The Effects of Cannabidiol (CBD) on Electrical and Autonomic Cardiac Function in Children With Severe Epilepsy

Study Overview
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Brief Summary
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The investigators propose to study the effects of cannabidiol (CBD) on cardiac electrical function and the autonomic nervous system in children with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), when the CBD is administered as an artisanal oil obtained through state dispensaries or other sources. The intent is to begin to assess potential risks and benefits of this therapy in a vulnerable patient population by characterizing the effects of CBD on EKG findings, heart rate variability and the occurrence of seizures.

Detailed Description
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Specific Aims/Study Objectives This is a pilot study to explore the effects of cannabidiol (CBD) on autonomic cardiac function in children with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS) when the CBD is administered as an artisanal oil. This will be achieved by addressing the following specific aims. Aim #1: To determine the effects of CBD on cardiac function in 30 children with DS and LGS. This is the primary aim of the study: The effects of CBD on the cardiac function of 30 children with DS or LGS will be assessed using a 15-lead electrocardiogram (EKG) and a 24-hour Holter monitor. Investigators hypothesize that there will be no alterations in ventricular repolarization and heart rate variability on the EKG and Holter monitoring, respectively, after taking CBD for 4-8 weeks, compared to when participants were not taking CBD. Note: The following aims are secondary to the primary outcome and goal of assessing the effects of CBD on cardiac function. Aim #2: To assess signs and symptoms of dysautonomia in the presence and absence of CBD. Signs and symptoms of dysautonomia include parental perception of body temperature, skin color in hands and feet, sweating, pupil size, flushing, feeding issues, heart rate, strong emotions, constipation, urination or bowel movement issues, and irritability. These signs and symptoms will be collected using a previously-established dysautonomia survey. Investigators hypothesize there will be no change in qualitative assessments of signs and symptoms of dysautonomia after taking CBD for 4-8 weeks, compared to when participants were not taking CBD. Aim #3: To determine the effects of CBD on the occurrence of seizures. The number of seizures in children who obtain CBD will be assessed using a 7-day seizure diary (Seizure tracker). Caregivers will record the number of seizures for a 7-day period prior to CBD administration, and repeat the seizure tracking after having received CBD for 4-8 weeks. Change in seizure numbers will be compared pre- and post-CBD administration. Investigators hypothesize that study participants will have lower seizure counts after being on CBD compared to when weren't taking CBD. Study Design and Methodology Study Design: Thirty patients with DS or LGS who are going to register to take medical cannabis (cannabidiol, or CBD) in the state of Minnesota will be offered the opportunity to participate in this study. If consent is obtained, the patient or guardian will be asked to complete a questionnaire developed for this study that documents observable signs and symptoms of dysautonomia, and to complete a seizure diary for 7 days prior to initially receiving the CBD. Each participant will also have a 15-lead electrocardiogram (EKG) and wear a 24-hour Holter monitor, both non-invasive measures of cardiac function, prior to being administered the CBD. The EKG and 24-hour Holter monitor will be interpreted by a cardiac electrophysiologist and will be reviewed for heart rate variability parameters. The dysautonomia questionnaire, seizure diary and cardiac measurements will be repeated 4-8 weeks after the subject has been on a stable regimen of CBD. This time-frame is based on availability of subjects schedules and clinic visits, and it is also greater than 5 half-lives previously reported for CBD (apparent half-life, 21 hours, (15)). Steady-state levels are achieved after 5 half-lives of drug dosing, thus we expect to be at steady-state concentrations. Subjects who are already on a stable regimen of CBD, yet plan to stop taking CBD at some point for some reason, are also eligible to participate. The parent or guardian will complete the dysautonomia questionnaire and seizure diary (and research staff will be available to help with questions), and the patient will have the 15-lead EKG and 24-hour Holter monitor while still on the CBD. The subjects will then come back 4-8 weeks after their last dose of CBD to have these assessments repeated while off of the CBD. This time frame is based on availability of subjects schedules and clinic visits as well as being substantially greater than 5 half-lives of CBD, the standard wash-out period for pharmacological studies.

Official Title
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The Effects of Cannabidiol (CBD) on Electrical and Autonomic Cardiac Function in Children

Conditions
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Lennox-Gastaut Syndrome, Dravet Syndrome

Intervention / Treatment
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* Procedure: 12-Lead ECG
* Drug: Cannabidiol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with Dravet syndrome or Lennox-Gastaut syndrome Patients who are planning to obtain medical cannabidiol Patients who are already taking medical cannabidiol and are planning to stop taking it Exclusion Criteria: Patients without a diagnosis of Dravet syndrome or Lennox-Gastaut syndrome

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Heart Function and Dysautonomia<br>This study looks at participants already receiving CBD from the state of MN. We are not providing the CBD. We are looking at heart function with ECGs and Holter monitoring before and after CBD is taken by the participant. We are also looking at dysautonomia signs and symptoms and seizure frequency before and after CBD is taken by the participant. | Procedure: 12-Lead ECG<br>* Subjects will be monitored while on cannabidiol with a 12-Lead ECG and/or Holter monitoring<br>* Other names: Holter Monitor;Drug: Cannabidiol<br>* Subjects who are planning to take state dispensed medical cannabidiol, or are already taking state dispensed medical cannabidiol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Holter SDNN Parameter Change | Change from baseline Holter SDNN parameter to follow up visit Holter SDNN parameter. | Baseline to 4 to 8 week follow up visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seizure Frequency | Change from baseline seizure frequency to follow up visit seizure frequency. | Baseline and 4 to 8 week follow up visit | 
| Dysautonomia Signs and Symptoms | signs and symptoms assessed by questionnaire developed for this study that documents observable signs and symptoms of dysautonomia | Baseline and 4 to 8 week follow up visit |