Faculty Bibliography

OBJECTIVE:Alprazolam administered via the Staccato® breath-actuated device is delivered into 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 endpoint of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 mins after administration of study drug and no recurrence of seizure activity within 2 hours. RESULTS:A total of 273 patients were screened, and 116 randomized patients received treatment with 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 with no treatment-related serious AEs. SIGNIFICANCE/CONCLUSIONS: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.

BACKGROUND:A Core Outcome Set (COS) is a standardised list of outcomes that should be reported as a minimum in all clinical trials. In epilepsy, the choice of outcomes varies widely among existing studies, particularly in clinical trials. This diminishes opportunities for informed decision-making, contributes to research waste and is a barrier to integrating findings in systematic reviews and meta-analyses. Furthermore, the outcomes currently being measured may not reflect what is important to people with epilepsy. Therefore, we aim to develop a COS specific to clinical effectiveness research for adults with epilepsy using Delphi consensus methodology. METHODS:The EPSET Study will comprise of three phases and follow the core methodological principles as outlined by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. Phase 1 will include two focused literature reviews to identify candidate outcomes from the qualitative literature and current outcome measurement practice in phase III and phase IV clinical trials. Phase 2 aims to achieve international consensus to define which outcomes should be measured as a minimum in future trials, using a Delphi process including an online consensus meeting involving key stakeholders. Phase 3 will involve dissemination of the ratified COS to facilitate uptake in future trials and the planning of further research to identify the most appropriate measurement instruments to use to capture the COS in research practice. DISCUSSION/CONCLUSIONS:Harmonising outcome measurement across future clinical trials should ensure that the outcomes measured are relevant to patients and health services, and allow for more meaningful results to be obtained. CORE OUTCOME SET REGISTRATION/UNASSIGNED:COMET Initiative as study 118 .

OBJECTIVE:To evaluate the exploratory time to exceed pre-randomization seizure count (T-PSC) in the determination of efficacy of adjunctive perampanel in participants with primary generalized tonic-clonic (PGTC) seizures in generalized-onset epilepsy. METHODS:In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743), participants ≥12 years of age with treatment-resistant idiopathic generalized epilepsy were randomized to receive placebo or adjunctive perampanel (≤8 mg/day) across a 17-week double-blind treatment phase (4-week titration; 13-week maintenance). We evaluated the pre-planned exploratory end point of the T-PSC using a Kaplan-Meier analysis. We also re-evaluated the correspondence of the primary end points of median percent seizure frequency change (MPC) and 50% responder rate (50RR) calculated at T-PSC and at the end of the trial. RESULTS:The exploratory end point of median T-PSC on placebo was 43 days and >120 days on perampanel (log-rank p < .001). The primary end points calculated at T-PSC did not differ significantly from the end points at the end of the trial (MPC -31% vs -42% at T-PSC; 50RR 32% vs 51% at T-PSC). After T-PSC was reached, participants had a median (interquartile range) of 5 (3-13) additional seizures on placebo and 5 (2-10) on perampanel. SIGNIFICANCE/CONCLUSIONS:The exploratory end point of T-PSC demonstrated the effectiveness of perampanel despite a shorter duration of monitoring. The seizures that occurred after T-PSC did not influence the conclusions of the trial; therefore, T-PSC may be a viable alternative to traditional trial end points that reduces the risk to participants.

INTRODUCTION/BACKGROUND:The lack of ideal measurement of treatment efficacy is a well acknowledged problem in the epilepsy community, both in clinical care and clinical trials. Whilst still the current gold-standard, self-reported seizure frequency significantly underestimates the true number of seizures and does not account for any other at least equally important outcome parameters, such as neurodevelopment and cognition. With the rise of disease modifying treatments, the need for more reliable endpoints in practice and clinical trials becomes more pressing. In this paper we assembled an expert panel to discuss the nature of these needs, current limitations, and obstacles based on a survey amongst these experts who were queried about the most important issues regarding the use of electroencephalography (EEG) parameters as endpoints in clinical drug and device development. METHODS:A structured survey was sent to a group of experts in the design and conduct of epilepsy trials in adults and children. This was followed by a virtual in-person meeting discussing the results of the trial and identifying a list of most important issues. RESULTS:Six clinical trialists and 5 individuals from pharmaceutical companies returned the survey containing 14 questions, and 8 clinical trialists and 10 pharma-representatives attended the meeting. Three main issues were identified (1) lack of accuracy of seizure diaries due to nocturnal seizures, subtle motor seizures, impairment of consciousness and lack of awareness of the seizure by the patient (2) inter-rater variability of EEG assessment (3) lack of standardization regarding definition(s) of seizures (clinical and electrographic), EEG recording methods and EEG data management. Recommended solutions included (1) validation of EEG parameters as biomarkers and use of wearables (2) development of a manual that describes EEG rating criteria, protocol for validation by > 1 central reader and use of a resolution of disagreements reporting template (3) standardization of EEG recording, data management and reporting. DISCUSSION & CONCLUSION/CONCLUSIONS:Current developments in research and technology seem promising to advance the use of EEG parameters as potential endpoints and offer partial solutions to the current needs. However, continuous, focused and collaborative efforts of all stakeholders (academia, industry and regulatory agencies) are needed to formulate guidelines, validate emerging technologies and approve them for use in trials. It is the intent of this opinion "position paper" to stimulate those efforts.

OBJECTIVES/OBJECTIVE:Drug treatment for children with epilepsy should, ideally, be governed by evidence from adequate and well-controlled clinical studies. However, these studies are difficult to conduct, and so direct evidence supporting the informed use of specific drugs is often lacking. The Research Roundtable for Epilepsy (RRE) met in 2020 to align on an approach to therapy development for focal seizures in children age 1 month <2 years of age. METHODS:The RRE reviewed the regulatory landscape, epidemiology, seizure semiology, antiseizure medicine pharmacology, and safety issues applicable to this population. RESULTS:After reviewing evidence, the conclusion was that pediatric efficacy trials would be impracticable to conduct but a waiver of the regulatory requirement to conduct any study would lead to an absence of information to guide dosing in a critical population. Review of available data and discussion of RRE attendees led to the conclusion that the requirements for extrapolation of efficacy from older children down to infants from age 1 month to <2 years old appeared to be met. After the RRE, the US Food and Drug Administration (FDA) approved brivaracetam for use in children with focal epilepsy above the age of 1 month in August 2021 and lacosamide in October 2021, both based on the principle of extrapolation from data in older children. SIGNIFICANCE/CONCLUSIONS:These recommendations should result in more rapid accessibility of antiseizure medications for infants.

OBJECTIVE:Assess the longer-term efficacy and safety of adjunctive perampanel (up to 12 mg/day) in patients aged ≥12 years with generalized tonic-clonic (GTC) seizures from the Open-label Extension (OLEx) Phase of Study 332 to determine whether responses obtained during the Core Study are maintained during long-term treatment. METHODS:Patients with GTC seizures previously enrolled in a randomized placebo-controlled trial of perampanel could enter an OLEx Phase comprising 6-week blinded conversion (during which patients previously randomized to placebo-switched to perampanel) and up to 136-week maintenance periods (maximum perampanel dose of 12 mg/day). A 4-week follow-up period was completed by all patients after the last on-treatment visit during the OLEx. We assessed seizure frequency outcomes from preperampanel baseline and the Core Study Pre-randomization Phase, retention rates, doses selected, and treatment-emergent adverse events (TEAEs). RESULTS:Overall, 138 patients entered the OLEx. Median percent reductions in GTC seizures per 28 days from preperampanel were 77% (Weeks 1-13) and 90% (Weeks 40-52). Retention rates were 88% (6 months) and 75% (12 months). Seizure-freedom rates were maintained for at least 2 years regardless of prior treatment received during the Core Study. Most common modal daily dose was >4-8 mg/day (n = 93). Across the Core and OLEx Phases, 120 (87%) patients experienced TEAEs; the most common was dizziness. SIGNIFICANCE/CONCLUSIONS:Perampanel was generally well-tolerated, and the TEAEs reported here are consistent with the known safety profile of perampanel. Perampanel offers a long-term treatment option for patients (aged ≥12 years) with GTC seizures.

OBJECTIVES/OBJECTIVE:As part of the COVID-19 and Epilepsy (COV-E) global study, we aimed to understand the impact of COVID-19 on the medical care and well-being of people with epilepsy (PWE) in the United States, based on their perspectives and those of their caregivers. METHODS:Separate surveys designed for PWE and their caregivers were circulated from April 2020 to July 2021; modifications in March 2021 included a question about COVID-19 vaccination status. RESULTS:We received 788 responses, 71% from PWE (n = 559) and 29% (n=229) from caregivers of persons with epilepsy. A third (n = 308) of respondents reported a change in their health or in the health of the person they care for. Twenty-seven percent (n = 210) reported issues related to worsening mental health. Of respondents taking ASMs (n = 769), 10% (n= 78) reported difficulty taking medications on time, mostly due to stress causing forgetfulness. Less than half of respondents received counseling on mental health and stress. Less than half of the PWE reported having discussions with their healthcare providers about sleep, ASMs and potential side effects, while a larger proportion of caregivers (81%) reported having had discussions with their healthcare providers on the same topics. More PWE and caregivers reported that COVID-19 related measures caused adverse impact on their health in the post-vaccine period than during the pre-vaccine period, citing mental health issues as the primary reason. SIGNIFICANCE/CONCLUSIONS:Our findings indicate that the impact of the COVID-19 pandemic in the US on PWE is multifaceted. Apart from the increased risk of poor COVID-19 outcomes, the pandemic has also had negative effects on mental health and self-management. Healthcare providers must be vigilant for increased emotional distress in PWE during the pandemic and consider the importance of effective counseling to diminish risks related to exacerbated treatment gaps.

Clinical practice guidelines (CPGs) are statements that provide evidence-based recommendations aimed at optimizing patient care. However, many other documents are often published as "guidelines" when they are not; these documents, although also important in clinical practice, are usually not systematically produced following rigorous processes linking the evidence to the recommendations. Specifically, the International League Against Epilepsy (ILAE) guideline development toolkit aims to ensure that high-quality CPGs are developed to fill knowledge gaps and optimize the management of epilepsy. In addition to adhering to key methodological processes, guideline developers need to consider that effective CPGs should lead to improvements in clinical processes of care and health care outcomes. This requires monitoring the effectiveness of epilepsy-related CPGs and interventions to remove the barriers to epilepsy CPG implementation. This article provides an overview of what distinguishes quality CPGs from other documents and discusses their benefits and limitations. We summarize the recently revised ILAE CPG development process and elaborate on the barriers and facilitators to guideline dissemination, implementation, and adaptation.

Importance/UNASSIGNED:Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking. Objective/UNASSIGNED:To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy. Design, Setting, and Participants/UNASSIGNED:A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018. Interventions/UNASSIGNED:Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years. Main Outcomes and Measures/UNASSIGNED:Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period. Results/UNASSIGNED:A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants; 390-mg cannabidiol, 62 participants; placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days; least squares mean difference, 0.014; 95% CI, -0.175 to 0.203; P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days; least squares mean difference, 0.096; 95% CI, -0.093 to 0.285; P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, -6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension. Conclusions and Relevance/UNASSIGNED:Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery. Trial Registration/UNASSIGNED:ACTRN12616000510448 (double-blind); ACTRN12616001455459 (open-label).