Adjunctive Perampanel Oral Suspension in Pediatric Patients From ≥2 to &lt;12 Years of Age With Epilepsy: Pharmacokinetics, Safety, Tolerability, and Efficacy

Renfroe, J. Ben; Mintz, Mark; Davis, Ronald L.; Ferreira, José Alexandre; Dispoto, Sharon; Ferry, Jim; Umetsu, Yuko; Rege, Bhaskar; Majid, Oneeb; Hussein, Ziad; Laurenza, Antonio

doi:10.1177/0883073819827407

Cited by 35 publications

(39 citation statements)

References 13 publications

(34 reference statements)

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“…In paediatric patients, two prospective, open-label, multicentre studies had extractable outcome data in generalised seizures: Study 311 (NCT02849626) [ 9 ] and Study 232 (NCT01527006) [ 10 ]. In Study 311, from a population of 180 patients aged 4 to < 12 years with focal seizure or PGTCS, 31 patients had generalised seizures, and among the 22 with PGTCS at baseline, seizure frequency was reduced by a median of 69% (95% CI 18–100; IQR 82) [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

“…In study 232, of 50 patients aged ≥ 2 to < 12 years, 22 had generalised seizures, with a median 35.8% reduction in overall seizure frequency and a responder rate of 59.1% in the 11-week core study treatment phase. Seizure data were presented by age subgroups for these 50 patients, but with small numbers and highly variable data (Supplemental Tables S8 and S9, see ESM 1 ) [ 10 ]. Safety outcomes were not reported for the generalised seizure subgroup.…”

Section: Resultsmentioning

confidence: 99%

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Exploring the Evidence for Broad-Spectrum Effectiveness of Perampanel: A Systematic Review of Clinical Data in Generalised Seizures

et al. 2021

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Background The effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary generalised tonic-clonic seizures (PGTCS) in idiopathic generalised epilepsies (IGEs). Objective We aimed to identify and review available evidence on outcomes with perampanel in generalised seizures and epilepsies to examine its potential as a broad-spectrum anti-seizure medication. Methods Bibliographic databases of publications, clinical trials, and conference abstracts were searched up to August 2020 to identify studies reporting seizure or safety outcomes in patients of any age, with any type of epilepsy-associated generalised seizures treated with perampanel. Data extracted from selected records were tabulated by seizure type and syndrome, and analysed qualitatively (PROSPERO protocol CRD42020201564). Results Ninety-one reports met inclusion criteria and were selected: 15 reports of 1 randomised controlled trial (RCT), 8 reports of 4 non-randomised interventional studies, 37 reports of observational studies, 21 case reports and 10 systematic reviews and meta-analyses. Extracted data included 359 patients with PGTCS of any aetiology, 251 with myoclonic seizures, 112 with absence seizures, 50 with tonic seizures and 32 children with epileptic spasms. The most commonly reported epilepsy type was IGE (N = 378) and the most common syndromes were juvenile myoclonic epilepsy (N = 92), progressive myoclonic epilepsies (N = 59) and absence epilepsies (N = 43). The RCT provided Class I evidence of the efficacy and tolerability of adjunctive perampanel for PGTCS in patients aged ≥ 12 years with IGE. Data from other studies provides weaker (observational) evidence of its effectiveness in multiple generalised seizure types, including myoclonic, absence and tonic seizures. There were no patterns suggesting seizure worsening or aggravation in any seizure or epilepsy type. Conclusions The identified studies suggest the potential of perampanel as a broad-spectrum antiseizure medication. Much of the available data, however, come from non-randomised, non-controlled studies and are open to high risk of bias. Further studies are warranted to provide more robust evidence.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Exploring the Evidence for Broad-Spectrum Effectiveness of Perampanel: A Systematic Review of Clinical Data in Generalised Seizures

et al. 2021

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“…Results from an open‐label pilot study (with long‐term extension; Study 232 [NCT01527006]) of once‐daily adjunctive perampanel oral suspension in patients with epilepsy aged ≥2 to <12 years showed that perampanel PK is independent of age, weight, or liver function. This suggests that the same perampanel dose (mg/day) can be given to adults and children (≥2 years of age) without the need for age or weight‐based adjustments to achieve exposures shown to be efficacious …”

Section: Introductionmentioning

confidence: 99%

Open‐label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (4 to <12 years) with inadequately controlled focal seizures or generalized tonic‐clonic seizures

Fogarasi¹,

Flamini

Milh

et al. 2020

Epilepsia

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Objective: Study 311 (NCT02849626) was a global, multicenter, open-label, singlearm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/ pharmacodynamics of once-daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic-clonic seizures [FBTCS]) or generalized tonic-clonic seizures (GTCS). Methods: In the 311 Core Study, a 4-week Pre-treatment Period (Screening/Baseline) preceded a 23-week Treatment Period (11-week Titration; 12-week Maintenance)and 4-week Follow-up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days from Baseline (Treatment Period), and 50% responder and seizure-freedom rates (Maintenance Period). Patients were stratified by age (4 to <7; 7 to <12 years) and concomitant enzyme-inducing anti-seizure drug (EIASD) use. Results: One hundred eighty patients were enrolled (FS, n = 149; FBTCS, n = 54; GTCS, n = 31). The Core Study was completed by 146 patients (81%); the most common primary reason for discontinuation was adverse event (AE) (n = 14 [8%]). Mean (standard deviation) daily perampanel dose was 7.0 (2.6) mg/day and median (interquartile range) duration of exposure was 22.9 (2.0) weeks. The overall incidence of treatment-emergent AEs (TEAEs; 89%) was similar between patients with FS (with/ without FBTCS) and GTCS. The most common TEAEs were somnolence (26%) and nasopharyngitis (19%). There were no clinically important changes observed for cognitive function, laboratory, or electrocardiogram (ECG) parameters or vital signs.Median percent reductions in seizure frequency per 28 days from Baseline were as follows: 40% (FS), 59% (FBTCS), and 69% (GTCS). Corresponding 50% responder and seizure-freedom rates were as follows: FS, 47% and 12%; FBTCS, 65% and 19%; 126 | FOGARASI et Al. | 127 FOGARASI et Al.

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“…Perampanel (up to 12 mg/day) demonstrated efficacy and tolerability in randomized, double‐blind, placebo‐controlled phase III studies in patients aged ≥12 years with uncontrolled focal seizures, with or without focal to bilateral tonic‐clonic (FBTC) seizures (previously secondarily generalized seizures), and in patients aged ≥12 years with idiopathic generalized epilepsy and GTC seizures 3‐7 . Perampanel oral suspension (up to 0.18 mg/kg/day) demonstrated efficacy and tolerability in a phase II study of patients aged ≥2 to <12 years with epilepsy 8 . However, there is limited information available on how data from these trials have been adapted to clinical practice in the real‐world epilepsy clinic.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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. The primary efficacy endpoint was retention rate. Secondary efficacy endpoints included median percent changes in seizure frequency, seizure‐freedom rate, and overall investigator impression of seizure effect. Results All enrolled patients (N = 1121) received perampanel. Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 16.6 (14.7) months; overall mean (SD) daily perampanel dose was 5.7 (2.7) mg. Perampanel uptitration occurred weekly (21.1%), biweekly (23.8%), every 3 weeks (1.5%), other (43.3%), and unknown (10.3%). Across the Safety Analysis Set (N = 1121), retention rate on perampanel at 24 months was 49.5% (n = 319/645). At 12 months, the median reduction in seizure frequency per 28 days from baseline in the small number of patients for whom data were available was 75.0% (n = 85), and 30/85 (35.3%) patients were seizure free. Based on investigator impression at the end of treatment, improvement, no change (ie, stable), or worsening of seizures was reported in 54.3%, 33.7%, and 12.0% of patients, respectively. Treatment‐emergent adverse events occurred in 500 (44.6%) patients; the most common were dizziness (9.2%), aggression (5.4%), and irritability (4.5%). Serious treatment‐emergent adverse events occurred in 32 (2.9%) patients. Significance Favorable retention and sustained efficacy were demonstrated for ≥12 months following initiation of perampanel during routine clinical care in patients with epilepsy.

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Adjunctive Perampanel Oral Suspension in Pediatric Patients From ≥2 to <12 Years of Age With Epilepsy: Pharmacokinetics, Safety, Tolerability, and Efficacy

Cited by 35 publications

References 13 publications

Exploring the Evidence for Broad-Spectrum Effectiveness of Perampanel: A Systematic Review of Clinical Data in Generalised Seizures

Exploring the Evidence for Broad-Spectrum Effectiveness of Perampanel: A Systematic Review of Clinical Data in Generalised Seizures

Open‐label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (4 to <12 years) with inadequately controlled focal seizures or generalized tonic‐clonic seizures

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

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