Cannabidiol (3) – Epidyolex®

• Clinical trials
  • In the double-blind, placebo-controlled study GWEP1332 (Part B), the efficacy of cannabidiol (20 mg/kg/day) as an adjunctive anti-epileptic treatment was investigated in comparison with placebo in children and adolescents (aged 2 to 18 years) with Dravet syndrome.
  • The GWEP1424 study is a randomised, double-blind, placebo-controlled, multicentre Phase III trial. The study investigated the efficacy and safety of cannabidiol as an adjunctive anti-epileptic treatment compared with placebo in children and adolescents (aged 2 to 18 years) with Dravet syndrome.

Patients aged 2 years and over with Dravet syndrome

• Overall, there is a hint of considerable additional benefit.
• mortality
  • No deaths occurred in the trials.
• Morbidity – frequency of convulsive and non-convulsive seizures
  • At the end of treatment, a statistically significant percentage reduction in the frequency of convulsive seizures (all classified as tonic-clonic, tonic, clonic or atonic) compared with baseline, totalling 37%.
  • For the 20 mg/kg/day dose, statistically significant effects were observed only in the sensitivity analysis.
  • At doses below 20 mg/kg/day, statistically significant advantages for cannabidiol were observed in reductions of 25%, 50% and 75%, as well as in the analysis of increases in the frequency of convulsive seizures (each analysed in the meta-analysis).
• Morbidity – status epilepticus
  • Status epilepticus, defined as any seizure lasting 30 minutes or longer, was also recorded via the telephone diary and occurred in some patients in both convulsive and non-convulsive forms in the studies. No statistically significant differences were observed.
• Morbidity – Hospitalisations
  • Hospital admissions which, in the opinion of the investigator, were epilepsy-related were recorded as epilepsy-related hospitalisations. During treatment with 10 mg/kg/day cannabidiol, 6 study participants were hospitalised for epilepsy-related reasons, compared with 2 participants in the placebo group. The difference between the treatment arms is not statistically significant.
  • In the 20 mg/kg/day cannabidiol group, 5 (GWEP1424) and 2 (GWEP1332 B) patients, respectively, were hospitalised for epilepsy-related reasons, compared with 0 and 2 patients, respectively, in the placebo group. The difference is not statistically significant in the meta-analysis.
  • The collected data were adjusted post-hoc where it was deemed that the hospitalisation could be considered non-epilepsy-related. The unadjusted data initially showed 5 hospitalised patients in the GWEP1332 Part B study, which resulted in a statistically significant effect compared with the placebo group (0 patients).
• Morbidity – Caregiver Global Impression (CGI-C)
  • The overall impression of health status was assessed in the studies using the Caregiver Global Impression Scale for Change (CGI-C).
  • At the end of the study, there were statistically significantly more patients showing an improvement in health status with cannabidiol (for both dosages) compared with the placebo arm. The results for the ‘worsening’ responder criterion at the end of the study showed no statistically significant differences.
• quality of life
  • Health-related quality of life was assessed using the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire.
  • There was no statistically significant difference in the change from baseline to the end of treatment between the treatment groups, either in the 16 subscales or in the overall scale.
  • The response rates for the ‘Cognition’ and ‘Well-being’ domains were below 70 per cent, meaning that these domains could not be used for the evaluation.
• Side effects
  • For the evaluated population, a statistically significant difference to the detriment of cannabidiol was observed between the treatment arms in the analysis of serious adverse events exclusively in Study GWEP1332 Part B.
  • At doses of less than 20 mg/kg/day of cannabidiol, there were statistically significantly more therapy discontinuations due to adverse events than with placebo.
  • When considering AEs with an incidence of ≥ 10%, at a dose of 10 mg/kg/day of cannabidiol, a statistically significant difference to the detriment of cannabidiol was observed only for the event ‘pneumonia’ (PT), at doses below 20 mg/kg/day, for AE in the system organ classes ‘Gastrointestinal disorders’, ‘General disorders and administration site conditions’, ‘Investigations’, ‘Metabolism and nutrition disorders’, ‘Nervous system disorders’ and ‘Psychiatric disorders’ in the individual studies.
  • Furthermore, at doses below 20 mg/kg/day, a statistically significant disadvantage was observed for the serious AE ‘infections and parasitic diseases’.
• Overall assessment
  • For the benefit assessment of cannabidiol in the treatment of Dravet syndrome in patients aged 2 years and over, the patient population defined in accordance with the summary of product characteristics (SmPC) is considered, i.e. those patients receiving additional clobazam treatment.
  • In the morbidity category, a reduction in seizure frequency in this therapeutic indication is an important therapeutic goal and of high clinical relevance. For the clinically relevant endpoints in this therapeutic indication – frequency of convulsive seizures and a 75% reduction in convulsive seizures – a statistically significant advantage of cannabidiol over placebo was demonstrated, and, for the 20 mg/kg/day dose, also for reductions of 25% and 50%, and for an increase of > 0%. The results regarding health status, assessed by the carer using the CGI-C, support this finding: an improvement in health status was noted significantly more frequently in the cannabidiol arms. No relevant effects were observed for the other morbidity endpoints relevant to the assessment (non-convulsive seizures, status epilepticus, hospitalisations). The advantages in the morbidity endpoint category are assessed as considerable overall.
  • In the quality of life category, the analyses of the QOLCE questionnaire revealed no statistically significant or clinically relevant advantages or disadvantages associated with cannabidiol.
  • In the side effects category, statistically significant disadvantages were observed in particular in the overall rate of therapy discontinuation due to AEs at doses of less than 20 mg/kg/day of cannabidiol.
  • These disadvantages, which were observed exclusively at the 20 mg/kg/d dosage, are not considered sufficient to outweigh the advantages in the morbidity category, which are assessed as considerable. In particular, it can be assumed that the risk of such adverse effects occurring in the everyday healthcare situation can be reduced through individual dose titration as envisaged in the marketing authorisation, which was not reflected in the studies.

Courtesy translation only, please refer to the German original.