CBD1: The Effects of Cannabidiol (CBD) on Electrical and Autonomic Cardiac Function in Children With Severe Epilepsy

• Sponsor: Gillette Children's Specialty Healthcare (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02815540
• Collaborator: (none)
• Enrollment: 2
• Location: 1
• Arm: 1
• Actual Duration (Months): 21.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Lennox-Gastaut Syndrome; Dravet Syndrome	Procedure: 12-Lead ECG; Drug: Cannabidiol	Phase 1/Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: The Effects of Cannabidiol (CBD) on Electrical and Autonomic Cardiac Function in Children
• Actual Study Start Date: Feb 16, 2017
• Actual Primary Completion Date: Dec 1, 2018
• Actual Study Completion Date: Dec 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: Observational 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; Subjects will be monitored while on cannabidiol with a 12-Lead ECG and/or Holter monitoring; Other Names: Holter Monitor ; Drug: Cannabidiol; Subjects who are planning to take state dispensed medical cannabidiol, or are already taking state dispensed medical cannabidiol.

Outcome Measures

Primary Outcome Measures

1. Holter SDNN Parameter Change [Baseline to 4 to 8 week follow up visit]

   Change from baseline Holter SDNN parameter to follow up visit Holter SDNN parameter.

Secondary Outcome Measures

1. Seizure Frequency [Baseline and 4 to 8 week follow up visit]

   Change from baseline seizure frequency to follow up visit seizure frequency.

2. Dysautonomia Signs and Symptoms [Baseline and 4 to 8 week follow up visit]

   signs and symptoms assessed by questionnaire developed for this study that documents observable signs and symptoms of dysautonomia

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Gillette Children's Specialty Healthcare	Saint Paul	Minnesota	United States	55101

Sponsors and Collaborators

• Gillette Children's Specialty Healthcare

Investigators

• Principal Investigator: Beverly S Wical, MD, Gillette Children's Specialty Healthcare

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 28, 2016
• Informed Consent Form - Feb 28, 2017

More Information

Publications

• 1. Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy (Dravet syndrome). In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P (eds) Epileptic syndromes in infancy, childhood and adolescence, 4th ed. John Libbey, London, 2005, pp 89 - 109.
• 15. Ohlsson A, Lindgren JE, Andersson S, Agurell S, Gillespie H, Hollister L. (1984). Single dose kinetics of cannabidiol in man. Cannabinoids: chemical, pharmacologic, and therapeutic aspects. S. Agurell, W. L. Dewey and R. Willette. Orlando, FL, Academic Press Inc.: 219-225. doi: 10.1016/B978-0-12-044620-9.50003-8
• 2. http://www.ninds.nih.gov/disorders/lennoxgastautsyndrome/lennoxgastautsyndrome.htm, Retrieved 6.10.2015
• 7. Wical, B, Wendorf H, Leighty D, Tervo M, Tervo R. Signs of Dysautonomia in Children with Dravet Syndrome. Presented at the Annual Meeting of the American Epilepsy Society, Boston, MA, Dec 2009.
• Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JE, Zuardi AW, Crippa JA. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011 May;36(6):1219-26. doi: 10.1038/npp.2011.6. Epub 2011 Feb 9.
• Delogu AB, Spinelli A, Battaglia D, Dravet C, De Nisco A, Saracino A, Romagnoli C, Lanza GA, Crea F. Electrical and autonomic cardiac function in patients with Dravet syndrome. Epilepsia. 2011 Apr;52 Suppl 2:55-8. doi: 10.1111/j.1528-1167.2011.03003.x.
• Ergul Y, Ekici B, Tatli B, Nisli K, Ozmen M. QT and P wave dispersion and heart rate variability in patients with Dravet syndrome. Acta Neurol Belg. 2013 Jun;113(2):161-6. doi: 10.1007/s13760-012-0140-z. Epub 2012 Oct 13.
• Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014 Mar 5;(3):CD009270. doi: 10.1002/14651858.CD009270.pub3. Review.
• Granjeiro EM, Gomes FV, Guimarães FS, Corrêa FM, Resstel LB. Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress. Pharmacol Biochem Behav. 2011 Oct;99(4):743-8. doi: 10.1016/j.pbb.2011.06.027. Epub 2011 Jul 12.
• Jehi L. Sudden death in epilepsy, surgery, and seizure outcomes: the interface between heart and brain. Cleve Clin J Med. 2010 Jul;77 Suppl 3:S51-5. doi: 10.3949/ccjm.77.s3.09. Review.
• Kalume F. Sudden unexpected death in Dravet syndrome: respiratory and other physiological dysfunctions. Respir Physiol Neurobiol. 2013 Nov 1;189(2):324-8. doi: 10.1016/j.resp.2013.06.026. Epub 2013 Jul 9. Review.
• Martin-Santos R, Crippa JA, Batalla A, Bhattacharyya S, Atakan Z, Borgwardt S, Allen P, Seal M, Langohr K, Farré M, Zuardi AW, McGuire PK. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des. 2012;18(32):4966-79. Review.
• Nei M, Sperling MR, Mintzer S, Ho RT. Long-term cardiac rhythm and repolarization abnormalities in refractory focal and generalized epilepsy. Epilepsia. 2012 Aug;53(8):e137-40. doi: 10.1111/j.1528-1167.2012.03561.x. Epub 2012 Jun 18.
• Sakauchi M, Oguni H, Kato I, Osawa M, Hirose S, Kaneko S, Takahashi Y, Takayama R, Fujiwara T. Mortality in Dravet syndrome: search for risk factors in Japanese patients. Epilepsia. 2011 Apr;52 Suppl 2:50-4. doi: 10.1111/j.1528-1167.2011.03002.x.
• Skluzacek JV, Watts KP, Parsy O, Wical B, Camfield P. Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia. 2011 Apr;52 Suppl 2:95-101. doi: 10.1111/j.1528-1167.2011.03012.x.

• Responsible Party: Gillette Children's Specialty Healthcare
• ClinicalTrials.gov Identifier: NCT02815540
• Other Study ID Numbers: CBD-001
• First Posted: Jun 28, 2016
• Last Update Posted: Jan 3, 2022
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Epilepsies, Myoclonic; Lennox Gastaut Syndrome; Syndrome; Cannabidiol

Study Results

Participant Flow

Arm/Group Title	Observational
Arm/Group Description	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. 12-Lead ECG: Subjects will be monitored while on cannabidiol with a 12-Lead ECG and/or Holter monitoring Cannabidiol: Subjects who are planning to take state dispensed medical cannabidiol, or are already taking state dispensed medical cannabidiol.
Period Title: Overall Study
STARTED	2
COMPLETED	0
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Observational
Arm/Group Description	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. 12-Lead ECG: Subjects will be monitored while on cannabidiol with a 12-Lead ECG and/or Holter monitoring Cannabidiol: Subjects who are planning to take state dispensed medical cannabidiol, or are already taking state dispensed medical cannabidiol.
Overall Participants	2
Age (Count of Participants)
<=18 years	2 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 50%
Male	1 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	2 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	2 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%

Outcome Measures

1. Primary Outcome

Title	Holter SDNN Parameter Change
Description	Change from baseline Holter SDNN parameter to follow up visit Holter SDNN parameter.
Time Frame	Baseline to 4 to 8 week follow up visit

Outcome Measure Data

Analysis Population Description

Physician left institution and study was discontinued due to no other investigators available.

Arm/Group Title	Observational
Arm/Group Description	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. 12-Lead ECG: Subjects will be monitored while on cannabidiol with a 12-Lead ECG and/or Holter monitoring Cannabidiol: Subjects who are planning to take state dispensed medical cannabidiol, or are already taking state dispensed medical cannabidiol.
Measure Participants	0

2. Secondary Outcome

Title	Seizure Frequency
Description	Change from baseline seizure frequency to follow up visit seizure frequency.
Time Frame	Baseline and 4 to 8 week follow up visit

Outcome Measure Data

Analysis Population Description

Physician left institution and study was discontinued due to no other investigators available.

Arm/Group Title	Observational
Arm/Group Description	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. 12-Lead ECG: Subjects will be monitored while on cannabidiol with a 12-Lead ECG and/or Holter monitoring Cannabidiol: Subjects who are planning to take state dispensed medical cannabidiol, or are already taking state dispensed medical cannabidiol.
Measure Participants	0

3. Secondary Outcome

Title	Dysautonomia Signs and Symptoms
Description	signs and symptoms assessed by questionnaire developed for this study that documents observable signs and symptoms of dysautonomia
Time Frame	Baseline and 4 to 8 week follow up visit

Outcome Measure Data

Analysis Population Description

Physician left institution and study was discontinued due to no other investigators available.

Arm/Group Title	Observational
Arm/Group Description	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. 12-Lead ECG: Subjects will be monitored while on cannabidiol with a 12-Lead ECG and/or Holter monitoring Cannabidiol: Subjects who are planning to take state dispensed medical cannabidiol, or are already taking state dispensed medical cannabidiol.
Measure Participants	0

Adverse Events

Time Frame	No data were collected.
Adverse Event Reporting Description	No data were collected.
Arm/Group Title	Observational
Arm/Group Description	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. 12-Lead ECG: Subjects will be monitored while on cannabidiol with a 12-Lead ECG and/or Holter monitoring Cannabidiol: Subjects who are planning to take state dispensed medical cannabidiol, or are already taking state dispensed medical cannabidiol.
All Cause Mortality
	Observational
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Serious Adverse Events
	Observational
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Observational
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

Physician left institution and study was discontinued due to no other investigators available. No outcome measures were collected or analyzed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.