Consensus panel recommendations for the optimization of EPIDIOLEX® treatment for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex.

Following the approval of Epidiolex® (cannabidiol; CBD) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC), healthcare professionals (HCPs) have had substantial experience in treating patients with Epidiolex. However, confusion still remains among HCPs, caregivers, and patients regarding dosing, drug interactions, safety monitoring, and differentiation between Epidiolex and nonapproved CBD products. To establish consensus recommendations for Epidiolex treatment optimization in LGS, DS, and TSC, a panel of seven HCPs with expertise in epilepsy was convened.

Effectiveness, safety and tolerability of perampanel by age group when used to treat people with focal and generalized epilepsy in clinical practice: The PERMIT Extension study.

Objective: To assess the effectiveness and safety/tolerability of perampanel (PER) in people with epilepsy (PWE) treated in everyday clinical practice for focal and generalized seizures, both in the total cohort and by age group.

Methods: The PERMIT Extension study was a pooled analysis of data from PWE included in two large previous clinical practice studies (PERMIT and PROVE). Retention was assessed over 12 months.

Sustainability of seizure reduction and seizure control with adjunctive cenobamate: Post hoc analysis of a phase 3, open-label study.

Objective: In this post hoc analysis of a subset of patients from a long-term, open-label phase 3 study, we assessed ≥50%, ≥75%, ≥90%, and 100% seizure reduction and sustainability of these responses with cenobamate using a time-to-event analytical approach.

Methods: Of 240 patients with uncontrolled focal seizures who had adequate seizure data available, 214 completed the 12-week titration phase and received ≥1 dose of cenobamate in the maintenance phase (max dose 400 mg/day) and were included in this post hoc analysis. Among patients who met an initial given seizure-reduction level (≥50%, ≥75%, ≥90%, or 100%), sustainability of that response was measured using a time-to-event methodology.

Long-term efficacy and safety of cannabidiol in patients with treatment-resistant epilepsies: Four-year results from the expanded access program.

Objective: Cannabidiol (CBD) expanded access program, initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsies (TREs) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019.

Methods: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/ml oral solution), increasing from 2 to 10 mg/kg/day to tolerance or maximum 25-50 mg/kg/day dose, depending on the study site.

Perampanel monotherapy for the treatment of epilepsy: Clinical trial and real-world evidence.

Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration's (FDA's) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries.

Post hoc analysis of a phase 3 study for treatment of uncontrolled focal seizures: Adjunctive cenobamate dose and seizure reduction by baseline seizure frequency.

This post hoc analysis (n = 240) of a subset of study sites (10 eligible US sites) from an open-label phase 3 study assessed whether baseline seizure frequency (<3 seizures/28 days vs ≥3 seizures/28 days) impacted mean cenobamate dose required to achieve 100% seizure reduction, duration of this response, and responder rates. Patients with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals.

Long-term open-label perampanel: Generalized tonic-clonic seizures in idiopathic generalized epilepsy.

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.

PROVE: Retrospective, non-interventional, Phase IV study of perampanel in real-world clinical care of patients with epilepsy.

Objective: To assess retention, dosing, efficacy, and safety of perampanel in a large cohort of patients with epilepsy during routine clinical care.

Methods: PROVE was a retrospective, non-interventional Phase IV study (NCT03208660). Data were obtained retrospectively from the medical records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinicians' recommendation.

Efficacy of cenobamate for uncontrolled focal seizures: Post hoc analysis of a Phase 3, multicenter, open-label study.

Objective: To report long-term post hoc efficacy and safety data from 10 US study sites from an open-label Phase 3 study of adjunctive cenobamate (NCT02535091).

Methods: Patients with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications (ASMs) were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day).

Post hoc analysis of a phase 3, multicenter, open-label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications.

Objective: To report post hoc results on how adjustments to baseline antiseizure medications (ASMs) in a subset of study sites (10 US sites) from a long-term, open-label phase 3 study of adjunctive cenobamate affected tolerability, efficacy, and retention.

Methods: Patients with uncontrolled focal seizures taking stable doses of one to three ASMs were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day).

A multivariable prediction model of a major treatment response for focal-onset seizures: A post-hoc analysis of Phase III trials of perampanel.

Objective: Although 50 % reduction in seizure frequency is a common efficacy endpoint in clinical trials of antiepileptic drugs (AEDs), 75 % or greater reductions may be required to improve patients' health-related quality of life. Identification of clinical factors that are associated with high responder rates may help to inform clinicians on which patients may optimally benefit from treatment. We evaluated potential predictive factors for achieving major treatment responses (≥75 % reduction in seizure frequency per 28 days from study baseline) in patients with drug-resistant focal-onset seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures in perampanel trials designed for regulatory approval.

Perampanel in real-world clinical care of patients with epilepsy: Interim analysis of a phase IV study.

Objective: To assess the retention rate, efficacy, safety, and dosing of perampanel administered to patients with epilepsy during routine clinical care in the retrospective phase IV, PROVE Study (NCT03208660).

Methods: Exposure, efficacy, and safety data were obtained from the medical records of patients initiating perampanel after January 1, 2014, across 29 US study sites. The cutoff date for this interim analysis was October 10, 2018.

Assessment of the long-term efficacy and safety of adjunctive perampanel in tonic-clonic seizures: Analysis of four open-label extension studies.

Objective: This post hoc analysis evaluated long-term efficacy and safety in patients with focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS) who entered open-label extension (OLEx) studies to receive long-term adjunctive perampanel.

Methods: Patients aged 12 years and older who completed phase II or III randomized, double-blind, placebo-controlled studies could enter an OLEx study, each comprising a blinded conversion period followed by an open-label maintenance period (32-424 weeks; maximum perampanel dose = 12 mg/d). Exposure, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed.

Adjunctive perampanel and myoclonic and absence seizures: Post hoc analysis of data from study 332 in patients with idiopathic generalized epilepsy.

Purpose: This post hoc analysis assessed the effects of adjunctive perampanel on myoclonic and absence seizure outcomes in patients (aged ≥12 years) with idiopathic generalized epilepsy (IGE) and generalized tonic-clonic seizures during the double-blind (up to 8 mg/day) and open-label extension (OLEx; up to 12 mg/day) phases of Study 332.

Methods: Patients experiencing myoclonic and/or absence seizures during study baseline were included. Assessments for myoclonic and absence seizures included: median percent change in seizure frequency, number of seizure days and seizure-free days (all per 28 days), 50 % and 75 % responder rates, seizure-freedom rates, seizure worsening, and monitoring of treatment-emergent adverse events (TEAEs).

Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study.

Objective: During the development of cenobamate, an antiseizure medication (ASM) for focal seizures, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. To mitigate the rate of DRESS, a start-low, go-slow approach was studied in an ongoing, open-label, multicenter study. Also examined were long-term safety of cenobamate and a method for managing the pharmacokinetic interaction between cenobamate, a 2C19 inhibitor, and concomitant phenytoin or phenobarbital.

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.

Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy.

Objective: To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal- (partial-) onset seizures.

Methods: This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400-1200 mg once daily), two phase 3 trials of ESL monotherapy (1200-1600 mg once daily), and their open-label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na ]), incidences of hyponatremia-related treatment-emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia.

Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator.

Objective: The objective of this phase 2a study was to assess the activity of PF-06372865, a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines, in the epilepsy photosensitivity model as a proof-of-principle of efficacy.

Methods: Seven participants with a photoparoxysmal response to intermittent photic stimulation (IPS) at baseline were randomized in a double-blind, 4-period cross-over study examining single doses of 17.5 and 52.

Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

Objective: Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.

Methods: Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included.

Effects of adjunctive eslicarbazepine acetate on serum lipids in patients with partial-onset seizures: Impact of concomitant statins and enzyme-inducing antiepileptic drugs.

Purpose: To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences.

Subjects And Methods: We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200 mg once daily) in patients with treatment-refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period.

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.).

Lacosamide for uncontrolled primary generalized tonic-clonic seizures: An open-label pilot study with 59-week extension.

Objective: Assess the safety of adjunctive lacosamide for the treatment of uncontrolled primary generalized tonic-clonic seizures in patients (16-65 years) with primary generalized (genetic) epilepsy (PGE).

Methods: An open-label pilot safety study (SP0961; NCT01118949), comprising 12 weeks' historical baseline, 4 weeks' prospective baseline, 3 weeks' titration (target: 400mg/day adjunctive lacosamide) and 6 weeks' maintenance. Patients who continued to the extension study (SP0962; NCT01118962) then received ≤59 weeks of flexible treatment (100-800mg/day lacosamide with flexible dosing of concomitant antiepileptic drugs).

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.