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Clobazam-treated patients with Lennox-Gastaut syndrome experienced fewer seizure-related injuries than placebo patients during trial OV-1012.

ABSTRACT: Drop seizures are especially problematic in patients with Lennox-Gastaut syndrome (LGS) because of their potential for serious injury. In this post hoc analysis of phase 3 OV-1012 data, a medical review was conducted of seizure-related injuries based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms from all adverse event (AE) listings. Patients receiving clobazam experienced fewer seizure-related injuries than those receiving placebo (8.9% all clobazam dosages vs. 27.1% placebo, p ? 0.05). Significant differences in the rates of seizure-related injuries were observed for the medium- and high-dosage clobazam treatment groups (4.8% and 10.2%, respectively, p ? 0.05). A total of 50 of 53 AEs considered seizure-related were mild or moderate in intensity; 3 severe AEs occurred in the placebo group (fall, contusion, and jaw fracture). A single serious AE (jaw fracture, which required hospitalization and surgery) occurred in a placebo-treated patient. Most injuries resolved by the end of the study. This analysis indicates that the reduction in drop-seizure frequency achieved with clobazam provides a clinically meaningful benefit, a reduced likelihood of experiencing seizure-related injuries.

SUBMITTER: Isojarvi J

PROVIDER: S-EPMC5021111 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Clobazam-treated patients with Lennox-Gastaut syndrome experienced fewer seizure-related injuries than placebo patients during trial OV-1012.

Isojarvi Jouko J Lee Deborah D Peng Guangbin G Sperling Michael R MR

Epilepsia 20160504 6

Drop seizures are especially problematic in patients with Lennox-Gastaut syndrome (LGS) because of their potential for serious injury. In this post hoc analysis of phase 3 OV-1012 data, a medical review was conducted of seizure-related injuries based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms from all adverse event (AE) listings. Patients receiving clobazam experienced fewer seizure-related injuries than those receiving placebo (8.9% all clobazam dosages vs. 27.1% p ...[more]

PMID: 27145465

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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:ObjectiveDrug 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).MethodsStudy 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.ResultsPatients 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.SignificanceBoth 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.

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:OBJECTIVE:Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial. METHODS:Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. RESULTS:This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE:In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

Dataset Information

Clobazam-treated patients with Lennox-Gastaut syndrome experienced fewer seizure-related injuries than placebo patients during trial OV-1012.

Publications

Clobazam-treated patients with Lennox-Gastaut syndrome experienced fewer seizure-related injuries than placebo patients during trial OV-1012.

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