Cannabidiol (CBD) to 27 Patients (Aged 2 Years - 19 Years) With Drug Resistant Epilepsy
Condition: Epilepsy
MeSH terms: Epilepsy
Study type: Interventional
Phase: Phase 1

Summary: 
      Part A: To evaluate the safety and tolerability of multiple ascending doses of GWP42003-P
      compared with placebo with respect to:

        -  Incidence, type and severity of adverse events (AEs)

        -  Effect on vital signs, including weight

        -  Effect on 12-lead electrocardiogram (ECG) findings

        -  Effect on laboratory parameters Part B: To make an assessment of the anti-epileptic
           efficacy of GWP42003-P compared with placebo with respect to the incidence in convulsive
           seizures

        -  To determine the plasma concentration time curves for GWP42003-P and its major human
           metabolite, following escalating multiple doses of GWP42003-P.

        -  To investigate the effect of GWP42003-P on the pharmacokinetics of concomitant
           anti-epileptic drugs (AEDs).

        -  To evaluate cognitive function, sleep quality and daytime sleepiness, in patients taking
           GWP42003-P in combination with AEDs.
    

Detailed description: 
      This multi-center study will consist of two parts: Part A and Part B. Part A will investigate
      the dose-ranging pharmacokinetics and tolerability of GWP42003-P.

      Part B is a 1:1 randomized, placebo-controlled 60 day comparison of GWP42003-P against
      placebo, at the dose which has been identified by Part A as the maximum tolerated dose. Part
      B will investigate the efficacy and safety of GWP42003-P.

      Following completion of Part B, all patients will be invited to continue to receive
      GWP42003-P in an open label extension study (which is separate to this protocol).

      Part A Following establishment of initial eligibility and baseline measurements, patients
      will enter Part A at Visit 1 and will begin the two month baseline observation period.
      Patients will record their number of convulsive seizures, and of other seizures, using an
      IVRS telephone diary system (recorded twice each day). Each call will take approximately five
      minutes to complete. Patients will return to the clinic at Visit 2 and the investigator will
      assess the patient's daily number of convulsive seizures from the patient's IVRS data.
      Patients who have experienced at least four convulsive seizures (tonic-clonic seizures and/or
      drop attacks) per month for each of the previous two months) and who meet all of the other
      inclusion/ exclusion criteria will be eligible to continue in the study. Patients will be
      asked for information regarding AEs, concomitant medications and/or changes to their
      medication.

      Eligible patients will enter into the pharmacokinetics part of the study at Visit 2 where
      blood samples will be taken using a sparse sampling strategy to minimize the blood volumes
      required for analysis of the plasma concentration/time curve for concomitant AEDs and routine
      safety bloods. This is conducted prior to the administration of Study medication at Dose
      Level 1.

      In each dose level, patients will be randomly assigned so that eight patients receive
      GWP42003-P and two patients receive placebo in each group. Patients will receive their study
      medication each day for the seven day exposure period. During this part of the study,
      patients will continue to record their daily number of convulsive seizures and of other
      seizures, using an IVRS telephone diary system.

      At Day 7 (Visit 3), blood will be taken for analysis of both the plasma concentration/time
      curve of GWP42003-P and its major metabolite, concomitant anti-epileptic medications and for
      routine safety purposes. At the end of the dosing period in Part A of the study patients will
      continue on placebo until they are ready to enter Part B of the study.

      Dose Level 2 will follow the same set of procedures as Dose Level 1, but dosing will not
      start until an evaluation of the clinical and pharmacokinetic results from Dose Group 1 has
      been completed. Subsequently Dose Groups 3 and 4 will be subject to the same procedures.

      When Dose Group 4 has completed the seven day Dosing Period, and subject to assessment of
      clinical safety and pharmacokinetics, patients will then be invited to continue into Part B,
      which is the double blind, randomized, placebo-controlled phase to investigate the efficacy
      and safety of GWP42003-P. There will be a washout period of at least two weeks between the
      last dosing day in Part A and randomization in Part B.

      Part B Patients, from any of the dosing groups, who have completed will be invited to
      participate into Part B which is a 1:1 randomized, placebo-controlled 60 day comparison of
      GWP42003-P against placebo. They will receive the dose which was identified by Part A as the
      maximum tolerated dose. Part B will investigate the efficacy and safety of GWP42003-P.

      During Part B, patients will continue to record their number of convulsive seizures and other
      seizures, using an IVRS telephone diary system (recorded twice each day). Assessments will
      also be made of cognitive function, nocturnal sleep quality and daytime sleepiness.

      Note: Eligible patients who have not previously participated in Part A, and who wish to
      participate in Part B will begin the two month baseline observation period to establish a
      baseline. Patients will follow the same procedures as outlined in Visit 1 (of Part A).
      Patients will record their number of convulsive seizures (and of other seizures), using an
      IVRS telephone diary system (recorded twice each day).

      Part A: The primary endpoint is the safety and tolerability profile of single and multiple
      ascending doses of GWP42003-P compared with placebo.

      The variables for analysis will be the difference in incidence, type and severity of AEs,
      vital signs, ECG, laboratory, and physical examination parameters of GWP42003-P compared with
      placebo.

      Part B: The primary endpoint is the number of patients experiencing at least a 50% reduction
      in the number of convulsive seizures (from baseline) on active treatment compared with
      placebo.

      Part A: Pharmacokinetic:

        1. GWP42003-P: The plasma concentration/time curve will be described following multiple
           doses of GWP42003-P, with the aim being to define

             -  Cmax

             -  tmax

             -  AUC0-∞, AUC0-t

             -  t½ The analytes for the pharmacokinetic analysis will be CBD and its major human
                metabolite 7-OH-CBD.

        2. Concomitant AEDs: The plasma concentration/time curve for concomitant AEDs will be
           described pre-treatment, and then after seven days of treatment with GWP42003-P, using a
           sparse sampling strategy. As far as possible, the plasma concentration/time relationship
           pre-treatment will be compared with the results following treatment with GWP42003-P.

      Part B: Efficacy:

        1. Number and type of non-convulsive seizures

        2. Cognitive function

        3. Sleep quality

        4. Caregiver Global Impression of Change
    

Intervention name(s): Cannabidiol
Intervention type(s): Drug
Intervention MeSH terms: Cannabidiol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Epilepsy; Dravet syndrome; Seizures; Intractable Epilepsy; Medically Refractory Epilepsy