Cannabidiol as add-on Therapy for Children With Refractory Epilepsy (CBD-uN1que), a High-quality Individualized Approach: a Series of N-of-1 Trials

Overview

The goal of this clinical trial is to learn if cannabidiol ("CBD-oil") works to treat severe epilepsy in children. It will also learn about the safety of cannabidiol. The main questions it aims to answer are: * Does cannabidiol lower the number of seizure in children with severe epilepsy? * Does cannabidiol effect other outcomes such as behaviour, sleep, communication, activities? * What medical problems do participants have when taking cannabidiol? Researchers will compare cannabidiol to a placebo (a look-alike oil that contains no cannabidiol) to see if drug cannabidiol works to treat severe epilepsy. All participants will receive both the cannabidiol and the placebo during different periods. At the end of the trial, we will evaluate for each patient seperately, whether seizures were less or more frequent during cannabidiol periods or placebo periods, to see what works best for every patient seperately. Participants will: * Register their seizures in a digital application during 4 to 6 periods. During these periods, CBD oil of placebo will be provided * Take CBD oil during 2 to 3 periods. One period will last around 7 weeks. * Also take placebo oil during the other 2 to 3 periods * Have a blood test every 7 weeks to monitor for safety and possible adverse effects * Visit the clinic once every 15 weeks for checkups and tests * Fill in questionnaires about quality of life, functioning, sleep, behaviour, epilepsy severity every 7 weeks.

Interventions

• Drug Cannabidiol (CBD) oral solution
  Bedrolite, which is a full spectrum cannabis extract with 10%CBD/0.4%THC. Cannabidiol will be titrated up to a dosage of 2.5-20mg/kg/day, dosed twice daily.
• Other Placebo
  Cannabis extract with less than 0.5% CBD/0.02%THC

Primary outcome measures

• Seizure frequency [Time frame: Daily, from start of baseline after enrollment to the end of the last treatment cycle (each cycle - consisting of two periods with run in, taper and washout phases - is 15 weeks). Adittionally, untill up to 6 months during open label extension phase.]

Secondary outcome measures (10)

• Seizure free days [Time frame: Registered daily using a seizure diary. Analysis endpoints specifically after completion of cycle 2 and (if applicable) cycle 3 and after 6 months of open label extension (if applicable), or else at withdrawal. Each cycle (two periods) lasts 15 weeks.]
• Response rates [Time frame: Seizures will be registered daily using a seizure diary. Analysis endpoints after cycle 2 and (if applicable) cycle 3 and after 6 months of open label extension (if applicable), or else at withdrawal. Each cycle (two periods) lasts 15 weeks.]
• Patient-centered outcome measures: QOLCE-55 [Time frame: - Once durine the 4-week baseline - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable).]
• Patient-centered outcome measures: GASE scale [Time frame: Once durine the 4-week baseline - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable).]
• Patient-centered outcome measures: GCI scale [Time frame: - Once durine the 4-week baseline. - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable).]
• Patient-centered outcome measures: ABC [Time frame: - Once durine the 4-week baseline. - Once every period (up to maximum of 2 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable).]
• Patient-centered outcome measures: VABS-III [Time frame: - Once durine the 4-week baseline. - Once every period (up to maximum of 2 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable).]
• Patient-centered outcome measures: SDSC [Time frame: - Once durine the 4-week baseline. - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable).]
• Patient-centered outcome measures: GAS [Time frame: - Once durine the 4-week baseline. - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable).]
• Patient-centered outcome measures: SSQ [Time frame: - Once durine the 4-week baseline. - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable).]

Eligibility criteria

Inclusion criteria

• Minimum age of 1 year old and maximum age of 18 years old.
• Confirmed diagnosis of refractory epilepsy according to ILAE criteria
• At least 4 countable seizures (not all in one week) of epileptic origin, during the 4-week baseline period while receiving care as usual.
• All medication doses or other interventions for epilepsy must have been stable for one month prior to screening and the participants/parents and treating physicians are willing to maintain the current treatment regimen throughout the trial.
• Informed consent/ of legal representative/ parents.
• Presence of a consistently available patient caregiver for proxy-reports.

Exclusion criteria

• Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the Investigational Medicinal Product (cannabis extract and refined peanut oil, generally safe for patients with peanut allergy)
• History or current signs of significantly impaired liver function, such as bilirubin level ≥ 2 x upper limit of normal, or presence of liver damage as indicated by levels of alanine aminotransferase and/or aspartate aminotransferase ≥ 3 x upper limit.
• Pregnancy, breastfeeding, or intention to become pregnant throughout the trial or within 3 months of completing treatment
• Cardiac disease including: Structural heart disease with hemodynamic significance, heart failure, ischemic heart disease, Brugada syndrome, long-QT syndrome, cardiac arrythmia
• Glaucoma
• Ongoing evaluation for epilepsy surgery
• Implementation of vagal nerve stimulation within 3 months prior to screening and unwillingness to delay inclusion until stable settings of vagal nerve stimulation are reached
• Starting a ketogenic diet within 3 months prior to screening and unwillingness to delay inclusion until a stable ketogenic diet is reached
• Unstable medical condition, other than refractory epilepsy, that is of significant influence on participation in the trial; significance to be determined with the treating physician/pediatric neurologist
• History of recreational or medicinal cannabis use, or cannabinoid-based medications, within three months prior to screening and the patient is unwilling to abstain for the duration of the study
• Planned intervention under general anesthesia interfering with the baseline period; or any planned major surgery within the duration of the trial
• Expected inability to undergo blood sampling due to anxiety or resistance
• Use of clobazam dosage of > 0,5 mg/kg/day in the last month

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Netherlands · 1 center

• University Medical Center Utrecht — Utrecht

Identifiers

NCT: NCT07668856 · 2023-507843-12-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗