Cannabidiol (1) – 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. It 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

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Overall, there is a hint of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• mortality
  • No deaths occurred in the study.
• 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%.
  • A sensitivity analysis revealed a similar, though not statistically significant, effect.
  • All other responder analyses (reduction of ≥25%, ≥50% or 100%) showed the same direction of effect, but no statistically significant differences.
  • In the analysis of the endpoint ‘change in non-convulsive seizures’ (all myoclonic, countable partial and other partial seizures, or absence seizures), only those patients who had already reported non-convulsive seizures at baseline were included. This therefore does not represent the entire patient population as defined in the prescribing information, which limits the interpretability of the results. No statistically significant difference was observed.
• 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 study arms, in both convulsive and non-convulsive forms. No statistically significant differences were observed.
• Morbidity – Hospitalisations
  • Hospital admissions deemed by the investigator to be epilepsy-related were recorded as epilepsy-related hospitalisations. Six study participants experienced epilepsy-related hospitalisations whilst on cannabidiol treatment, compared with two participants on placebo. The difference between the treatment arms is not statistically significant.
• Morbidity – Caregiver Global Impression (CGI-C)
  • Despite the subjective nature of the carer’s assessment, this measure should be taken into account for the therapeutic indication.
  • At both the end of treatment and the end of the study, there were statistically significantly more patients showing an improvement in health status in the cannabidiol group compared with the placebo group.
• Quality of life – Quality of Life in Childhood Epilepsy Questionnaire (QOLCE)
  • Health-related quality of life was assessed using the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire.
  • In the study, data were collected at baseline and at the end of treatment. No statistically significant difference in the change from baseline to the end of treatment was observed 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 included in the analysis.
• Side effects
  • For the population under evaluation, the study found no statistically significant difference between the treatment arms in the assessment of serious adverse events.
  • No suitable data were available for the endpoint of severe AEs, as the study did not provide a standardised definition based on severity.
  • There were no therapy discontinuations due to adverse events.
  • When considering AEs with an incidence of ≥ 10%, a statistically significant difference to the detriment of cannabidiol was observed only for the event ‘pneumonia’ (PT).
• Overall assessment
  • In the category of morbidity, a reduction in seizure frequency in the therapeutic indication is an important therapeutic goal and of high clinical relevance. For the clinically relevant endpoints— frequency of convulsive seizures and a 75% reduction in convulsive seizures —cannabidiol demonstrated a statistically significant advantage over placebo.
  • Further responder analyses show the same direction of effect, but no statistical significance. The results on 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 arm.
  • No clinically 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 of cannabidiol.
  • In the side effects category, there were no statistically significant differences in the overall rates of serious adverse events, and there were no therapy discontinuations due to adverse events.
  • The results for the 10 mg/kg/d dose of cannabidiol indicate advantages that are assessed as considerable in extent. Overall, however, it is not possible to quantify the extent of the additional benefit of cannabidiol, as data on dosages of up to 20 mg/kg/day – which are also relevant for the benefit assessment – were not available.
• Strength of the evidence
  • The patient population compliant with the guidelines (combination with clobazam) was not planned a priori, nor was it stratified by randomisation. Furthermore, no data on adult patients were presented.
  • Overall, these uncertainties regarding the validity of the evidence provide a hint of additional benefit.

Courtesy translation only, please refer to the German original.