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

ABSTRACT: Objective:Drug development for patients with Lennox-Gastaut syndrome (LGS) is based on clinical trials that use drop seizure counts. However, such counts do not assess total seizure burden and affect a patient's quality of life (QoL). In this post hoc analysis, we evaluated two novel seizure efficacy parameters related to QoL in pediatric patients with LGS, using seizure diary data from rufinamide Study 303 (NCT01405053). Methods:Study 303 was a phase III, multicenter, randomized, controlled, open-label study involving patients aged ?1 to <4 years with inadequately controlled LGS. Patients were randomized 2:1 to receive add-on therapy with rufinamide or any other approved antiseizure drug (ASD), in addition to their existing treatment of 1-3 ASDs, across a 106-week treatment phase. Seizure diaries, completed by parents or caregivers, recorded seizure occurrence, and were used in this post hoc analysis to evaluate two novel efficacy parameters comparing baseline vs postbaseline mean number of seizure-free days and assessing time to reach the number of prerandomization seizures for patients receiving rufinamide or any other ASD. Results:Patients received rufinamide (n = 25) or any other ASD (n = 12). For rufinamide, mean number of seizure-free days was 42.2% greater postbaseline compared with baseline (P < 0.0001); only one rufinamide patient experienced a decrease in number of seizure-free days postbaseline. Median time to reach the baseline number of seizures increased by 10.5 days for rufinamide and 0.5 days for the any-other-ASD group during the treatment phase, to 46.0 and 54.0 days, respectively. Significance:Both of these novel and contrasting endpoints demonstrated potential improvements in seizure outcomes in patients receiving rufinamide postbaseline vs baseline. Although these parameters should be investigated in larger patient populations, our initial findings suggest that they could be applied as predefined primary endpoints for seizure assessment in future clinical trials for LGS drug development.

SUBMITTER: Auvin S

PROVIDER: S-EPMC6546073 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Auvin Stéphane S Williams Betsy B McMurray Rob R Kumar Dinesh D Perdomo Carlos C Malhotra Manoj M

Epilepsia open 20190313 2

<h4>Objective</h4>Drug development for patients with Lennox-Gastaut syndrome (LGS) is based on clinical trials that use drop seizure counts. However, such counts do not assess total seizure burden and affect a patient's quality of life (QoL). In this post hoc analysis, we evaluated two novel seizure efficacy parameters related to QoL in pediatric patients with LGS, using seizure diary data from rufinamide Study 303 (NCT01405053).<h4>Methods</h4>Study 303 was a phase III, multicenter, randomized, ...[more]

PMID: 31168494

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Project description:IntroductionManagement of Lennox-Gastaut syndrome (LGS) in adulthood can be particularly challenging. Published reports describing the use of rufinamide specifically in adult patients with LGS are scarce. A post hoc subgroup analysis of data from a phase III trial was conducted to investigate the efficacy and safety/tolerability of rufinamide in adults with LGS.MethodsA randomized, double-blind, placebo-controlled trial was conducted in patients with LGS, aged 4 years and above. During an 84-day, double-blind treatment period, patients received either adjunctive rufinamide therapy or placebo. Efficacy and safety/tolerability were assessed in a post hoc subgroup analysis of adult patients (≥18 years). Efficacy was assessed as change from baseline in 28-day seizure frequency, 50% responder rate, and seizure freedom rate; each calculated for total seizures and drop attacks. Safety/tolerability assessments included the evaluation of adverse events (AEs).ResultsThirty-one adults aged 18-37 years with LGS received treatment with either rufinamide (n = 21) or placebo (n = 10). Three patients in the rufinamide group did not complete the trial. The median change from baseline in seizure frequency was -31.5% for rufinamide versus +22.1% for placebo (P = 0.008) for all seizures and -54.9% versus +21.7% (P = 0.002) for drop attacks. Responder rates were 33.3% for rufinamide versus 0% for placebo (P = 0.066) for all seizures and 57.1% versus 10.0% (P = 0.020) for drop attacks. No patient achieved freedom from all seizures but two rufinamide-treated patients (9.5%) became free of drop attacks. Overall, 71.4% of patients treated with rufinamide and 60.0% of patients treated with placebo experienced AEs; most commonly, somnolence (33.3% vs. 20.0%) and vomiting (19.0% vs. 0%). Most AEs were of mild or moderate intensity.ConclusionRufinamide demonstrated favorable efficacy and was generally well tolerated when used as adjunctive treatment for adults with LGS.FundingEisai.

Project description:ObjectiveTo determine long-term safety and efficacy of adjunctive clobazam for patients with Lennox-Gastaut syndrome (LGS).MethodsEligible patients from two randomized controlled trials (Phase II OV-1002 and Phase III OV-1012) were able to enroll in open-label extension (OLE) study OV-1004 beginning in December 2005 and received clobazam until they discontinued (mandatory at 2 years for patients outside the United States) or until study completion in March 2012. Patients in the United States could have received clobazam for 6 years before it became commercially available. Efficacy assessments included changes in rates of drop seizures and total seizures, responder rates (≥50%, ≥75%, or 100% decreases in seizure frequency vs. baseline), sustained efficacy over time, concomitant antiepileptic drug (AED) use, and global evaluations. Safety assessments included exposure to clobazam, laboratory assessments, physical and neurologic examinations, vital sign monitoring, electrocardiography monitoring, and adverse event reporting.ResultsOf 267 patients who enrolled in the OLE, 188 (70%) completed the trial. Two hundred seven patients were from the United States, which was the only country in which patients could be treated with clobazam for >2 years. Forty-four patients were treated with clobazam for 5 years, and 11 for 6 years. Because of the low number of Year 6 patients, this group is not reported separately. Improvements in baseline seizure rates were very stable over the course of the study, with a median 85% decrease in drop seizures at Year 1, 87% at Year 2, 92% at Year 3, 97% at Year 4, and a 91% decrease for patients who had reached Year 5. Similar results were observed for total seizures (79% decrease at both Years 1 and 2, 82% decrease at Year 3, 75% decrease at Year 4, and 85% decrease at Year 5). Responder rates were also stable for the duration of the trial. Of patients who had achieved a ≥50% decrease in median drop-seizure frequency from baseline to Month 3, 86% still had that degree of drop-seizure reduction at Year 3 (and 14% lost their initial responses), and 47% were drop-seizure-free. Most patients who had achieved drop-seizure freedom in the original controlled trials remained drop-seizure-free in the OLE. Based on parents' and physicians' ratings of global evaluations, 80% of patients were "very much improved" or "much improved" after 3 years. Of the 43 patients with concomitant AED data who were treated for 5 years, 30% increased, 19% decreased, and 51% had no change in numbers of AEDs versus their Week 4 regimens. The mean modal clobazam dosage was 0.90 mg/kg/day at Year 1 and 0.97 mg/kg/day at Year 5, suggesting that study patients did not need significant increases in dosage over time. The safety profile was what would be expected for clobazam for LGS patients over a 5-year span, and no new safety concerns developed over time.SignificanceIn this largest and longest-running trial in LGS, adjunctive clobazam sustained seizure freedom and substantial seizure improvements at stable dosages through 3 years of therapy in this difficult- to-treat patient population. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Project description:ObjectivesThis study aimed to investigate the functional network effects of corpus callosotomy (CC), a well-recognized palliative surgical therapy for patients with Lennox-Gastaut syndrome (LGS). Specifically, we sought to gain insight into the effects of CC on LGS remission, based on brain networks in LGS by calculating network metrics and evaluating by network measures before and after surgery.MethodsElectroencephalographic recordings made during preoperative and 3-month postoperative states in 14 patients with LGS who had undergone successful CC were retrospectively analyzed. First, undirected correlation matrices were constituted for the mathematical expression of functional networks. Then, we plotted these networks to analyze the effects of CC on connectivity. In addition, conventional local and global network measures were applied to evaluate differences in network topology between preoperative and postoperative states.ResultsIn the preoperative state, hubs were mainly distributed around the paramedian regions. After CC, the hubs moved from the paramedian regions to the dual-hemisphere and even the lateral regions. Thus, the general connectivity state became more homogeneous, which was verified by network plots and statistical analysis of local measures. The results of global network measures indicated a decreased clustering coefficient in the delta band, decreased characteristic path length in both the delta and gamma bands, and increased global efficiency in the gamma band.ConclusionOur results showed a consistent variation in the global brain network that converted to a small-world topology with an optimal balance of functional integration and segregation of the network. Such changes were positively correlated with satisfactory surgery results, which could be interpreted as being indicative of LGS recovery process after CC. For patients with refractory LGS along with no focal epileptogenic zone findings, which were not suitable for the resective surgical therapy, our results verified that CC could work as an effective surgical treatment option.

Project description: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.

Dataset Information

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

Publications

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

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