Cannabidiol (5) – Epidyolex®

Patients aged 2 years and over with seizures associated with tuberous sclerosis, adjuvant treatment

• For cannabidiol in the therapeutic indication for adjuvant treatment for patients aged 2 years and over with seizures associated with tuberous sclerosis (TSC), there is a hint of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Overall, there is a hint of an additional benefit which, however, is non-quantifiable on the basis of the available scientific data.
• mortality
  • No deaths occurred in the study.
• Morbidity – frequency of TSC-associated seizures and other epileptic seizures
  • At the end of treatment, there was a statistically significant percentage reduction in the frequency of TSC-associated seizures with cannabidiol compared with placebo, totalling 30% compared with baseline.
  • The overall frequency of all seizures was also statistically significantly reduced, but not the frequency of other seizures.
  • For responders, a statistically significant advantage of cannabidiol was observed in both the reduction of ≥ 75 per cent in the frequency of TSC-associated seizures and in the frequency of all seizures.
• Morbidity – status epilepticus
  • Status epilepticus, defined as any convulsive or non-convulsive seizure lasting 30 minutes or longer, was also recorded via the IVRS and occurred in the study in both convulsive and non-convulsive forms in some patients.
  • No statistically significant differences were observed.
• Morbidity – Hospitalisations
  • Hospital admissions which, in the opinion of the trial staff, were epilepsy-related were recorded as epilepsy-related hospitalisations.
  • Eight study participants experienced epilepsy-related hospitalisations whilst on the cannabidiol treatment, compared with one participant on the placebo.
  • No statistical analysis is available.
• Morbidity – Clinician Global Impression (CGI-C) / Global Impression of Change (CGI-C/SGI-C)
  • At 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.
  • The result for the ‘worsening’ responder criterion at the end of the study was not statistically significant.
• Morbidity – Behaviour
  • No statistically significant difference was observed between the treatment arms in any of the subscales or total scores when analysing the change in mean values from baseline.
• quality of life
  • Only in the ‘Physical Limitations’ subscale was there a statistically significant difference in favour of cannabidiol, although the possibility that this difference is not clinically relevant when considering the standardised mean differences (using Hedge’s g) cannot be ruled out.
  • The other subscales and the total scale showed no statistically significant differences in change from baseline to the end of treatment between the treatment groups.
• Side effects
  • Statistically significant results to the detriment of cannabidiol were observed in the overall rates of serious adverse events (SAEs) and in therapy discontinuations due to adverse events.
  • When considering AEs with an incidence of ≥ 10%, statistically significant differences to the detriment of cannabidiol were observed in the system organ class ‘General disorders and administration site conditions’ and in the system organ class ‘Investigations’.
• Overall assessment
  • Data are available for the benefit assessment of cannabidiol in the treatment of seizures associated with tuberous sclerosis in patients treated with the maximum marketing authorisation-authorised dose of 25 mg/kg/day.
  • No deaths occurred in the study.
  • In the morbidity category, a statistically significant advantage of cannabidiol over placebo was observed for the clinically relevant endpoints in this therapeutic indication: the frequency of TSC-associated seizures, the frequency of seizures overall, as well as a 75 per cent reduction in TSC-associated seizures and a 75 per cent reduction in all seizures, a statistically significant advantage of cannabidiol over placebo (in each case in addition to treatment with other antiepileptic drugs).
  • The findings on health status, assessed by the carer using the CGI-C, support these results: an improvement in health status was noted significantly more frequently in the cannabidiol arm.
  • No relevant effects were observed for the other morbidity endpoints relevant to the assessment (further seizures, status epilepticus, behaviour).
  • 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 category of side effects, statistically significant disadvantages were observed in particular in the overall rate of SAEs and therapy discontinuations due to AEs under cannabidiol.
  • Due to the fixed dosage regimen in the study, whereby all participants were treated with the maximum dose rather than being individually titrated to an effective dose within the range of 10 to 25 mg/kg/day as intended under the marketing authorisation, the observed effects cannot be conclusively used to assess the extent of the additional benefit.
  • Overall, there is an additional benefit; however, this is a non-quantifiable benefit on the basis of the available scientific evidence.
• Significance of the evidence
  • Uncertainties also arise from the fixed titration regimen in the study, which does not reflect the procedure specified in the marketing authorisation: instead of a weekly increase of 5 mg/kg/day, the dose was increased in the study at significantly shorter intervals of two days each.
  • Furthermore, the treatment duration, including the titration phase, of 16 weeks is considered rather short for the indicated therapeutic indication.
  • Overall, the uncertainties mentioned regarding the validity of the evidence provide a hint of additional benefit.

Courtesy translation only, please refer to the German original.