Abstract
O’Brien TJ, Berkovic SF, French JA, Messenheimer JA, Sebree TB, Bonn-Miller MO, Gutterman DL; STAR 1/STAR 2 Study Group. JAMA Netw Open. 2022;5(7):e2220189. doi:10.1001/jamanetworkopen.2022.20189. Erratum in: JAMA Netw Open. 2022;5(8): e2228862. Erratum in: JAMA Netw Open. 2022;5(12):e2249107. PMID: 35802375; PMCID: PMC9270696 Importance: Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking. Objective: To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018. Interventions: Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years. Main Outcomes and Measures: Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period. Results: A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants; 390-mg cannabidiol, 62 participants; placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days; least squares mean difference, 0.014; 95% CI, −0.175 to 0.203; P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days; least squares mean difference, 0.096; 95% CI, −0.093 to 0.285; P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, −6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension. Conclusions and Relevance: Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery. Trial registration: ACTRN12616000510448 (double-blind); ACTRN12616001455459 (open-label).
Kühne F, Becker LL, Bast T, Bertsche A, Borggraefe I, Boßelmann CM, Fahrbach J, Hertzberg C, Herz NA, Hirsch M, Holtkamp M, Janello C, Kluger GJ, Kurlemann G, Lerche H, Makridis KL, von Podewils F, Pringsheim M, Schubert-Bast S, Schulz J, Schulze-Bonhage A, Steinbart D, Steinhoff BJ, Strzelczyk A, Syrbe S, De Vries H, Wagner C, Wagner J, Wilken B, Prager C, Klotz KA, Kaindl AM. Epilepsia Open. 2023. doi:10.1002/epi4.12699. Epub ahead of print. PMID: 36693811
Objective: Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest anti-seizure effects also beyond these three epilepsy syndromes. Methods: In a retrospective multi-center study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers. Results: The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0-72) years (235 children and adolescents, 76 adults). Therapy with CBD was off-label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co-medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%). Significance: Our study highlights that CBD has an anti-seizure effect comparable to other anti-seizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children <2 years of age.
Commentary
Despite the advent of numerous second-generation anti-seizure medications (ASMs) in the past 3 decades, one third of persons with epilepsy still experience disabling seizures. 1,2 When nonpharmacological (e.g., ketogenic diet) or surgical (e.g., destructive or neuromodulatory) treatment options are not available, indicated or desired, these patients inevitably rely on further trials of the approved ASMs, at times in different formulations, doses, or indications than the labeled ones.
Cannabidiol (CBD), a nonpsychotropic phytocannabinoid, was first approved in 2018 in oral form as an adjunct treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex. 3 -9 Its synergistic promise for seizure frequency reduction in conjunction with more commonly prescribed ASMs through interaction with serotonin, opioid, and non-endocannabinoid G protein-coupled receptors, in addition to its potential benefit in mood, sleep, appetite, spasticity and hence, overall quality of life, made it appealing for children with such developmental epileptic encephalopathies (DEEs). 3 -9 The current 2 studies 10,11 investigate whether its therapeutic spectrum can be extended to other seizure types, through other formulations and across the age spectrum.
The first study 10 is a double-blind, placebo-controlled, multicenter, randomized clinical trial (RCT) of transdermally administered CBD conducted in 14 epilepsy centers in Australia and New Zealand on adult patients with drug-resistant focal epilepsy. A total of 188 participants were randomized in 195 mg/daily or 390 mg/daily of CBD versus placebo for 12 weeks, while being maintained on a stable ASMs regimen that excluded clobazam. Participants completing that double-blind period were offered enrollment into a 2-year open-label extension (OLE) of 390 mg CBD daily, during which medication adjustments, including CBD increments, were permitted. The findings were analyzed for both study periods in terms of efficacy, safety, and pharmacokinetics. While no statistically significant reduction in seizure frequency compared to placebo was noted during the RCT stage, nearly 60% of the participants demonstrated at least 50% seizure frequency reduction 6 months into the OLE. Notwithstanding the possibility of a pervasive high placebo effect and the influence of other ASMs adjustments, this positive response sustained in the long run. No dose-relationship response was observed, and plasma levels were highly variable. During the RCT stage, treatment-emergent adverse events occurred in approximately 9% more patients in the treatment groups compared to placebo, they were mild to moderate, and they were not dose related. The vast majority of participants continued in the OLE stage, where excellent tolerability and safety were also noted, both on clinical as well as paraclinical (e.g., liver function tests) grounds, even when higher CBD doses were used. 10
The second study 11 is a retrospective, multicenter study from 16 epilepsy centers in Germany providing real-world data on the add-on use of oral CBD. The study cohort comprised of 311 patients, almost a quarter of whom were adults. Three quarters of the patients were drug-resistant on polypharmacy (including nearly 46% on clobazam) and two-thirds of them had epilepsy syndromes other than the approved CBD indications. Cannabidiol was used off-label in >90% of cases (i.e., for different seizure types, ages or doses than approved for, or without clobazam that is required in the European labeling due to previously established synergistic effect) with a median end dose of 17.8 mg/kg/day. 11 One-third of the cohort terminated the treatment for various reasons, including lack of efficacy, poor tolerability, pregnancy, suboptimal compliance, and insurability. In the end of the follow-up period of nearly 16 months, approximately 37% of the whole cohort experienced >50% seizure frequency reduction, typically those on higher doses, regardless of seizure type or comedication with clobazam. Factoring in the retrospective study design, adverse effects were observed in nearly 47% of the patients, foremost in the form of sleepiness and diarrhea. Within the confines of inconsistent CBD plasma levels collection, these were not dose-dependent, and their profile did not differ between in-label versus off-label use. Liver enzymes elevation was observed rarely, typically in conjunction with valproate administration. Conversely, improvement of soft signs (e.g., mood, sleep, appetite, spasticity) was seen in 41% of the patients. 11
Notably, both studies 10,11 share common points. They are both industry-sponsored, multicenter investigations that provide evidence on the adjunctive use of CBD for focal seizures also in adults. Additionally, the former 10 informs on its transdermal application. In that sense they cumulatively raise 3 important questions: (1) How does CBD work, both in terms of safety and tolerability, compared to other ASMs; (2) How does CBD work for alternative seizure types and populations than those originally approved for; (3) How does CBD work as a transdermal gel compared to its approved oral version?
The first question is hard to answer with the available data in hand, as CBD has only been used as adjunctive treatment and no head-to-head comparisons have ever been done with other ASMs. 1,2 Yet, the accumulated evidence from the initial RCTs and OLEs 3 -9 suggest fairly similar rates of seizure response, at least as a second-line treatment, and satisfactory tolerability. 1,2 One should not discount, however, the high public expectations of cannabis that may result in higher response rates in retrospective or open-label studies and the potential of regression to the mean in patients with high seizure counts at baseline. 12
Preliminary data to answer the second and third question are provided by the studies discussed herein, 10,11 as well as a prior nonrandomized controlled trial on the use of transdermal gel for children with DEEs. 12 In adults, the transdermal formulation in the OLE of the first study 10 resulted in fairly similar efficacy for focal seizures compared to the oral formulation evaluated in a mixed pediatric and adult population in the real world experience of the second study. 11 A prior study on the use of CBD gel in skin patches for children with DEEs 12 led to a comparable 50% responder rate of approximately 40% compared to the DS 4 and LGS 6 studies conducted with the oral formulation. Despite the lack of a dose–response effect, 10 the measured plasma concentrations with transdermal administration overlapped with those observed with oral CBD. 8 Tolerability of the transcutaneous delivery both in the adults with focal seizures 10 and in children with DEEs 12 was linked to lower rates of discontinuation compared to its oral counterparts for these indications. 3 -9,11 The reduced rates of liver function test elevation and gastrointestinal adverse effects with the transdermal application may be attributable to the reduced first-pass metabolism. 10
In conclusion, these 2 studies 10,11 converge with the extant literature that: (1) CBD is a reasonably safe and well tolerated adjunct for drug resistant epilepsy (DRE), with RCT based data for its proven-albeit not mind-boggling efficacy in DEEs in the pediatric population and preliminary, open-label/real world data for a fairly similar efficacy in focal seizures in the adult population and (2) transdermal delivery of ASMs may be an alternative option for patients facing difficulties with oral administration, with potentially better tolerability compared to oral formulation, at least in the case of CBD. Foremost, they highlight the need for further research on CBD to clarify the optimal dose and delivery mode in other populations (e.g., elderly), for additional indications (e.g., autoimmune or tumoral epilepsy), its comparative effectiveness and standalone efficacy earlier on in the disease process (e.g., monotherapy), the optimal combination with other pharmacological (e.g., pharmacodynamic interactions with ASMs) and nonpharmacological (e.g., ketogenic diet) treatments, its interaction with drugs used for other medical comorbidities (e.g., cardiovascular or neoplastic diseases), the need for drug level monitoring, the role in addressing common epilepsy-related comorbidities (e.g., mood problems), the long-term efficacy and tolerability (e.g., potential impact on bone health and teratogenicity), its cost-effectiveness, as well as any effect on the mechanisms underlying epileptogenesis and pharmacoresistance.
