Long-term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open-label extension trial.
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ABSTRACT: Objective
To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.Methods
Patients who completed the randomized trial enrolled to receive CBD (Epidiolex® in the United States; Epidyolex® in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC-associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC).Results
Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/kg/day mean modal dose. Most patients (92%) had an adverse event (AE). Most common AEs were diarrhea (42%), seizure (22%), and decreased appetite (20%). AEs led to permanent discontinuation in 6% of patients. There was one death that was deemed treatment unrelated by the investigator. Elevated liver transaminases occurred in 17 patients (9%) patients; 12 were taking valproate. Median percentage reductions in seizure frequency (12-week windows across 48 weeks) were 54%-68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.Significance
In patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement.
SUBMITTER: Thiele EA
PROVIDER: S-EPMC9305454 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveAdd-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5.MethodsPatients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d.ResultsBy November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale.SignificanceThis trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.
| S-EPMC7379690 | biostudies-literature
Project description:AIM:To investigate the interdependence between risk factors associated with long-term intellectual development in individuals with tuberous sclerosis complex (TSC). METHOD:The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo). In phase 2, at an average of 8 years later, intellectual abilities were estimated for 88 participants with TSC and 35 unaffected siblings. Structural equation modelling was used to determine the risk pathways from genetic mutation through to IQ at phase 2. RESULTS:Intellectual disability was present in 57% of individuals with TSC. Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment. Individuals with TSC who had a slower gain in IQ from infancy to middle childhood were younger at seizure onset and had increased infant seizure severity. Structural equation modelling indicated indirect pathways from genetic mutation, to tuber count, to seizure severity in infancy, through to IQ in middle childhood and adolescence. INTERPRETATION:Early-onset and severe epilepsy in the first 2 years of life are associated with increased risk of long-term intellectual disability in individuals with TSC, emphasizing the importance of early and effective treatment or prevention of epilepsy. WHAT THIS PAPER ADDS:Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC). Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings. Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability. Risk pathways through seizures in the first 2 years predict long-term cognitive outcomes in individuals with TSC.
| S-EPMC7027810 | biostudies-literature
Project description:ImportanceEfficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC).ObjectiveTo evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC.Design, setting, and participantsThis double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication.InterventionsPatients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks.Main outcomes and measuresThe prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period.ResultsOf 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo.Conclusions and relevanceCannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage.Trial registrationClinicalTrials.gov Identifier: NCT02544763.
| S-EPMC7754080 | biostudies-literature
Project description:ObjectiveEvaluate long-term efficacy (percent seizure frequency reduction and responder rates), safety, and tolerability of adjunctive cenobamate in an open-label extension (OLE) of the randomized, double-blind, placebo-controlled study.MethodsPatients (aged 18-70 years) with uncontrolled focal seizures despite treatment with 1-3 antiseizure medications who completed the 18-week double-blind study (n=360) could enter the OLE, where they underwent a 2-week blinded conversion to cenobamate (target dose, 300 mg/day; min/max, 50/400 mg/day).ResultsThree hundred fifty-five patients were included in the OLE safety population (265 originally randomized to cenobamate, 90 originally randomized to placebo), and 354 were included in the OLE modified intent-to-treat population. As of July 2019, 58.9% (209/355) of patients were continuing cenobamate treatment and 141 had discontinued, including 16.6% (59/355) due to lack of efficacy, 8.7% (31/355) due to withdrawal by patient, and 7.6% (27/355) due to adverse events. Median (range) duration of OLE exposure was 53.9 (1.1-68.7) months. Retention rates at 12, 24, 36, and 48 months were 83%, 71%, 65%, and 62%, respectively. Median percent seizure frequency reduction over baseline increased with each 6-month OLE interval, up to 76.1% at months 43-48. Among observed patients, 16.4% (36/220) achieved 100% and 39.1% (86/220) achieved ≥90% seizure reduction during >36-48 months. Among the initial OLE mITT population, 10.2% (36/354) of patients achieved 100% and 24.3% (86/354) achieved ≥90% seizure reduction during >36-48 months. Similar to the double-blind study, adverse events (AEs) included dizziness, somnolence, fatigue, and headache. Serious AEs occurred in 20.3% (72/355) of patients.ConclusionLong-term efficacy, including 100% and ≥90% seizure reduction, was sustained during 48 months of cenobamate treatment, with 71% retention at 24 months. No new safety issues were identified. These results confirm the findings of the double-blind study and support the potential long-term clinical benefit of cenobamate.RegistrationClinicalTrials.gov NCT01866111.Classification of evidenceThis study provides Class IV evidence that oral Cenobamate 50-400 mg/day is effective as an adjunctive treatment for the long-term management of patients with uncontrolled focal seizures previously treated with 1 to 3 ASMs.
| S-EPMC9519254 | biostudies-literature
Project description:ObjectiveThis study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968).MethodsPatients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis.ResultsOne hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity.SignificanceLong-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs.
| S-EPMC8456960 | biostudies-literature
Project description:ObjectiveThe present analysis examined the exposure-response relationship by means of the predose everolimus concentration (Cmin ) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin .MethodsA model-based approach was used to predict patients' daily Cmin . Time-normalized Cmin (TN-Cmin ) was calculated as the average predicted Cmin in a time interval. TN-Cmin was used to link exposure to efficacy and safety end points via model-based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure-response relationship for seizure frequency (SF). An extended Cox regression model was used to link exposure to the time to first adverse event.ResultsThere was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by TN-Cmin and SF, regardless of patient's age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors/inducers. Results of an extended Cox regression analyses indicated that twofold increases in TN-Cmin were not associated with statistically significant increases in the risk of stomatitis or infections.SignificanceThe recommended TDM is to target everolimus Cmin within a range of 5-7 ng/mL initially and 5-15 ng/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of CYP3A4/P-glycoprotein inducers/inhibitors.
| S-EPMC6033043 | biostudies-literature
Project description:ObjectiveEpilepsy is commonly seen in Tuberous Sclerosis Complex (TSC). The relationship between seizures and developmental outcomes has been reported, but few studies have examined this relationship in a prospective, longitudinal manner. The objective of the study was to evaluate the relationship between seizures and early development in TSC.MethodsAnalysis of 130 patients ages 0-36months with TSC participating in the TSC Autism Center of Excellence Network, a large multicenter, prospective observational study evaluating biomarkers predictive of autism spectrum disorder (ASD), was performed. Infants were evaluated longitudinally with standardized evaluations, including cognitive, adaptive, and autism-specific measures. Seizure history was collected continuously throughout, including seizure type and frequency.ResultsData were analyzed at 6, 12, 18, and 24months of age. Patients without a history of seizures performed better on all developmental assessments at all time points compared to patients with a history of seizures and exhibited normal development at 24months. Patients with a history of seizures not only performed worse, but developmental progress lagged behind the group without seizures. All patients with a history of infantile spasms performed worse on all developmental assessments at 12, 18, and 24months. Higher seizure frequency correlated with poorer outcomes on developmental testing at all time points, but particularly at 12months and beyond. Patients with higher seizure frequency during infancy continued to perform worse developmentally through 24months. A logistic model looking at the individual impact of infantile spasms, seizure frequency, and age of seizure onset as predictors of developmental delay revealed that age of seizure onset was the most important factor in determining developmental outcome.ConclusionsResults of this study further define the relationship between seizures and developmental outcomes in young children with TSC. Early seizure onset in infants with TSC negatively impacts very early neurodevelopment, which persists through 24months of age.
| S-EPMC5497719 | biostudies-literature
Project description:ObjectiveThis post hoc analysis evaluated long-term efficacy and safety in patients with focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS) who entered open-label extension (OLEx) studies to receive long-term adjunctive perampanel.MethodsPatients aged 12 years and older who completed phase II or III randomized, double-blind, placebo-controlled studies could enter an OLEx study, each comprising a blinded conversion period followed by an open-label maintenance period (32-424 weeks; maximum perampanel dose = 12 mg/d). Exposure, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed.ResultsBaseline characteristics were generally balanced between patients with FBTCS (n = 720) and GTCS (n = 138). Mean (standard deviation) cumulative duration of perampanel exposure was 102.3 (70.3) weeks (FBTCS) and 83.9 (38.4) weeks (GTCS). Retention rates were 50.0% for up to 4 years (FBTCS) and 49.2% for up to 2 years (GTCS). Across OLEx treatment durations, median reductions in seizure frequency per 28 days were 66.7% (FBTCS) and 80.6% (GTCS). Fifty percent and 75% responder and seizure-freedom rates were 59.5%, 45.3%, and 18.4%, respectively (FBTCS), and 72.5%, 51.5%, and 16.7%, respectively (GTCS). Efficacy was sustained for up to 4 years (FBTCS) and up to 3 years (GTCS), even when accounting for early dropouts. TEAE incidence was highest during Year 1 (FBTCS, 85.3%; GTCS, 86.2%); most common were dizziness and somnolence. During Year 1, serious TEAEs were reported in 81 (11.3%; FBTCS) and 10 (7.2%; GTCS) patients. TEAEs were consistent with the known safety profile of perampanel; no new safety signals were identified with long-term treatment.SignificanceThis post hoc analysis suggests long-term (up to 4 years) adjunctive perampanel (up to 12 mg/d) is efficacious and well tolerated in patients (aged 12 years and older) with FBTCS or GTCS.
| S-EPMC7497073 | biostudies-literature
Project description:BACKGROUND:Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad neurodevelopmental disorders, including autism spectrum disorder symptomatology. Preclinical TSC studies have indicated altered neuronal chloride homeostasis affecting the polarity of ?-aminobutyric acid (GABA) ergic transmission as a potential treatment target. Bumetanide, a selective NKCC1 chloride importer antagonist, may attenuate depolarizing GABA action, and in that way reduce disease burden. In this open-label pilot study, we tested the effect of bumetanide on a variety of neurophysiological, cognitive, and behavioral measures in children with TSC. METHODS:Participants were treated with bumetanide (2dd 0.5-1.0?mg) for 13?weeks in an open-label trial. The Aberrant Behavior Checklist-Irritability (ABC-I) subscale was chosen as the primary endpoint. Secondary endpoints included other behavioral questionnaires in addition to event-related potentials (ERP) and neuropsychological tests if tolerated. Additionally, the treatment effect on seizure frequency and quality of life was assessed. Endpoint data were collected at baseline, after 91?days of treatment and after a 28-day wash-out period. RESULTS:Fifteen patients (8-21-years old) with TSC were included of which 13 patients completed the study. Treatment was well-tolerated with only expected adverse events due to the diuretic effects of bumetanide. Irritable behavior (ABC-I) showed significant improvement after treatment in 11 out of 13 patients (t(12) = 4.41, p = .001, d = .773). A favorable effect was also found for social behavior (Social Responsiveness Scale) (t(11) = 4.01, p = .002, d = .549) and hyperactive behavior (ABC-hyperactivity subscale) (t(12) = 3.65, p = .003, d = .686). Moreover, patients rated their own health-related quality of life higher after treatment. At baseline, TSC patients showed several atypical ERPs versus typically developing peers of which prepulse inhibition was significantly decreased in the TSC group. Neuropsychological measurements showed no change and bumetanide had no effect on seizure frequency. LIMITATIONS:The sample size and open-label design of this pilot study warrant caution when interpreting outcome measures. CONCLUSIONS:Bumetanide treatment is a potential treatment to alleviate the behavioral burden and quality of life associated with TSC. More elaborate trials are needed to determine the application and effect size of bumetanide for the TSC population. Trial registration EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.
| S-EPMC7204231 | biostudies-literature
Project description:Seizures are clinically significant manifestations associated with 79%-90% of patients with tuberous sclerosis complex. Often occurring within the first year of life in the form of infantile spasms, seizures interfere with neuropsychiatric, social, and cognitive development and carry significant individual and societal consequences. Prompt identification and treatment of seizures is an important focus in the overall management of tuberous sclerosis complex patients. Medical management, either after seizure onset or prophylactically in infants with electroencephalographic abnormalities, is considered first-line therapy. Vigabatrin and adrenocorticotropic hormone have emerged over the past few decades as mainstay pharmacologic modalities. Furthermore, emerging research on mammalian target of rapamycin inhibitors demonstrated promise for the management of seizures and subependymal giant cell astrocytoma. For appropriate surgical candidates with an epileptogenic zone associated with one or more glioneuronal hamartomas, ideally in noneloquent cortex, resective surgery can be considered, which provides a cure in 56% of patients. For medically refractory patients who do not meet criteria for curative surgery, palliative surgical approaches focused on reducing seizure burden, in the form of corpus callosotomy and vagus nerve stimulation, are alternative management options. Lastly, the ketogenic diet, a reemerging therapy based on the anticonvulsant effects of ketone bodies, can be utilized independently or in conjunction with other treatment modalities for the management of difficult-to-treat seizures.
| S-EPMC4211915 | biostudies-literature