Cannabidiol (2) – Epidyolex®

• Clinical trials
  • The GWEP1414 trial 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 adults (aged 2 to 55 years) with Lennox-Gastaut syndrome.
  • The double-blind, placebo-controlled GWEP1423 trial investigated the efficacy of cannabidiol (20 mg/kg/day) as an adjunctive anti-epileptic treatment compared with placebo in children and adults (aged 2 to 55 years) with Lennox-Gastaut syndrome.

Patients aged 2 years and over with Lennox-Gastaut 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.
• The patient population defined in accordance with the product information (combination with clobazam) was not planned a priori, nor was it stratified and randomised.
• The validity of the evidence is limited, as the patient population compliant with the prescribing information—which was used here for the benefit assessment—was not planned a priori nor was it stratified and randomised.
• 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.
  • Here, a statistically significant advantage for cannabidiol was observed among responders with a reduction of ≥ 50% in the frequency of convulsive seizures.
  • Further responder analyses (reduction of ≥25% or ≥75%) showed the same direction of effect, but no significant differences.
  • No patient achieved seizure freedom (a reduction of 100%).
  • 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.
  • A statistically significant difference was also observed here.
  • Responder analyses were not presented for non-convulsive seizures.
• 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 – Caregiver Global Impression (CGI-C)
  • The overall impression of the patient’s health status was assessed in the study using the Caregiver Global Impression Scale for Change (CGI-C).
  • At the end of treatment, there were statistically significantly more patients showing an improvement in health status in the cannabidiol group compared with the placebo arm.
• Quality of life – Quality of Life in Childhood Epilepsy Questionnaire (QOLCE) and Quality of Life in Epilepsy (QOLIE-31-P)
  • Health-related quality of life was assessed using the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire, which is generally considered suitable for patients up to the age of 18.
  • In the present study, however, the questionnaire was used for some patients over the age of 18, although the exact number is unclear.
  • As it is therefore not possible to determine the response rate, the analysis of the QOLCE cannot be used for the benefit assessment.
  • Due to its unclear validity, the Quality of Life in Epilepsy version 2 (QOLIE-31-P) questionnaire for adult patients is also not used to derive the additional benefit.
• Side effects
  • For the population assessed, the study revealed no statistically significant difference between the treatment arms in the analysis of serious adverse events.
  • One case of therapy discontinuation due to adverse events occurred in the cannabidiol arm (not statistically significant).
  • When considering AEs with an incidence of ≥ 10%, statistically significant differences to the detriment of cannabidiol were observed for the PT categories of fatigue, pneumonia, somnolence, and, for the SOC, nervous system disorders, with statistically significant differences to the detriment of cannabidiol; and in the PT, nasopharyngitis showed a statistically significant difference in favour of cannabidiol.
• Overall assessment / Conclusion
  • For the benefit assessment of cannabidiol in the treatment of Lennox-Gastaut syndrome in patients aged 2 years and over, the patient population defined in accordance with the summary of product characteristics (SmPC), i.e. those patients receiving additional clobazam treatment, from the GWEP1414 study at a dose of 10 mg/kg/day in the cannabidiol arm.
  • No deaths occurred in the patient population under consideration.
  • In terms of morbidity, a reduction in seizure frequency in this therapeutic indication is an important therapeutic goal and is of high clinical relevance.
  • For the clinically relevant endpoints – frequency of convulsive and non-convulsive seizures and a 50% reduction in convulsive seizures – cannabidiol demonstrated a statistically significant advantage over placebo in each case.
  • Further responder analyses show the same direction of effect, but no statistical significance.
  • 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 arm.
  • Although there is a statistically significant difference in favour of cannabidiol for the endpoint of frequency of non-convulsive seizures, the results are biased as they do not relate to the entire patient population.
  • No relevant effects were observed for the additional morbidity endpoint of status epilepticus, which is relevant to the assessment.
  • The advantages in the morbidity endpoint category are assessed as considerable overall.
  • No suitable data were available for the quality of life category.
  • In the category of side effects, there are no statistically significant differences in the overall rates of serious adverse events or therapy discontinuations due to adverse events.
  • The results for the 10 mg/kg/d dose of cannabidiol indicate advantages which 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.

Courtesy translation only, please refer to the German original.