A randomized phase 2b efficacy study in patients with seizure episodes with a predictable pattern using Staccato® alprazolam for rapid seizure termination.

OBJECTIVE: Alprazolam administered via the Staccato® breath-actuated device is delivered into the deep lung for rapid systemic exposure and is a potential therapy for rapid epileptic seizure termination (REST). We conducted an inpatient study (ENGAGE-E-001 [NCT03478982]) in patients with stereotypic seizure episodes with prolonged or repetitive seizures to determine whether Staccato alprazolam rapidly terminates seizures in a small observed population after administration under direct supervision. METHODS: Adult patients with established diagnosis of focal and/or generalized epilepsy with a documented history of seizure episodes with a predictable pattern were enrolled. They were randomized 1:1:1 to double-blind treatment of a single seizure event with one dose of Staccato alprazolam 1.0 mg or 2.0 mg, or Staccato placebo in an inpatient unit. The primary end point of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 min after administration of study drug and no recurrence of seizure activity within 2 h. RESULTS: A total of 273 patients were screened, and 116 randomized patients received treatment with the study drug in the double-blind part. The proportion of treated patients who were responders was 65.8% for each of Staccato alprazolam 1.0 mg (n = 38; p = .0392) and 2.0 mg (n = 38; p = .0392), compared with 42.5% for Staccato placebo (n = 40). Staccato alprazolam was well tolerated when administered as a single dose of 1.0 or 2.0 mg: cough and somnolence were the most common adverse events (AEs) (both 14.5%), followed by dysgeusia (13.2%). AEs were mostly mild or moderate in intensity; there were no treatment-related serious AEs. SIGNIFICANCE: Both 1.0 mg and 2.0 mg doses of Staccato alprazolam demonstrated efficacy in rapidly terminating seizures in an inpatient setting and were well tolerated. The next step is a Phase 3 confirmatory study to demonstrate efficacy and safety of Staccato alprazolam for rapid cessation of seizures in an outpatient setting.

The interactions between reproductive hormones and epilepsy.

There are complex interactions between hormones, epilepsy, and antiepileptic drugs (AEDs). While there is ample evidence that hormones influence epilepsy, it is also apparent that epileptic activity influences hormones in both women and men. In addition, AEDs may disturb endocrine function. The clinical importance of these interactions is primarily related to the effects on reproductive hormones, which is the focus of this article. Reproductive endocrine dysfunction is common among women and men with epilepsy. Menstrual disorders, polycystic ovaries, and infertility have been described among women with epilepsy, while reduced potency and sperm abnormalities have been found in men. Sexual problems and endocrine changes have been frequently described in both sexes. Epilepsy and AEDs can target a number of substrates to impact hormone levels. These include the limbic system, hypothalamus, pituitary, peripheral endocrine glands, liver, and adipose tissue. AEDs may also alter the synthesis of steroids and binding proteins, as well as hormone metabolism, and produce direct gonadal effects.

Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants.

OBJECTIVE: Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. METHODS: Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. RESULTS: Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. SIGNIFICANCE: This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.

Development of a classifier to identify patients with probable Lennox-Gastaut syndrome in health insurance claims databases via random forest methodology.

Objective: Describe the development of a claims-based classifier utilizing machine learning to identify patients with probable Lennox-Gastaut syndrome (LGS) from six state Medicaid programs. Methods: Patients were included if they had ≥2 medical claims ≥30 days apart for specified or unspecified epilepsy, excluding those with ≥1 claim for petit mal status. The LGS classifier utilized a random forest algorithm, a compilation of thousands of binary decision trees in which machine-generated predictor variables split the data set into branches that predict the presence or absence of LGS. To construct the splitting rules, the importance of each candidate variable was determined by calculating the mean decrease in Gini impurity. Training and testing were performed on two data sets (30% and 70%) using a "true" LGS and non-LGS patient population. Performance was compared with logistic regression and single tree methodology. Results: Using a 60% probability threshold, which yielded the highest sensitivity (97.3%) and specificity (95.6%), the classifier identified approximately 4% of patients with epilepsy as probable LGS. The most important input variables included number of distinct antiepileptic drugs received, epilepsy-related outpatient/inpatient visits, electroencephalogram procedures and claims for delayed development. The random forest methodology outperformed logistic regression and single tree methodology. Most of the important LGS predictor characteristics identified by the classifier were statistically significantly associated with LGS status (p < .05). Conclusions: The claims-based LGS classifier showed high sensitivity and specificity, outperformed single tree and logistic regression methodologies and identified a prevalence of probable LGS that was similar to previously published estimates.

Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: Meta-analysis of pivotal trials.

OBJECTIVE: In the absence of randomized clinical trials (RCTs) assessing the relative efficacy of antiepileptic drugs (AEDs), meta-analyses are useful resources for informing treatment choices. This meta-analysis assesses the relative efficacy and tolerability of AEDs for adjunctive treatment of refractory partial onset seizures (POS). METHODS: A systematic literature review was conducted to identify pivotal AED trials serving as the basis for US Food and Drug Administration (FDA) approval. INCLUSION CRITERIA: 1) double-blind, placebo-controlled, parallel-group design, with 8- to 14-week maintenance period; 2) enrolled patients ≥16years with refractory POS, including complex partial seizures; 3) study was conducted between 1993 and 2013; and; 4) patients received FDA-approved dosage. Outcomes analyzed: 1) 50% responder rate (≥50% reduction from baseline in seizure frequency); 2) seizure freedom (proportion of seizure-free patients); and 3) discontinuation due to adverse events (AEs). DerSimonian and Laird random-effects model was used to derive odds ratios (OR) and 95% confidence intervals (CI). RESULTS: A total of 29 publications for 11 AEDs (eslicarbazepine, ezogabine, gabapentin, lacosamide, levetiracetam, perampanel, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide) were included in the meta-analysis. Tiagabine 56mg/day (OR 8.82, 95% CI: 2.77-28.11), pregabalin 600mg/day (OR 8.08, 95% CI: 5.45-11.98), and vigabatrin 3000mg/day (OR 6.23, 95% CI: 1.46-26.20) had the highest OR versus placebo of 50% response. The odds of seizure freedom were ≥7 times greater than placebo for levetiracetam 3000mg/day (OR 11.00, 95% CI: 2.08-58.06), vigabatrin 3000mg/day (OR 7.41, 95% CI: 1.31-41.84), and ezogabine 1200mg/day (OR 7.09, 95% CI: 0.36-58.06). Patients were more likely to discontinue any AED (except low-dose pregabalin) than placebo. CONCLUSION: In this meta-analysis of >9000 patients, those treated with AEDs were more likely than placebo to achieve seizure response or freedom. Patients receiving pregabalin, tiagabine, and vigabatrin had the highest odds of ≥50% reduction in seizures, and patients receiving ezogabine, levetiracetam, and vigabatrin had the highest odds of seizure freedom.

Optimizing clobazam treatment in patients with Lennox-Gastaut syndrome.

Given the complexities managing Lennox-Gastaut syndrome (LGS)-comorbid conditions, multiple associated seizure types that tend to be refractory to treatment-dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal clobazam lead-in studies. During the lead-in studies, patients received either placebo or clobazam (0.25, 0.50, or 1.0mg/kg/d) (maximum 40mg/d); during OLE, patients received clobazam up to 2.0mg/kg/d (maximum 80mg/d). The post hoc analysis population comprised patients who had ≥25%, ≥50%, or ≥75% seizure reduction from baseline during lead-in clobazam treatment and ≥12months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥20% clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or >50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in clobazam dosage received. The findings of the analysis indicated that clobazam dosage increases of ≥20% during long-term treatment improved seizure control >80% of patients with LGS who responded to clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥75%) lead-in response.

Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Tardive dyskinesia results from exposure to dopamine receptor antagonists, such as typical and atypical antipsychotics. If clinically appropriate, clinicians often manage this disorder by lowering the dose of, or discontinuing, the causative drug. There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses. We aimed to assess the efficacy, safety, and tolerability of fixed doses of deutetrabenazine-a novel vesicular monoamine transporter-2 inhibitor-in patients with tardive dyskinesia. METHODS: We did this double-blind, randomised, placebo-controlled, phase 3 trial at 75 centres in the USA and Europe. Patients aged 18-80 years with tardive dyskinesia (≥3 months before screening) were randomly assigned centrally (1:1:1:1), via interactive response technology, to receive one of three fixed doses of deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or matching placebo. Randomisation was stratified by baseline use of dopamine receptor antagonists. Patients were started on oral deutetrabenazine 12 mg/day, and this dose was increased through week 4 until the randomised dose was achieved, then maintained over 8 weeks. During the treatment period, patients, investigators, their site personnel, and sponsor were masked to group assignment. The primary efficacy endpoint was change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to week 12 in patients with at least one post-baseline rating. The primary efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score ≥6 and at least one post-baseline rating). The safety analysis was done in patients who received any study drug. This trial is registered with ClinicalTrials.gov, number NCT02291861. FINDINGS: Between Oct 29, 2014, and Aug 19, 2016, we randomly assigned 298 patients to receive at least one dose of placebo (n=74), deutetrabenazine 12 mg/day (n=75), 24 mg/day (n=74), or 36 mg/day (n=75); 222 patients comprised the modified intention-to-treat population and 293 patients comprised the safety population. From baseline to week 12, the least-squares mean AIMS score improved by -3·3 points (SE 0·42) in the deutetrabenazine 36 mg/day group, -3·2 points (0·45) in the 24 mg/day group, and -2·1 points (0·42) in the 12 mg/day group, with a treatment difference of -1·9 points (SE 0·58, 95% CI -3·09 to -0·79; p=0·001), -1·8 points (0·60, -3·00 to -0·63; p=0·003), and -0·7 points (0·57, -1·84 to 0·42; p=0·217), respectively, versus -1·4 points (0·41) in the placebo group. The rate of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (n=38/74 [51%]), 24 mg/day group (n=32/73 [44%]), and 12 mg/day group (n=36/74 [49%]), and those in the placebo group (n=34/72 [47%]). Serious adverse events were reported in four (5%) patients given deutetrabenazine 36 mg/day, six (8%) patients given 24 mg/day, and two (3%) patients given 12 mg/day, compared with four (6%) patients given placebo. Two (1%) patients in the safety population died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigator or sponsor. INTERPRETATION: Deutetrabenazine 24 mg/day and 36 mg/day provided a significant reduction in tardive dyskinesia, with favourable safety and tolerability. These findings suggest that dosing regimens could be individualised and tailored for patients on the basis of dyskinesia control and tolerability. FUNDING: Teva Pharmaceutical Industries.

Assessment of treatment patterns and healthcare costs associated with probable Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is a chronic and severe form of epilepsy characterized by intractable seizures, cognitive impairment, and abnormal electroencephalogram findings with slow spike-wave complexes. It typically presents before age 8, but symptoms continue into adulthood and require lifelong treatment associated with significant clinical burden. Data on LGS-associated healthcare utilization and costs are limited. In this study we use a claims-based LGS classifier based on random forest methodology to identify patients with probable LGS from the a Medicaid multi-state database and assess its prevalence across the age spectrum, healthcare utilization, treatment patterns, costs, and comorbid conditions. The classifier identified patients with probable LGS across all ages, with up to 8% of 10-year-old patients with epilepsy identified as having probable LGS. The prevalence of probable LGS was lower in older age cohorts, indicating that it may be under-recognized in older patients. Our analysis showed that probable LGS is associated with considerably higher total healthcare and medical costs than non-LGS patients. The costs were generally consistent between age cohorts, suggesting that the cost burden extends beyond childhood and has a lifelong impact. Analysis of treatment patterns suggest that while the majority of probable LGS patients in this study received widest-spectrum AEDs, a considerable proportion did not and therefore may have been inadequately treated. Further, usage of clobazam and rufinamide was decreased in older compared to younger patient cohorts, indicating that older patient cohorts are less likely to be receiving optimum treatment for LGS. These findings indicate the need for increased clinical attention to LGS beyond pediatric years, with a focus on optimization of treatment for LGS patients of all ages with widest-spectrum AEDs. Timely recognition and adequate treatment of LGS are likely to result in improved outcomes and less costly management of this condition.

Women treated for epilepsy during pregnancy: outcomes from a nationwide population-based cohort study.

INTRODUCTION: Women with epilepsy (WWE) are generally treated as a risk group during pregnancy, but over 90% of pregnant WWE have favorable pregnancies. However, the risk of some pregnancy and delivery complications may be increased among WWE, especially those on antiepileptic drugs. MATERIAL AND METHODS: This nationwide, retrospective population-based cohort study includes WWE who gave birth in Finland during 1987-2008 (n = 1737) and the reference cohort of a random sample of women without epilepsy (n = 4357). Identification of the cohorts, and information on hospitalizations and deliveries were obtained from the Finnish Health Registers and population statistics. Multivariate analyses were conducted by binomial regression. RESULTS: WWE were more often hospitalized during pregnancy for accidents or other external causes [adjusted risk ratio (aRR) 1.74, 95% confidence interval (CI) 0.98-3.09], premature rupture of membranes (aRR 1.75, 95% CI 1.14-2.69) and premature contractions (aRR 1.75, 95% CI 1.36-2.23). Hospitalizations for infections were more frequent in WWE (1.4% vs. 0.4%, aRR 3.15, 95% CI 1.72-5.76). The risk for induction of delivery or a cesarean section was increased in WWE. There was no difference in premature deliveries between the groups, but the risk of being small for gestational age (aRR 1.57, 95% CI 1.23-2.01), admission to neonatal intensive care unit (aRR 1.66, 95% CI 1.39-1.97), and need for respiratory care (aRR 2.37, 95% CI 1.57-3.60) was clearly increased in the offspring of WWE. CONCLUSIONS: WWE are at an increased risk of complications and hospitalizations during pregnancy and delivery. However, the majority of WWE have a normal pregnancy and delivery.

Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study.

OBJECTIVE: To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome. METHODS: Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg-1·d-1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg-1·d-1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ≥40% and increasing seizure rates. RESULTS: Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ≥75% responders demonstrated a consistent response over time. Few patients had a dosage increase ≥40% associated with an increase in seizure rates. CONCLUSIONS: Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated. CLINICALTRIALSGOV IDENTIFIER: NCT00518713 and NCT01160770. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment.

Retinal structure and function in vigabatrin-treated adult patients with refractory complex partial seizures.

OBJECTIVE: Evaluate visual-field and retinal-structure changes following adjunctive vigabatrin treatment in vigabatrin-naive adults with refractory complex partial seizures (rCPS). METHODS: Prospective, longitudinal, single-arm, open-label study (NCT01278173). Eligible patients (≥2 seizures/month who failed ≥3 therapies) who could reliably perform perimetry (Humphrey automated static) and retinal-structure assessment (spectral-domain optical coherence tomography) prior to vigabatrin exposure. Following vigabatrin initiation, testing occurred within 1 month (reference) and 3, 6, 9, and 12 months. End points included mean change from reference in mean deviation (dB) and average retinal nerve fiber layer (RNFL) thickness, visual-acuity changes from baseline, and number of patients who met predefined vision-parameter changes at two (confirmed) or three (persistent) consecutive visits. RESULTS: Sixty-five of 91 screened patients received ≥1 vigabatrin dose (all-patients-treated set [APTS]); 55 had valid reference and ≥1 post-reference assessments (full-analysis set [FAS]). Thirty-six APTS patients with valid pre-/post-reference values completed all planned visits (per-protocol set [PPS]). Thirty-eight (59%) APTS patients completed the study; 27 (42%) withdrew (none for visual-field changes); 32% and 15% had abnormally thin RNFL and abnormal visual acuity at baseline, respectively; 20% had abnormal central 30 degree visual fields in the reference period. No significant mean near visual-field changes were observed (PPS); mean change in average RNFL thickness increased significantly (1-year data: Left-eye: 6.37 µm, confidence interval (CI) 4.66-8.09; right-eye: 7.24 µm CI 5.47-9.01; PPS). No confirmed three-line decreases in visual acuity (FAS) were observed; five patients had predefined confirmed/persistent visual-field changes (FAS). All vision-related adverse events were nonserious; the most common was vision blurred (9%). SIGNIFICANCE: Prior to vigabatrin initiation, rCPS patients may already exhibit vision deficits. Up to 1 year of adjunctive vigabatrin treatment did not significantly change population near visual fields. Five patients met predefined visual-field-change criteria. RNFL thickening of unknown clinical significance was observed. Limitations include single-arm, open-label design; patients' inability to perform ophthalmic/visual-field examinations; and limited vigabatrin-exposure duration.

Clobazam and clonazepam use in epilepsy: Results from a UK database incident user cohort study.

OBJECTIVE: To compare patient characteristics and treatment patterns among clobazam (CLB) and clonazepam (CZP)-treated patients with epilepsy in a longitudinal primary care database. METHODS: In this pharmacoepidemiological study, real-life usage data from the Clinical Practice Research Database (CPRD) were evaluated. The CPRD collects data from approximately 690 primary care practices throughout the UK. Data included were from patients with ≥1 incident CLB or CZP prescription from 1995 to 2011 and were present in the database for ≥182 days prior to the index date (date patient was first prescribed CLB or CZP within the study period). RESULTS: Of 21,099 patients who met inclusion criteria, 18.4% were receiving CLB and 81.6% were receiving CZP. More patients used CLB for epilepsy than CZP (76.1% vs 8.7%). CLB-treated adults (≤18years) were younger than those treated with CZP (41.0 vs 48.2 years; p<0.001), while CLB-treated children (≤18 years) were older than those treated with CZP (8.8 vs 7.3 years, p<0.001). The median CLB dosage did not change from baseline to last follow-up, while median CZP dosage increased 25% in adults and 50% in children. Median treatment duration, as well as retention rate up to 10 years, was similar between CLB and CZP in each age group. CONCLUSIONS: Among adult and pediatric patients in the UK, CLB is more often prescribed for epilepsy than CZP. The median CLB dosage used by both adults and children remained stable over the 16-year study period, while the median CZP dosage increased in both adults and children.

Which children receive vigabatrin? Characteristics of pediatric patients enrolled in the mandatory FDA registry.

Vigabatrin (Sabril®) is an antiepileptic drug (AED) currently indicated in the US as a monotherapy for patients 1month to 2years of age with infantile spasms (IS) and as adjunctive therapy for patients ≥10years of age with refractory complex partial seizures (rCPS) whose seizures have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss. The approval required an FDA mandated registry. This article describes 5years of demographic and treatment exposure data from US pediatric patients (<17years). Participation is mandatory for all US Sabril® prescribers and patients. A benefit-risk assessment must be documented for patient progression to maintenance therapy. This includes demographic diagnosis and reports of ophthalmologic assessments (where available). Patient data were grouped by age as proxies for indication (IS: <3years, rCPS: ≥3 to <17years). As of August 26, 2014, 5546/6823 enrolled patients were pediatric/total; 4472 (81%) were vigabatrin-naïve. Seventy-one percent of patients were <3years of age; 29% were ≥3 to <17years of age. Etiologies of IS were identified as cryptogenic (21%), symptomatic tuberous sclerosis (17%), and symptomatic other (42%). The majority of patients with IS (56%) attempted no prior treatments; 16% received adrenocorticotropic hormone prior to vigabatrin. A third of patients with IS were receiving 1 concomitant treatment with vigabatrin. For patients with rCPS, 39% attempted 1-3 prior treatments; 27% were receiving 2 concomitant treatments at enrollment. A total of 1852 (41%) patients did not undergo baseline ophthalmological assessment; 25% of patients with IS and 42% of patients with rCPS were exempted for neurologic disabilities. Kaplan-Meier estimates predict that 71% and 65% of vigabatrin-naïve patients with IS and rCPS, respectively, would remain in the registry at 6months. Most pediatric vigabatrin patients have IS as an underlying diagnosis, especially those <3years of age. A proportion of those with rCPS remain on long-term vigabatrin despite the risk of adverse events.

Clobazam-treated patients with Lennox-Gastaut syndrome experienced fewer seizure-related injuries than placebo patients during trial OV-1012.

Drop seizures are especially problematic in patients with Lennox-Gastaut syndrome (LGS) because of their potential for serious injury. In this post hoc analysis of phase 3 OV-1012 data, a medical review was conducted of seizure-related injuries based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms from all adverse event (AE) listings. Patients receiving clobazam experienced fewer seizure-related injuries than those receiving placebo (8.9% all clobazam dosages vs. 27.1% placebo, p ≤ 0.05). Significant differences in the rates of seizure-related injuries were observed for the medium- and high-dosage clobazam treatment groups (4.8% and 10.2%, respectively, p ≤ 0.05). A total of 50 of 53 AEs considered seizure-related were mild or moderate in intensity; 3 severe AEs occurred in the placebo group (fall, contusion, and jaw fracture). A single serious AE (jaw fracture, which required hospitalization and surgery) occurred in a placebo-treated patient. Most injuries resolved by the end of the study. This analysis indicates that the reduction in drop-seizure frequency achieved with clobazam provides a clinically meaningful benefit, a reduced likelihood of experiencing seizure-related injuries.

Sabril® registry 5-year results: Characteristics of adult patients treated with vigabatrin.

Vigabatrin (Sabril®), approved in the US in 2009, is currently indicated as adjunctive therapy for refractory complex partial seizures (rCPS) in patients ≥ 10 years old who have responded inadequately to several alternative treatments and as monotherapy for infantile spasms (IS) in patients 1 month to 2 years of age. Because of reports of vision loss following vigabatrin exposure, FDA approval required a risk evaluation mitigation strategy (REMS) program. Vigabatrin is only available in the US through Support, Help, And Resources for Epilepsy (SHARE), which includes a mandated registry. This article describes 5 years of demographic and treatment exposure data from adult patients (≥ 17 years old) in the US treated with vigabatrin and monitored in the ongoing Sabril® registry. Registry participation is mandatory for all US Sabril® prescribers and patients. A benefit-risk assessment must be documented by the physician for a patient to progress to maintenance therapy, defined as 1 month of vigabatrin treatment for patients with IS and 3 months for patients with rCPS. Ophthalmologic assessments must be documented during and after completion of therapy. As of August 26, 2014, a total of 6823 patients were enrolled in the registry, of which 1200 were adults at enrollment. Of these patients, 1031 (86%) were naïve to vigabatrin. The majority of adult patients (n=783, 65%) had previously been prescribed ≥ 4 AEDs, and 719 (60%) were receiving ≥ 3 concomitant AEDs at vigabatrin initiation. Prescribers submitted an initial ophthalmological assessment form for 863 patients; an ophthalmologic exam was not completed for 300 (35%) patients and thus, were considered exempted from vision testing. Of these patients, 128 (43%) were exempted for neurologic disabilities. Clinicians discontinued treatment in 8 patients because of visual field deficits (VFD) (5 patients naïve to vigabatrin and 3 patients previously exposed). Based on Kaplan-Meier survival estimates, it is estimated that approximately 71%, 55%, and 40% of adult patients naïve to vigabatrin would remain in the registry at 3, 6, and 12 months, respectively. These demographic data suggest that a proportion of adult patients remain on vigabatrin long-term despite the risks of adverse events and significant underlying AED resistance and neurologic disease.

Epilepsy, excess deaths and years of life lost from external causes.

We systematically quantified excess mortality in epilepsy patients by cause of death using the population-attributable fraction and epilepsy-attributable years of potential life lost (YPLL) by age 75 years at ages 15 and over. We updated and undertook a re-review of mortality studies from our previous systematic review following PRISMA guidelines to identify cohort studies of general epilepsy populations reporting a relative risk (RR) of death by cause relative to the background rates in the population. Studies on epilepsy prevalence were identified through published reviews. Country-specific mortality figures were obtained from the WHO World Mortality Database. We performed a pooled analysis with the DerSimonian-Laird random effects method. In countries with very high Human Development Indices, epilepsy contributed to 0.5-1.1 % of all deaths in the total population. Among external causes, suicides (RR 2.9, 95 % confidence interval 2.2-3.8; I(2) 52 %) were the major contributor to YPLL, corresponding to 6.7 % and 4.2 % of excess YPLL due to epilepsy in the United States (US) and in the United Kingdom (UK) in 2010, with 541 (346-792) and 44 (28-65) excess suicide cases, respectively. Fatal accidental falls were more common, with 813 (610-1064) and 95 (71-125) excess deaths in the US and in the UK, but these caused only 2.0 % of excess YPLL as they occurred in older age groups. Suicides were the most important external cause of death in epilepsy patients in terms of excess YPLL, whereas other external causes were either more common in older ages or caused less excess deaths.

Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: Analysis of data pooled from three randomized, double-blind, placebo-controlled clinical trials.

OBJECTIVE: The objective of this study was to describe a priori protocol-defined analyses to evaluate the safety and tolerability of adjunctive oral lacosamide (200-600 mg/day) in adults (ages 16-70 years) with partial-onset seizures (POS) using data pooled from three similarly designed randomized, double-blind, placebo-controlled trials (SP667, SP754 [NCT00136019], SP755 [NCT00220415]). METHODS: Patients with POS (≥2 years' duration, ≥2 previous antiepileptic drugs [AEDs]) uncontrolled by a stable dosing regimen of 1-3 concomitant AEDs were randomized to treatment with lacosamide at doses of 200 mg/day, 400 mg/day, or 600 mg/day, or placebo. Studies comprised a 4- to 6-week titration phase to target dose followed by a 12-week maintenance phase. Safety outcomes included treatment-emergent adverse events (TEAEs) of particular relevance to patients with POS, overall TEAEs, and discontinuations due to TEAEs. Post hoc analyses included evaluation of TEAEs potentially related to cognition and TEAEs leading to discontinuation analyzed by concomitant AEDs. RESULTS: One thousand three hundred eight patients were randomized to and received treatment; 944 to lacosamide and 364 to placebo. Most patients (84.4%) were taking 2 or 3 concomitant AEDs. The most common drug-associated TEAEs (reported by ≥5% of patients in any lacosamide dose group and with an incidence at least twice that reported for placebo during the treatment phase) were dizziness (30.6% for lacosamide vs 8.2% for placebo), nausea (11.4% vs 4.4%), and diplopia (10.5% vs 1.9%). Common drug-associated TEAEs generally appeared to be dose-related, and the incidence of each was lower during the 12-week maintenance phase than during the titration phase. Most TEAEs were either mild or moderate in intensity; severe TEAEs were predominantly observed with lacosamide 600 mg/day. No individual serious TEAE occurred in ≥1% of all lacosamide-treated patients. Treatment-emergent adverse events led to discontinuation in 8.1%, 17.2%, and 28.6% of the lacosamide 200-, 400-, and 600-mg/day groups, respectively (vs 4.9% of placebo). Few TEAEs were related to rash, weight loss/gain, changes in clinical chemistry parameters, or psychiatric disturbances, or were seizure-related. The odds of reporting any potential cognition-related TEAE vs placebo increased with dose and were similar between lacosamide doses of 200 and 400mg/day and placebo (odds ratio 1.3, 95% confidence interval 0.7-2.4). Discontinuations due to TEAEs based on most commonly used AEDs taken in combination with lacosamide (all doses combined) were carbamazepine (15.3% [51/334] vs 3.9% [5/129] placebo), lamotrigine (19.2% [56/291] vs 4.3% [5/117]), and levetiracetam (10.1% [28/278] vs 3.9% [4/103]). CONCLUSIONS: The safety and tolerability profile of adjunctive lacosamide in this detailed evaluation was similar to that observed in the individual double-blind trials. Adjunctive lacosamide was associated with TEAEs related to the nervous system and gastrointestinal tract, predominantly during titration.

Clobazam and Aggression-Related Adverse Events in Pediatric Patients With Lennox-Gastaut Syndrome.

BACKGROUND: Lennox-Gastaut syndrome is an intractable epileptic encephalopathy marked by frequent drop seizures. Most patients develop moderate intellectual disability and behavioral problems, including hyperactivity, aggressiveness, insecurity, and autistic features. Treatment with benzodiazepines, including clobazam, may increase aggression/behavioral problems in patients with Lennox-Gastaut syndrome. Post hoc analyses of data from the OV-1012 trial assessed the potential for behavioral effects with clobazam treatment in pediatric (2 to 18 years) patients with Lennox-Gastaut syndrome. METHODS: OV-1012 was a phase 3, randomized, double-blind, parallel-group trial comprising a 4-week baseline period, 3-week titration period, and a 12-week maintenance period. Data from 194 patients were analyzed for a history of aggression/behavioral problems, occurrence of aggression-related adverse events, and by assessment of potential drug-related effects on four behavior domains of the Child Behavior Checklist. RESULTS: Twenty-nine aggression-related adverse events were reported for 27 (13.9%) patients. Similar percentages of clobazam-treated patients with and without a history of aggressive behavior experienced an aggression-related adverse event (16.7% versus 15.5%, respectively). In the medium- and high-dosage clobazam groups, onset of aggression-related adverse effects occurred within the 3-week titration period with 63.2% resolving by the end of the study. Aggression-related adverse event onset and resolution were similar for the low-dosage clobazam and placebo groups. Analysis of baseline to postbaseline T scores for the behavior domains of the Child Behavior Checklist indicated no significant differences between clobazam and placebo. CONCLUSIONS: Post hoc analyses indicate that the overall rate of aggression with clobazam treatment was low and dosage dependent. Clobazam treatment was effective in reducing drop seizures regardless of aggression experience.

Clobazam is equally safe and efficacious for seizures associated with Lennox-Gastaut syndrome across different age groups: Post hoc analyses of short- and long-term clinical trial results.

The peak age at onset of Lennox-Gastaut syndrome (LGS) is between 3 and 5years. Patients with LGS frequently experience multiple types of treatment-refractory seizures and require lifelong therapy with several antiepileptic drugs. Here, post hoc analyses of clinical trials (phase III trial OV-1012 and open-label extension trial OV-1004) provide short- and long-term efficacy and safety data of adjunctive clobazam in patients with LGS stratified by age at baseline (≥2 to <12years, ≥12 to <17years, and ≥17years). In OV-1012, 301 patients were screened, 238 were randomized, 217 comprised the modified intention-to-treat population, and 177 completed the study. A total of 267/306 patients (61 of 68 from phase II trial OV-1002 and 206 of 238 from phase III trial OV-1012) entered the open-label extension trial. Demographics and clinical characteristics were similar between different age groups in OV-1012 and OV-1004. No differences in efficacy or adverse events were observed across age groups in OV-1012 and OV-1004. The results of these post hoc analyses show that adjunctive clobazam over the short and longterm was similarly effective and well-tolerated in both pediatric and adult patients with LGS.

Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years.

Long-term (up to 8 years of exposure) safety and efficacy of the antiepileptic drug lacosamide was evaluated in this open-label extension trial (SP615 [ClinicalTrials.gov identifier: NCT00552305]). Patients were enrolled following participation in a double-blind trial or one of two open-label trials of adjunctive lacosamide for partial-onset seizures. Dosage adjustments of lacosamide (100-800 mg/day) and/or concomitant antiepileptic drugs were allowed to optimize tolerability and seizure reduction. Of the 370 enrolled patients, 77%, 51%, and 39% had >1, >3, or >5 years of lacosamide exposure, respectively. Median lacosamide modal dose was 400mg/day. Common treatment-emergent adverse events (TEAEs) were dizziness (39.7%), headache (20.8%), nausea (17.3%), diplopia (17.0%), fatigue (16.5%), upper respiratory tract infection (16.5%), nasopharyngitis (16.2%), and contusion (15.4%). Dizziness (2.2%) was the only TEAE that led to discontinuation in >2% of patients. Ranges for median percent reductions in seizure frequency were 47-65%, and those for ≥ 50% responder rates were 49-63% for 1-, 3-, and 5-year completer cohorts. Exposure to lacosamide for up to 8 years was generally well tolerated, with a safety profile similar to previous double-blind trials, and efficacy was maintained.