Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex

Abstract

for the GWPCARE6 Study Group IMPORTANCE Efficacy 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).OBJECTIVE To 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 medicationresistant 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.INTERVENTIONS Patients 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 RELEVANCE Cannabidiol 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.

Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox–Gastaut Syndrome

“…Several mechanisms have been proposed to mediate antiseizure proprieties so far, including the inhibition of the GPR55 orphan receptor and adenosine reuptake, as well as the activation/desensitization of TRPV1 ( 2 , 3 ). A pharmaceutical formulation of highly purified CBD has been recently approved by US Food and Drug Administration (FDA) ( 4 ) and European Medicine Agency (EMA) ( 5 ) for the treatment of seizures associated with two treatment-resistant epilepsies (TREs), Dravet (DS), and Lennox–Gastaut (LGS) syndromes, typically refractory to currently available antiseizure medications (ASMs) and more recently for the treatment of seizures associated with tuberous sclerosis ( 6 ). Pharmacokinetic and pharmacodynamic drug–drug interactions can occur between CBD and clobazam (CLB), with an up to 5-fold increase in N -desmethylclobazam plasma concentration.…”

Cannabidiol and the central nervous system: translating into clinics

“…Further than the debated action on CB receptors, CBD inhibits adenylyl cyclase and voltage gated calcium channels activity, while activates potassium channels and mitogen activated protein kinase (MAPK) and it has been suggested to increase mTOR pathway activity (11). This effect is highly debatable considering the more recent observation that CBD is effective in Tuberous sclerosis (characterized by hyperactivation of mTOR pathway) patients and animal models (12,13). In fact, CBD has also been shown to inhibit apoptosis in human breast cancer cells by inhibiting the expression of cyclin D1 and mTOR pathway, and by increasing the peroxisome proliferator-activated (PPARγ) receptor expression (14).…”

“…Nowadays, CBD's efficacy was demonstrated in five placebo-controlled pivotal trials, two conducted in LGS (190,191), two in DS (53,192), and one in epilepsy associated with TSC (13). Furthermore, numerous expanded access use studies as well as open label extension of RTCs have been published so far (193)(194)(195)(196)(197)(198) and numerous comprehensive reviews and metanalysis investigating the clinical…”

“…Recently, a systematic review summarized the currently available data beyond DS and LGS, evidencing the highest-quality evidence available for TSC (201). In the one RCT performed enrolling patients with TSC, CBD at both 25 and 50 mg/kg/die doses produced a significantly greater reduction in focal and generalized seizure frequency and total seizure frequency (13). A 40% responder rate (at least 50% reduction) was reported in approximatively 40% of patients, a data overlapping with prior expanded access study of CBD (50 mg/kg/day of maximum dose).…”

Syndromspezifische Therapien, Impfung gegen Corona und Epileptologie in der DDR

“…In den letzten 5 Jahren erfolgte die Zulassung von Everolimus (2017) für die Behandlung therapierefraktärer fokaler Epilepsie bei der tuberösen Hirnsklerose (TSC) [1,2], von Cannabidiol in Kombination mit Clobazam (2019) in der Behandlung des Dravet-Syndroms und des Lennox-Gastaut-Syndroms [3,4] sowie von Fenfluramin (Ende 2020) in der Behandlung des Dravet-Syndroms [5][6][7]. Demnächst wird die Zulassung von Cannabidiol in der Behandlung der TSC ohne die zusätzliche Gabe von Clobazam erwartet [8]. Aber auch die alte und inzwischen nachweisbar bewährte Therapieform der ketogenen Diät [9] und die eigentlich schon immer nicht nur "syndromspezifisch", sondern auch "personalisiert" angelegten epilepsiechirurgischen Eingriffe [10]…”