterol, and 8.5 mg/dL in HDL cholesterol; triglycerides remained unchanged. The proportion of patients with elevated total cholesterol levels (above the upper limit of the reference range) did not change in the LCM treatment group (37.0% at Baseline; 34.8% at 12 months), but increased from 30.8% (at Baseline) to 49.6% (at 12 months) in the CBZ treatment group. SIGNIFICANCE: This study provides Class II evidence that CBZ elevates serum lipids, whereas LCM has no effect on lipids. It supports LCM as an appropriate choice for new-onset focal epilepsy.
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Anticonvulsivantes/uso terapéutico , Carbamazepina/uso terapéutico , Epilepsia/tratamiento farmacológico , Lacosamida/uso terapéutico , Lípidos/sangre , Anticonvulsivantes/efectos adversos , Carbamazepina/efectos adversos , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Método Doble Ciego , Epilepsia/sangre , Humanos , Lacosamida/efectos adversos , Triglicéridos/sangreRESUMEN
OBJECTIVE: To evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal seizures by the number of lifetime (previous and concomitant) antiepileptic drugs (AEDs). METHODS: Post-hoc analysis of data from N01358 (NCT01261325), a randomized, double-blind, placebo (PBO)-controlled Phase III trial evaluating BRV 100 and 200 mg/day in patients ≥16 years of age with uncontrolled focal seizures. Efficacy and tolerability outcomes were assessed for the 12-week Treatment Period in subgroups of patients with 1-2, 3-4, 5-6, or ≥7 lifetime AEDs. RESULTS: 764 patients received at least one dose of trial medication (BRV: 503; PBO: 261; Safety Set), of whom 14.3% had 1-2, 20.8% had 3-4, 21.3% had 5-6, and 43.6% had ≥7 lifetime AEDs. In all lifetime AED subgroups, >85% of patients completed the trial. Patients with a higher number of lifetime AEDs had a younger age at epilepsy onset, longer epilepsy duration, and higher baseline seizure frequency. In patients on BRV, 50% responder rates were 49.3%, 44.4%, 47.2% and 27.4% in patients with 1-2 (n = 75), 3-4 (n = 99), 5-6 (n = 108) and ≥7 (n = 219) lifetime AEDs; 75% responder rates were 36.0%, 21.2%, 22.2% and 12.3%. In patients on PBO, 50% responder rates were 35.3%, 25.9%, 20.4% and 15.9% in patients with 1-2 (n = 34), 3-4 (n = 58), 5-6 (n = 54) and ≥7 (n = 113) lifetime AEDs; 75% responder rates were 26.5%, 6.9%, 3.7% and 4.4%. The Kaplan-Meier estimated probability of patients achieving a sustained 50% or 75% response from the first day of treatment was generally higher in patients with a lower number of lifetime AEDs (both in patients on BRV and PBO). In patients on adjunctive BRV, the incidence of drug related treatment-emergent adverse events (TEAEs) was 34.7%, 26.0%, 44.4% and 47.7% in patients with 1-2 (n = 75), 3-4 (n = 100), 5-6 (n = 108) and ≥7 (n = 220) lifetime AEDs; the incidence of discontinuations due to TEAEs was 1.3%, 3.0%, 8.3% and 10.5%. CONCLUSIONS: This post-hoc analysis suggests a numerically higher response to adjunctive BRV in patients with fewer lifetime AEDs. The lowest response was observed in patients with ≥7 lifetime AEDs, although these patients could also benefit from adjunctive BRV treatment. Patients with fewer lifetime AEDs had lower discontinuation of BRV due to TEAEs.
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Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Pirrolidinonas/uso terapéutico , Convulsiones/tratamiento farmacológico , Adolescente , Adulto , Método Doble Ciego , Quimioterapia Combinada/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To assess tolerability and efficacy of lacosamide in adults with cerebrovascular epilepsy etiology (CVEE). MATERIALS AND METHODS: Exploratory post hoc analyses of a double-blind, initial monotherapy trial of lacosamide vs carbamazepine-controlled release (carbamazepine-CR) (SP0993; NCT01243177); a double-blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741); and an observational study of adjunctive lacosamide added to one antiepileptic drug (SP0973 VITOBA; NCT01098162). Patients with CVEE were identified based on epilepsy etiology recorded at baseline. RESULTS: In the initial monotherapy trial, 61 patients had CVEE (lacosamide: 27; carbamazepine-CR: 34). 20 (74.1%) patients on lacosamide (27 [79.4%] on carbamazepine-CR) reported treatment-emergent adverse events (TEAEs), most commonly (≥10%) headache, dizziness, and fatigue (carbamazepine-CR: headache, dizziness). A numerically higher proportion of patients on lacosamide than carbamazepine-CR completed 6 months (22 [81.5%]; 20 [58.8%]) and 12 months (18 [66.7%]; 17 [50.0%]) treatment without seizure at last evaluated dose. In the conversion to monotherapy trial, 26/30 (86.7%) patients with CVEE reported TEAEs, most commonly (≥4 patients) dizziness, convulsion, fatigue, headache, somnolence, and cognitive disorder. During lacosamide monotherapy, 17 (56.7%) patients were 50% responders and six (20.0%) were seizure-free. In the observational study, 36/83 (43.4%) patients with CVEE reported TEAEs, most commonly (≥5%) fatigue and dizziness. Effectiveness was assessed for 75 patients. During the last 3 months, 60 (80%) were 50% responders and 42 (56.0%) were seizure-free. CONCLUSIONS: These exploratory post hoc analyses suggested lacosamide was generally well tolerated and effective in patients with CVEE, with data from the initial monotherapy trial suggesting numerically better efficacy than carbamazepine-CR.
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Anticonvulsivantes/uso terapéutico , Trastornos Cerebrovasculares/complicaciones , Trastornos Cerebrovasculares/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Epilepsia/etiología , Lacosamida/uso terapéutico , Adolescente , Adulto , Anciano , Carbamazepina/uso terapéutico , Trastornos Cerebrovasculares/diagnóstico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Epilepsia/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Psychiatric comorbidities are common in patients with epilepsy. A double-blind noninferiority monotherapy trial (SP0993; NCT01243177) enrolled newly diagnosed patients (≥16 years) with focal or generalized tonic-clonic seizures. Patients were randomized 1:1 to lacosamide or carbamazepine controlled-release (carbamazepine-CR). Here, we report data from an exploratory post hoc analysis of patients who reported ongoing psychiatric conditions (Medical Dictionary for Regulatory Activities System Organ Class). Of 886 treated patients in the trial, 126 (14.2%; 64 on lacosamide; 62 on carbamazepine-CR) reported at least one ongoing psychiatric condition at screening, most commonly depression (38.1%), insomnia (27.8%), and anxiety (26.2%). In this subgroup, 32/64 (50.0%) patients on lacosamide and 22/62 (35.5%) on carbamazepine-CR completed the trial. The most common reasons for discontinuation in patients on lacosamide and carbamazepine-CR were adverse events (10.9%, 24.2%) and lack of efficacy (18.8%, 11.3%). Treatment-emergent adverse events (TEAEs) were reported in 52 (81.3%) of patients on lacosamide and 56 (90.3%) of patients on carbamazepine-CR, most commonly (≥10% patients in either treatment group; lacosamide, carbamazepine-CR) dizziness (12.5%, 16.1%), headache (12.5%, 14.5%), nasopharyngitis (12.5%, 9.7%), fatigue (7.8%, 14.5%), nausea (7.8%, 11.3%), somnolence (1.6%, 12.9%), and gamma-glutamyltransferase increase (1.6%, 12.9%). Overall, 15 (23.4%) lacosamide-treated and 10 (16.1%) carbamazepine-CR treated patients reported psychiatric TEAEs, most commonly (≥3 patients in either treatment group; lacosamide, carbamazepine-CR) depression (4.7%, 0) and anxiety (3.1%, 6.5%). There were no reports of psychotic disorder, epileptic psychosis, acute psychosis, or serious psychiatric TEAEs. Stratified Kaplan-Meier estimates for 6- and 12-month seizure freedom at the last evaluated dose were similar with lacosamide and carbamazepine-CR (6 months 81.0%, 75.6%; 12 months 62.5%, 66.6%). A higher proportion of patients on lacosamide than carbamazepine-CR completed 6 (67.2%, 45.2%) and 12 months (50.0%, 37.1%) of treatment at the last evaluated dose without a seizure. This exploratory post hoc analysis indicated that lacosamide monotherapy was efficacious and generally well tolerated in patients with newly diagnosed epilepsy and concomitant psychiatric conditions. In this subpopulation, lacosamide showed similar efficacy and numerically better effectiveness than carbamazepine-CR.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Carbamazepina/uso terapéutico , Preparaciones de Acción Retardada/uso terapéutico , Epilepsia/tratamiento farmacológico , Lacosamida/uso terapéutico , Adulto , Anciano , Anticonvulsivantes/administración & dosificación , Ansiedad/complicaciones , Carbamazepina/administración & dosificación , Carbamazepina/efectos adversos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Depresión/complicaciones , Método Doble Ciego , Epilepsia/complicaciones , Femenino , Humanos , Lacosamida/administración & dosificación , Lacosamida/efectos adversos , Masculino , Persona de Mediana Edad , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures. METHODS: In this double-blind trial (SP0969; NCT01921205), patients (age ≥4-<17 years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide/placebo. After a 6-week titration, patients who reached the target dose range for their weight (<30 kg: 8-12 mg/kg/d oral solution; ≥30-<50 kg: 6-8 mg/kg/d oral solution; ≥50 kg: 300-400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance. RESULTS: Three hundred forty-three patients were randomized; 306 (lacosamide 152 of 171 [88.9%]; placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1%; placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% (p = 0.0003). During maintenance, median percent reduction in focal seizure frequency per 28 days was 51.7% for lacosamide and 21.7% for placebo. Fifty percent responder rates (≥50% reduction) were 52.9% and 33.3% (odds ratio 2.17, p = 0.0006). During treatment, treatment-emergent AEs were reported by 67.8% lacosamide-treated patients (placebo 58.1%), most commonly (≥10%) somnolence (14.0%, placebo 5.2%) and dizziness (10.5%, placebo 3.5%). CONCLUSIONS: Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures. CLINICALTRIALSGOV IDENTIFIER: NCT01921205. CLASSIFICATION OF EVIDENCE: This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Lacosamida/administración & dosificación , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Adolescente , Anticonvulsivantes/sangre , Niño , Preescolar , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Lacosamida/sangre , Masculino , Estudios Prospectivos , Convulsiones/sangre , Resultado del TratamientoRESUMEN
OBJECTIVE: The online PatientsLikeMe® Epilepsy Community allows patients with epilepsy to record, monitor, and share their demographic, disease, and treatment characteristics, providing valuable insights into patient perceptions and understanding of epilepsy. The objective of this retrospective analysis was to characterize the profile of users and their disease and identify factors predictive of poor health-related quality of life (HRQoL), while assessing the platform's potential in providing patient-reported data for research purposes. METHODS: Data recorded (January 2010-November 2011) by Epilepsy Community members, with an epilepsy diagnosis and who reported >1 seizure, included the following: sociodemographic and disease characteristics, treatments, symptoms, side effects perceived as medication-related, seizure occurrence, and standardized questionnaires (Quality of Life in Epilepsy Inventory [QOLIE-31/P], EuroQoL 5-Dimensions Scale, 3 Levels [EQ-5D-3L], and Hospital Anxiety and Depression Scale [HADS]). Univariate and multivariate logistic regressions were conducted to identify predictors of poor HRQoL. RESULTS: During the study period, the Epilepsy Community comprised 3073 patients, of whom 71.5% were female, had a mean age of 37.8years, and had a mean epilepsy duration of 17.7years. The most frequently reported moderate/severe symptoms (n=2135) included memory problems (60.2%), problems concentrating (53.8%), and fatigue (50.0%). Medication-related side effects (n=639) included somnolence (23.2%), fatigue (17.2%), and memory impairment (13.8%). The QOLIE-31/P scores (n=1121) were significantly worse in patients who experienced a recent seizure. For QOLIE-31/P, highly predictive factors for poor HRQoL included the following: mild/moderate problems concentrating, depression, memory problems, treatment side effects, occurrence of tonic-clonic seizures, and epilepsy duration ≤1year. For EQ-5D-3L, highly predictive factors for poor HRQoL included the following: pain, depression, and comorbidities. Patients on newer AEDs were less likely to report poor HRQoL (QOLIE-31/P). SIGNIFICANCE: These findings move further towards supporting the feasibility and usefulness of collecting real-world, anonymized data recorded by patients online. The data provide insights into factors impacting HRQoL, suggesting that a holistic treatment approach beyond seizure control should be considered in epilepsy.
Asunto(s)
Epilepsia/psicología , Calidad de Vida , Apoyo Social , Adulto , Epilepsia/terapia , Femenino , Estado de Salud , Humanos , Internet , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Lacosamide (LCM) is a functionalized amino acid specifically developed for use as an antiepileptic drug (AED) and is currently indicated as adjunctive treatment for partial-onset seizures in adults with focal epilepsy (maximum approved dose 400 mg/day). Characterization of the pharmacokinetic profile is an important aspect in the development of LCM. Studies in healthy subjects and in patients with focal epilepsy have established that LCM has several favorable pharmacokinetic characteristics, including rapid absorption and high oral bioavailability not affected by food, linear and dose-proportional pharmacokinetics, low inter- and intraindividual variability, low plasma protein binding, renal elimination, and a low potential for clinically relevant pharmacokinetic drug-drug interactions both with AEDs and other common medications. Studies have demonstrated bioequivalence among the three LCM formulations (oral tablets, oral solution, and solution for intravenous (IV) infusion), allowing direct conversion to or from oral and IV administration without titration. Thus, the favorable and predictable pharmacokinetic profile and bioequivalence of LCM formulations, coupled with the low potential for clinically relevant pharmacokinetic drug-drug interactions, make LCM an easy-to-use adjunctive treatment for the management of patients with focal epilepsy.
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Acetamidas/farmacocinética , Anticonvulsivantes/farmacocinética , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Acetamidas/uso terapéutico , Animales , Anticonvulsivantes/uso terapéutico , Interacciones Farmacológicas/fisiología , Humanos , Lacosamida , Resultado del TratamientoRESUMEN
The objective of this study was to examine the prevalence of IgG and IgM anticardiolipin antibodies (aCL) in schizophrenic patients and to determine the relation of aCL levels with neuroleptic medication and psychotic symptoms. Twenty-three patients with acute episodes of chronic schizophrenia, drug-free for at least 3 months before entering the study, were tested for aCL at admission (T1) and 42 days (T2) after neuroleptic treatment started. Blood samples were taken from 20 healthy volunteers as well. Diagnosis was performed according to DSM-IV. Serum samples were analysed for IgG and IgM autoantibodies against beta2-glycoprotein-1-cardiolipin complex by commercially available ELISA kits (Binding-site, UK). Significantly higher levels of aCL antibodies of both isotypes were found in schizophrenic patients versus controls. In patients IgM-aCL positivity was significantly more frequent than in controls. The elevated IgM-aCL and IgG-aCL values were not associated with neuroleptic treatment and psychotic symptoms, as measured by the Positive and Negative Syndrome Scale and the Pentagonal Structural Model of Schizophrenic Symptoms. The negative correlation of IgM-aCL and IgG-aCL with the positive symptoms scale and the autistic preoccupation scale (Pentagonal Structural Model) may indicate the consumption of these antibodies in the exacerbation of the disease.
Asunto(s)
Anticuerpos Anticardiolipina/sangre , Antipsicóticos/uso terapéutico , Cardiolipinas/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Esquizofrenia/sangre , Esquizofrenia/tratamiento farmacológico , Adulto , Antipsicóticos/farmacología , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Sistema Inmunológico/efectos de los fármacos , Modelos Lineales , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Esquizofrenia/inmunología , Factores de TiempoRESUMEN
Recent epidemiological observations suggest that acetaminophen (paracetamol) may contribute to asthma morbidity. Impaired endogenous antioxidant defences may have a role in the pathogenesis of a number of inflammatory pulmonary diseases, including asthma. We studied the effect of acetaminophen on the intracellular level of reduced glutathione (GSH) with and without inhibitors of cytochrome P450 or prostaglandin H synthetase, and TNF-alpha, IL-6 and IL-8 protein production in human alveolar macrophages and type II pneumocytes in vitro. Following a 20 h incubation with acetaminophen, cytotoxicity was apparent from > or = 5 and > or = 10 mM in macrophages and type II pneumocytes, respectively. A time- and concentration-dependent decrease of intracellular GSH occurred after acetaminophen (0.05-1 mM) exposure (1-4 h) in pulmonary macrophages (up to 53%) and type II pneumocytes (up to 34%). Diethyldithiocarbamic acid, potassium ethyl xanthate, and indomethacin decreased significantly acetaminophen-induced GSH depletion in the two cell types tested, suggesting the involvement of cytochrome P450 (mainly CYP2E1) and/or prostaglandin H synthetase. In macrophages, acetaminophen decreased the secretion of TNF-alpha (at 4 and 24 h, concentration-related) and IL-6 (at 24 h, at 0.1 mM), and did not affect significantly IL-8 production. These in vitro observations demonstrate that clinically relevant concentrations of acetaminophen decreased: (i) intracellular GSH in human pulmonary macrophages and type II pneumocytes and (ii) the secretion of TNF-alpha and possibly IL-6 by human pulmonary macrophages. These findings provide experimental plausibility to the challenging observations that frequent use of APAP may be a risk factor for asthma morbidity.
Asunto(s)
Acetaminofén/farmacología , Citocinas/biosíntesis , Glutatión/metabolismo , Pulmón/efectos de los fármacos , Macrófagos Alveolares/efectos de los fármacos , Anciano , Inhibidores Enzimáticos/farmacología , Humanos , Técnicas In Vitro , Pulmón/citología , Pulmón/metabolismo , Pulmón/ultraestructura , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/ultraestructura , Microscopía Electrónica , Persona de Mediana EdadRESUMEN
The aim of this study was to develop a high-speed digital imaging system and related software for ciliary beat frequency (CFB) analysis in order to establish an automated and reliable method that is observer independent and faster compared to the conventional computerized microscope photometry method. Using primary human nasal epithelial cell cultures, the CBF was recorded with a computerized microscope photometry system and a high-speed digital imaging system. To obtain a wide range of frequencies, glycocholate (0.5%) and chlorocresol (0.005%) were used as ciliostimulatory and cilio-inhibitory reference compounds, respectively. The mean values in hertz (+/- s.d.) obtained with the photometry and high-speed digital imaging systems were: controls 8.2 +/- 0.9 and 7.9 +/- 1.1; chlorocresol 5.0 +/- 0.9 and 5.1 +/- 1.1; glycocholate 9.8 +/- 1.0 and 9.7 +/- 0.8. A similar increase (by 20 and 24%) and decrease (by 38 and 35%) in CBF was determined by the two methods after glycocholate and chlorocresol treatment, respectively. The mean difference between the photometry and high-speed digital imaging methods was 0.2 +/- 0.6 Hz, and the Bland-Altman limits of agreement were from -1.0 to +1.4 Hz, suggesting that the results obtained by these two methods could be used interchangeably. These results show the reliability of the high-speed digital imaging system and the software developed for in-vitro CBF measurements. The advantages of the system include: (i) fast data acquisition and calculation, (ii) whole field automated CBF analysis and (iii) reduction in selection bias.