Seizure-free days as a novel outcome in patients with Lennox-Gastaut syndrome: Post hoc analysis of patients receiving cannabidiol in two randomized controlled trials.

OBJECTIVE: In this post hoc analysis, we aimed to assess seizure-free days as a potential new outcome measure to use in randomized placebo-controlled trials (RCTs) of patients with Lennox-Gastaut syndrome (LGS). METHODS: In two phase 3 RCTs (GWPCARE3, GWPCARE4), eligible patients were randomized to receive plant-derived highly purified cannabidiol (CBD; Epidiolex® in the USA; 100 mg/mL oral solution) at 10 mg/kg/day (CBD10; GWPCARE3 only), at 20 mg/kg/day (CBD20), or matched placebo. The treatment period comprised a 2-week dose titration and a 12-week maintenance period. This post hoc analysis evaluated the least-squares (LS) mean changes from baseline and difference versus placebo in the number of drop or total seizure-free days per 28 days during the treatment period or maintenance period alone. LS mean changes were estimated using an analysis of covariance model, with categorical age and baseline number of drop or total seizure-free days as covariates, and treatment group as a fixed factor. RESULTS: A total of 396 patients were included in this post hoc analysis. During the 14-week treatment period, LS mean changes from baseline in number of drop seizure-free days per 28 days for patients receiving placebo (n = 161), CBD10 (n = 73), and CBD20 (n = 162) were 2.81 (95% confidence interval [CI] = 1.75-3.88), 5.64 (95% CI = 4.08-7.20), and 6.45 (95% CI = 5.39-7.52), respectively. The LS mean differences in number of drop seizure-free days versus placebo were 2.83 (95% CI = .98-4.68) for CBD10 and 3.64 (95% CI = 2.18-5.10) for CBD20. For total seizure-free days, LS mean differences versus placebo were 2.63 (95% CI = .92-4.34) for CBD10 and 3.50 (95% CI = 2.16-4.85) for CBD20. The improvements from baseline in seizure-free days during the maintenance period alone were similar to the entire treatment period. SIGNIFICANCE: Drop and total seizure-free days represent potential new and clinically meaningful endpoints for future RCTs in patients with LGS.

Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials.

OBJECTIVE: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome. METHODS: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. RESULTS: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients. SIGNIFICANCE: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period.

Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. METHODS: Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. RESULTS: Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

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.

Clobazam is equally safe and efficacious for seizures associated with Lennox-Gastaut syndrome across different age groups: Post hoc analyses of short- and long-term clinical trial results.

The peak age at onset of Lennox-Gastaut syndrome (LGS) is between 3 and 5years. Patients with LGS frequently experience multiple types of treatment-refractory seizures and require lifelong therapy with several antiepileptic drugs. Here, post hoc analyses of clinical trials (phase III trial OV-1012 and open-label extension trial OV-1004) provide short- and long-term efficacy and safety data of adjunctive clobazam in patients with LGS stratified by age at baseline (≥2 to <12years, ≥12 to <17years, and ≥17years). In OV-1012, 301 patients were screened, 238 were randomized, 217 comprised the modified intention-to-treat population, and 177 completed the study. A total of 267/306 patients (61 of 68 from phase II trial OV-1002 and 206 of 238 from phase III trial OV-1012) entered the open-label extension trial. Demographics and clinical characteristics were similar between different age groups in OV-1012 and OV-1004. No differences in efficacy or adverse events were observed across age groups in OV-1012 and OV-1004. The results of these post hoc analyses show that adjunctive clobazam over the short and longterm was similarly effective and well-tolerated in both pediatric and adult patients with LGS.

Stable dosages of clobazam for Lennox-Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years.

OBJECTIVE: To determine long-term safety and efficacy of adjunctive clobazam for patients with Lennox-Gastaut syndrome (LGS). METHODS: Eligible 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. RESULTS: Of 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. SIGNIFICANCE: In 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.

Clobazam is efficacious for patients across the spectrum of disease severity of Lennox-Gastaut syndrome: post hoc analyses of clinical trial results by baseline seizure-frequency quartiles and VNS experience.

Lennox-Gastaut syndrome (LGS) severity varies considerably, so the potential impact of differences in baseline severity on patient outcome following treatment is clinically informative. Here, two surrogate indicators of LGS severity (baseline seizure frequency and vagus nerve stimulation [VNS] use) were used in post hoc analyses of both short- and long-term clobazam trials (Phase III OV-1012 [CONTAIN] and open-label extension [OLE] OV-1004). In CONTAIN, 217 patients comprised the modified, intention-to-treat population. Each baseline seizure-frequency quartile had ~40 patients, and baseline weekly drop-seizure frequency ranges were as follows: <10 (Quartile 1), 10-30 (Quartile 2), 32-86 (Quartile 3), and 86-1077 (Quartile 4). Mean percentage decreases in average weekly drop and total seizures were similar for all quartiles. More than 50% of patients in all 4 quartiles demonstrated ≥ 50% decreases in weekly drop- and total-seizure frequency. The percentage of patients achieving 100% reduction in drop seizures was 33% for clobazam-treated patients (vs. 7% for placebo) in Quartile 1. Five percent of clobazam-treated patients in Quartile 4 (most severe LGS) vs. 0% for placebo achieved 100% reduction in drop seizures. A total of 267 of 306 possible patients entered the OLE (61/68 from a Phase II study and 206/238 from Phase III CONTAIN). Each quartile had ~66 patients, and baseline weekly drop-seizure ranges were as follows: <10 (Quartile 1), 10-31 (Quartile 2), 32-110 (Quartile 3), and 111-1147 (Quartile 4). Median percentage decreases in average weekly drop and total seizures were similar between quartiles. Through 5 years of therapy, >50% of patients in all 4 quartiles demonstrated ≥ 50% decreases in weekly frequency for drop seizures. More than 12% of patients in Quartile 4 achieved 100% reduction in drop seizures from Month 3 through Year 5. For the VNS analyses in CONTAIN, the least-squares mean decreases in average weekly rate of drop seizures (mITT population) were 52% for VNS patients receiving clobazam vs. -22% for placebo (p < 0.01). For non-VNS patients, these percentages were 53% for clobazam and 26% for placebo (p < 0.01). Moreover, 50% and 54% of clobazam-treated patients in the VNS and non-VNS groups demonstrated ≥ 50% decreases in average weekly drop- and total-seizure frequencies, and 11% and 14% in the two groups achieved drop-seizure freedom, respectively. Analyses using baseline seizure frequency and VNS use as surrogates for disease severity showed that clobazam treatment of patients with less severe or severe LGS was equally efficacious.

Caregiver-reported outcomes with real-world use of cannabidiol in Lennox-Gastaut syndrome and Dravet syndrome from the BECOME survey.

PURPOSE: Plant-derived highly purified cannabidiol (CBD) reduced the frequency of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) and improved the overall condition of patients in placebo-controlled phase 3 clinical trials. Anecdotal reports also suggest a positive effect on nonseizure outcomes. In this study, we aimed to identify, through a caregiver survey which nonseizure outcomes were most likely to change in these patients. METHODS: The BEhavior, COgnition, and More with Epidiolex® (BECOME) was a 20-minute, cross-sectional, online survey that was developed with extensive input from caregivers, healthcare professionals, and epilepsy researchers, and was based on questions from validated measures and previously published caregiver reports. US-based caregivers (from Jazz Pharmaceuticals patient/caregiver database) of people with LGS or DS who were treated with CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months were asked to compare the past month to the period before CBD initiation and rate their impression of changes using symmetrical Likert scales. RESULTS: A total of 498 caregivers (97% parents) of patients with LGS (80%) or DS (20%) completed the survey. Mean (range) age of patients was 16 (1-73) years, and 52% were male. Patients were taking a median CBD dose of 14 mg/kg/d and median 4 concomitant antiseizure medications. A large proportion of respondents reported improvements in ≥1 survey question for all nonseizure-related domains: alertness, cognition, and executive function (85%); emotional functioning (82%); language and communication (79% in nonverbal patients and 74% in verbal); activities of daily living (51%); sleep (51%); and physical functioning (46%). Respondents reported improvements in seizure-related domains, including overall seizure frequency (85%), overall seizure severity (76%), seizure-free days per week for ≥1 seizure type (67%), and seizure freedom during the past month (16%). The majority of respondents who reported reduction in seizure frequency also reported improvements in nonseizure outcomes domains (51-80%). However, improvements in nonseizure outcomes (18-56%) were also reported in patients who either had no change or worsening of seizure frequency. CONCLUSIONS: This survey characterized and quantified caregiver impression of changes in the seizure and nonseizure outcomes in patients taking add-on CBD treatment. Overall, 93% of caregivers reported planning to continue CBD treatment, primarily because of reduced seizure burden but also because of improvements in nonseizure-related outcomes. Despite the limitations that are associated with a retrospective survey-based study design, these results support further evaluation of the effect of CBD treatment on nonseizure outcomes among patients with LGS or DS.

Single-Institution Comparative Study of Magnetic Resonance-Guided Laser Interstitial Thermal Therapy and Open Corpus Callosotomy.

OBJECTIVE: Open corpus callosotomy (CC) poses a higher risk of perioperative morbidity than does magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) for treatment of drop and generalized seizures without documented superiority. We present a single-institution comparison between open and MRgLITT CC. METHODS: A 2-year retrospective review was performed of patients who underwent open and MRgLITT CC (January 2019-January 2021). Demographics, surgical outcome data, hospital costs, and interhemispheric connectivity with diffusion tensor imaging were compared. RESULTS: The average age in years was 9.3 and 11.4 for CC (n = 4) and MRgLITT (n = 9), respectively. Preoperative drop seizure frequency was higher in CC (25 vs. 14.5 seizures/day; P = 0.59). At 10 months follow-up, the reduction in drop seizure frequency was better in open CC, but not statistically significant (93.8% vs. 64.3%; P = 0.21). The extent of CC ablation did not correlate with seizure reduction (Pearson coefficient = 0.09). An inverse correlation between interhemispheric connectivity change (diffusion tensor imaging analysis) and drop seizure frequency reduction was noted (Pearson coefficient = -0.97). Total hospital cost was significantly lower in MRgLITT ($67,754 vs. $107,111; P = 0.004), attributed to lower intensive care unit (1.1 vs. 4 days; P= 0.004) and total hospital stay (1.8 vs. 10.5 days; P = 0.0001). Postoperative hydrocephalus was present in 75% of patients in the CC group compared with zero in the MRgLITT group. CONCLUSIONS: Our middle-volume single-institution experience shows the safety, efficacy, and cost-effective benefit of MRgLITT compared with the traditional CC with therapeutic equipoise. This study is limited by the number of patients and, hence, further patient enrollment or multicenter study is warranted.

Corpus callosum and epilepsies.

PURPOSE: Corpus callosum (CC) is the largest forebrain commissure. This review focuses on the significance of CC for seizure disorders, the role of CC in seizure spread and the surgical disruption of callosal fibers (callosotomy) for treatment of patients with drug-resistant epilepsy. METHODS: Personal experience/extensive literature review. RESULTS: Structural CC pathologies comprise developmental abnormalities, callosal involvement in identified disorders, transient imaging findings and microstructural changes. Epilepsies are reported in up to two thirds of patients with complete or partial CC agenesis (AgCC). However, AgCC per se is not indicative for seizure disorders. Moreover, additional malformations of cortical development (MCD) are causal. Microstructural CC abnormalities are detected by advanced imaging techniques, are part of diffuse white matter disturbances and are related to cognitive deficits. The etiological significance remains unexplained. However, they are also found in non-epileptic benign and transient disorders. In drug-resistant epilepsies with violent drops to the floor ("drop seizures") callosotomy may be beneficial in seizure reduction. Since the EEG after callosotomy exhibits a single seizure focus in up to 50% of patients, consecutive resective surgical methods might be successful. CONCLUSION: CC is part of cerebral white matter and anomalies cannot act per se as seizure onset zone. Imaging techniques demonstrate additional lesions in patients with epilepsies. CC is the major pathway for seizure generalization. Therefore, callosotomy is used to prevent generalized drop seizures.

Comprehensive overview: efficacy, tolerability, and cost-effectiveness of clobazam in Lennox-Gastaut syndrome.

Clobazam is the newest medication approved by the US Food and Drug Administration (FDA) for the treatment of Lennox-Gastaut syndrome (LGS) in patients at least 2 years of age, although the medication has been available in countries around the world to treat epilepsy and anxiety disorders for many years. Though classified as a benzodiazepine, the drug differs structurally from other drugs in the class as it possesses nitrogen atoms at the 1 and 5 positions within the heterocyclic ring rather than at the 1 and 4 positions. This difference and the classification of clobazam as a partial agonist are believed to be responsible for the decreased incidence of sedative effects compared to other benzodiazepines. Adverse events associated with clobazam use in clinical trials have generally been mild to moderate in nature. Data from an open-label extension trial have confirmed that clobazam is efficacious for the treatment of seizures associated with LGS, particularly atonic seizures (drop seizures), over the long term. Tolerance to the drug's antiepileptic effects does not seem to be a common occurrence. The drug has proven to be a cost-effective option for therapy, particularly due to its ability to decrease the number of seizures that require medical treatment. Clobazam represents a welcome addition to the treatment options for LGS.

Clobazam and Aggression-Related Adverse Events in Pediatric Patients With Lennox-Gastaut Syndrome.

BACKGROUND: Lennox-Gastaut syndrome is an intractable epileptic encephalopathy marked by frequent drop seizures. Most patients develop moderate intellectual disability and behavioral problems, including hyperactivity, aggressiveness, insecurity, and autistic features. Treatment with benzodiazepines, including clobazam, may increase aggression/behavioral problems in patients with Lennox-Gastaut syndrome. Post hoc analyses of data from the OV-1012 trial assessed the potential for behavioral effects with clobazam treatment in pediatric (2 to 18 years) patients with Lennox-Gastaut syndrome. METHODS: OV-1012 was a phase 3, randomized, double-blind, parallel-group trial comprising a 4-week baseline period, 3-week titration period, and a 12-week maintenance period. Data from 194 patients were analyzed for a history of aggression/behavioral problems, occurrence of aggression-related adverse events, and by assessment of potential drug-related effects on four behavior domains of the Child Behavior Checklist. RESULTS: Twenty-nine aggression-related adverse events were reported for 27 (13.9%) patients. Similar percentages of clobazam-treated patients with and without a history of aggressive behavior experienced an aggression-related adverse event (16.7% versus 15.5%, respectively). In the medium- and high-dosage clobazam groups, onset of aggression-related adverse effects occurred within the 3-week titration period with 63.2% resolving by the end of the study. Aggression-related adverse event onset and resolution were similar for the low-dosage clobazam and placebo groups. Analysis of baseline to postbaseline T scores for the behavior domains of the Child Behavior Checklist indicated no significant differences between clobazam and placebo. CONCLUSIONS: Post hoc analyses indicate that the overall rate of aggression with clobazam treatment was low and dosage dependent. Clobazam treatment was effective in reducing drop seizures regardless of aggression experience.

Experience in the use of clobazam in the treatment of Lennox-Gastaut syndrome.

Clobazam is a 1,5-benzodiazepine used successfully worldwide since the 1970s as an anxiolytic and antiepileptic drug. Since its recent Food and Drug Administration (FDA) approval in the United States in 2011 as adjunctive treatment for Lennox-Gastaut syndrome, it has continued to show sustained efficacy and a better safety and tolerability profile compared with other benzodiazepines. The two randomized, controlled studies that led to the US FDA approval, as well as the follow-up multicenter, open-label study of clobazam, showed ≥50% seizure reduction for more than 50% of Lennox-Gastaut syndrome patients, while none of the other FDA-approved treatments for LGS have demonstrated efficacy rates better than 50%. Clobazam appears to have a safe profile and sustained effectiveness over the first 3 years of use in LGS and other epilepsy syndromes with intractable seizures, which makes it a viable long-term treatment option.