Novel seizure outcomes in patients with Lennox‐Gastaut syndrome: Post hoc analysis of seizure‐free days in rufinamide Study 303

Auvin, Stéphane; Williams, Betsy; McMurray, Rob; Kumar, Dinesh; Perdomo, Carlos; Malhotra, Manoj

doi:10.1002/epi4.12314

Cited by 16 publications

(30 citation statements)

References 13 publications

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“…In the open-label optimized treatment and titration period of this placebo-controlled, double-blind, randomized withdrawal trial in adult participants with narcolepsy with cataplexy [ 16 ], LXB monotherapy reduced cataplexy frequency and increased cataplexy-free days, a measure of symptom control similar to ones used in other neurologic disease states including migraine (headache-free days) [ 17 ] and epilepsy (seizure-free days) [ 18 ]. The overall TEAE profile of LXB was consistent with that previously observed for SXB.…”

Section: Discussionmentioning

confidence: 99%

Changes in Cataplexy Frequency in a Clinical Trial of Lower-Sodium Oxybate with Taper and Discontinuation of Other Anticataplectic Medications

et al. 2022

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Background Lower-sodium oxybate (LXB) is an oxybate medication with the same active moiety as sodium oxybate (SXB) and a unique composition of cations, resulting in 92% less sodium. LXB was shown to improve cataplexy and excessive daytime sleepiness in people with narcolepsy in a placebo-controlled, double-blind, randomized withdrawal study (NCT03030599). Additional analyses of data from this study were conducted to explore the effects of LXB on cataplexy, including the clinical course and feasibility of transition from other anticataplectics to LXB monotherapy. Objective The aim of these analyses was to evaluate cataplexy frequency during initiation/optimization of LXB and taper/discontinuation of prior antidepressant/anticataplectic medications. Methods Eligible participants (adults aged 18–70 years with narcolepsy with cataplexy) entered the study taking SXB only (group A), SXB + other anticataplectics (group B), or anticataplectic medication other than SXB (group C), or were cataplexy-treatment naive (group D). LXB was initiated/optimized during a 12-week, open-label, optimized treatment and titration period (OLOTTP). Other anticataplectics were tapered/discontinued during weeks 3–10 of OLOTTP. A 2-week stable-dose period (SDP; during which participants took a stable dose of open-label LXB) and 2-week double-blind randomized withdrawal period (during which participants were randomized to continue LXB treatment or switch to placebo) followed OLOTTP. Treatment-emergent adverse events (TEAEs) were recorded throughout the duration of the study. Results At the beginning of OLOTTP, median weekly cataplexy attacks were lower in participants taking SXB at study entry (SXB only [2.00]; SXB + other anticataplectics [0.58]) versus participants who were taking other anticataplectics (3.50) or were anticataplectic naive (5.83). Median weekly cataplexy attacks decreased during weeks 1–2 of OLOTTP in all groups. Increased cataplexy frequency was observed in participants tapering/discontinuing other anticataplectics during weeks 3–10 and was more prominent in participants taking other anticataplectics alone compared with those taking SXB plus other anticataplectics. Cataplexy frequency decreased throughout initiation/optimization in anticataplectic-naive participants. Median number of cataplexy-free days/week at the end of SDP (study week 14) was similar in all groups (6.0, 6.1, 6.0, and 6.2 in groups A, B, C, and D, respectively). During OLOTTP and SDP, TEAEs of worsening cataplexy were reported in 0%, 47.8%, 16.7%, and 2.2% of participants in groups A, B, C, and D, respectively; most TEAEs of worsening cataplexy were reported during tapering/discontinuation of other anticataplectics. Conclusions LXB monotherapy was effective in reducing cataplexy and increasing cataplexy-free days. These results illustrate the feasibility of switching from SXB to LXB while tapering/discontinuing other anticat...

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Section: Discussionmentioning

confidence: 99%

Changes in Cataplexy Frequency in a Clinical Trial of Lower-Sodium Oxybate with Taper and Discontinuation of Other Anticataplectic Medications

et al. 2022

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“…The median (95% CI) time from the start of the titration period to the first and second PGTC seizure was 12 days (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) T A B L E 1 Baseline demographics, inclusion, and epilepsy-specific medical history F I G U R E 1 Kaplan-Meier time to end point curves with censoring starting with titration or maintenance for the time to first, second, or exceeding pre-randomization monthly seizure count (PSC). + represents a censored observation.…”

Section: Time-to-event Analysesmentioning

confidence: 99%

“…2,3 As a result, new methodologies have been explored to reduce placebo exposure. [4][5][6][7][8][9][10] One of these proposed methodologies is "time to event," which could maintain or improve statistical power while reducing participant risk. 8,[11][12][13] This end point proposes that participants can be observed on investigative treatment for a pre-specified number of seizures instead of a pre-specified number of weeks.…”

Section: Introductionmentioning

confidence: 99%

Time to exceed pre‐randomization monthly seizure count for perampanel in participants with primary generalized tonic–clonic seizures: A potential clinical end point

et al. 2022

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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 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.

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“…Overall, behavioural outcomes were comparable between the rufinamide and ‘any other AED’ groups, although the small sample size and difficulties assessing behaviour are important caveats that should be acknowledged (Table 2 ) [ 68 ]. In addition, in a post-hoc analysis, the mean number of seizure-free days was 42.2% greater post-baseline compared with baseline in patients treated with rufinamide ( p < 0.0001), with only one rufinamide patient experiencing a decrease in the number of seizure-free days post-baseline [ 72 ]. The median time to reach the baseline number of seizures increased by 10.5 days for rufinamide and 0.5 days for the ‘any other AED’ group during the treatment phase, to 46.0 and 54.0 days, respectively.…”

Section: Pharmacologic Agentsmentioning

confidence: 99%

Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies

Strzelczyk

Schubert‐Bast

2021

CNS Drugs

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Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient’s lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%–68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%–78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat–OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a ‘one size fits all’ approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.

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Novel seizure outcomes in patients with Lennox‐Gastaut syndrome: Post hoc analysis of seizure‐free days in rufinamide Study 303

Cited by 16 publications

References 13 publications

Changes in Cataplexy Frequency in a Clinical Trial of Lower-Sodium Oxybate with Taper and Discontinuation of Other Anticataplectic Medications

Changes in Cataplexy Frequency in a Clinical Trial of Lower-Sodium Oxybate with Taper and Discontinuation of Other Anticataplectic Medications

Time to exceed pre‐randomization monthly seizure count for perampanel in participants with primary generalized tonic–clonic seizures: A potential clinical end point

Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies

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