University of Alabama at Birmingham (UAB) Pediatric CBD Program

• Sponsor: University of Alabama at Birmingham (Other)
• Overall Status: Completed
• CT.gov ID: NCT02695537
• Collaborator: (none)
• Enrollment: 89
• Location: 1
• Arm: 1
• Actual Duration (Months): 46.9
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of Epidiolex at various doses between 5 mg/kg/day and 50 mg/kg/day as an additional (add-on) drug for treating debilitating, drug-resistant epilepsy.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy; Seizures	Drug: Epidiolex	Phase 1

Detailed Description

The specific goals of this phase I dose finding study, conducted in consecutively enrolled patients 1-19 years of age, are to prospectively and longitudinally assess the safety and tolerability, including cognitive effects, of Cannabidiol (CBD) at various doses between 5 mg/kg/day and 25 mg/kg/day, with additional titration in some cases up to 50 mg/kg/day. In order to participate in the study, participants will need to fulfill the inclusion and exclusion criteria.

The goal of the study is to fulfill the mandate of "Carly's Law" and to provide patients with debilitating epileptic conditions with access to CBD as an add-on treatment. Other care including routine neurological care unrelated to participation in the CBD study will need to be provided by patients' primary/current treating neurologist.

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: University of Alabama at Birmingham (UAB) Pediatric CBD Program
• Actual Study Start Date: Apr 1, 2015
• Actual Primary Completion Date: Feb 27, 2019
• Actual Study Completion Date: Feb 27, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Epidiolex 100 milligram/milliliter (mg/mL) oral solution Participants will receive a CBD starting dose of 5 mg/kg/day in twice daily dosing and titrate by 5 mg/kg/2 weeks up to 25 mg/kg/day. Additional increases in dosing, by 5 mg/kg/day up to a maximum of 50 mg/kg/day, may be instituted at the discretion of the treating Principle Investigator (PI). If a subject experiences a "clinically significant" or "dose limiting" adverse event (AE) or severe adverse event (SAE) attributable to CBD, the investigator will determine if a dose reduction or taper is necessary (decreases will occur in 5 mg/kg/2 week increments or at a rate felt appropriate by the treating PI).

Drug: Epidiolex; Epidiolex oral solution (100 mg/mL CBD concentration) with inactive ingredients including anhydrous ethanol, sesame seed oil, strawberry flavor, and sucralose).; Other Names: Cannabidiol CBD

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Severe Adverse Events (Increase in Seizure Frequency by More Than 100% Leading to Emergency Room Visit or Hospitalization). [For 1 Year following Enrollment]

   Severe adverse events (SAEs) were defined as increase in seizure frequency by more than 100% leading to emergency room visit or hospitalization. During study clinic and phone visits, adverse and severe adverse event monitoring and reporting were assessed among all participants. Data was recorded and stored in the UAB RedCap System.

2. Number of Participants With Change in Resting Blood Pressure or Heart Rate by 25% if Considered Significant by Managing Neurologist. [For 1 Year following Enrollment]

   During study clinic visits, participant vital signs, including blood pressure and heart rate, were collected. Data was recorded and stored in the UAB RedCap System. Clinically significant was determined by using the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. Adverse events categorized as a grade 3 or above were considered clinically significant. Adverse events grade 4 or above were considered severe adverse events.

3. Number of Participants With Change in Laboratory Tests Considered by Managing Neurologists as Clinically Significant. [For 1 Year following Enrollment]

   During study clinic visits, participants received laboratory testing to assess for side effects and toxicity. Data was recorded and stored in the UAB RedCap System. Laboratory testing included Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP; included Liver Function Tests (LFTs) mainly looking at alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), Urine Analysis (UA), and Antiepileptic Drug (AED) levels. Clinically significant was determined by using the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. Adverse events categorized as a grade 3 or above were considered clinically significant. Adverse events grade 4 or above were considered severe adverse events.

Secondary Outcome Measures

1. Change in Seizure Frequency as Measured in Total Number of Seizures Per Month. [For 1 Year following Enrollment]

   Participants were given seizure diary logs and dairy data collection was done at study clinic visits. Data was recorded and stored in the UAB RedCap System. The analysis plan was to assess the pattern of change in seizure frequency over time, relative to baseline, following CBD exposure. Since the baseline measure was reported at the time of screening, there was some tendency to overestimate the frequency of seizures in the historically reported interval. This was examined by comparing the initial study visits improvement versus the pattern of control over time, and was assessed using graphic techniques and summary statistics.

2. Change in Seizure Severity Measured by the Chalfont Seizure Severity Scale (Duncan & Sander, 1991, JNNP). [For 1 Year following Enrollment]

   Seizure severity was collected during study clinic and phone visits using the Chalfont Seizure Severity Scale (CSSS) (Duncan & Sander, 1991, JNNP) through verbal reporting. The CSSS measured components of seizures most disturbing or disruptive to the participants. The total scores for a given seizure type was its severity score. High scores indicated high severity of the seizures (no fixed maximum value), while a score of zero indicated low severity. Scores were recorded and stored in the UAB RedCap System. The analysis plan was to assess the pattern of change in seizure severity scores over time, relative to baseline, following CBD exposure. Since the baseline measure was reported at the time of screening, there was some tendency to overestimate the severity of seizures in the historically reported interval. This was examined by comparing the initial study visits improvement versus the pattern of control over time, and was assessed using graphic techniques and summary statistics.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 19 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients between 1 years (12 months)-18 years with drug resistant epilepsy confirmed by video EEG recording report, and

• Patient should have history of a trial of at least four anti-epileptic drugs (AEDs), including one trial of a combination of two concomitant drugs without successful seizure control. Vagal nerve stimulation (VNS), Responsive Neurostimulation (RNS) deep brain stimulation, or the ketogenic diet can be considered equivalent to a drug trial. Patient suffering from an epileptic syndrome that is known to be refractory to treatment, such as Dravet or Lennox-Gastaut Syndrome, may be included after a trial of only two drugs, and

• Between 1-4 baseline anti-epileptic drugs at stable doses for a minimum of 4 weeks prior to submitting records for review by the CBD Treatment Approval Committee.

• VNS or RNS must be on stable settings for a minimum of 3 months.

• If on ketogenic diet, must be on stable ration for a minimum of 3 months.

• Review of the following patient medical information:

• Most recent Brain MRI report,

• Most recent ECG report,

• Video/EEG monitoring report confirming the diagnosis of epilepsy,

• Evidence that the patient has failed 4 AEDs as indicated above,

• Patient must have at least 4 clinically countable seizures per month,

• Seizure history to include a documented history of generalized (drop, atonic, tonic clonic, and/or myoclonic) seizures, focal seizures without loss of consciousness with a motor component, focal seizures with loss of consciousness, or focal seizures with secondary generalization, complex partial seizures with a motor or tonic component, and I or altered awareness seizures,

• Results of routine testing including blood work (Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), Liver Function Tests (LFTs), renal panel, Urinary Analysis (UA), and levels of all AEDs) and digital copy of a routine EEG along with the formal written report performed within 3 months prior to submitting records for CBD Treatment Approval review. If applicable, results of any metabolic or genetic testing performed should be included in submitted records for review. If any AED dose was adjusted in the preceding 3 months, level on the new dose will need to be provided.

• If applicable, documentation (including date of surgery) of prior VNS, RNS, Corpus Callosotomy, or other epilepsy surgery the patient has received.

• Acceptable method of contraception (or abstinence) for women of childbearing potential and for male patients with partners of childbearing potential, and female patients must have a negative urine pregnancy test on the day of initiating CBD.

• For patients who agree to participate in the optional neuroimaging sub-study, an MRI screen will be obtained to show that the patient does not have contraindication to receiving MRI/functional MRI (fMRI) at 3 Tesla (e.g., metallic artifact).

• Patients are able to supply investigator with seizure calendars for the past 3 months prior to submitting records for CBD Treatment Approval Committee review. The patient will need to provide an updated calendar at the time of enrollment.

• Approval for inclusion by the CBD Treatment Approval Committee.

• Current State of Alabama Resident

• Acceptable documentation of Alabama residency includes the following:

• a state issued identification (ID), such as a driver's license, from patient or patient's parent/ legally authorized representative (LAR).

• documents showing the patient or patient's parent/LAR rents/owns property in the state,

• state voter registration from patient or patient's parent/LAR, or

• a recent state tax return from patient or patient's parent/LAR.

Exclusion Criteria:

• Active Psychogenic non-epileptic seizures (PNES); Patients with more than 1 year freedom from PNES will not be excluded,

• Patients who are pregnant, breastfeeding, or not using acceptable methods of contraception during the course of the study and for three months thereafter,

• Male patient's partner is of child bearing potential; unless willing to ensure that they (male patients) or their partner(s) are using acceptable methods of contraception during the course of the study and for three months thereafter

• History of substance abuse/addiction,

• Use of medical marijuana or CBD based product in the past 30 days,

• Initiation of felbamate within last 12 months,

• Allergy to CBD or any marijuana-type products,

• Alanine Aminotransferase (ALT) >5 x Upper Limit of Normal (ULN) or Aspartate Aminotransferase (AST) >5 x ULN, as seen in participant's laboratory results submitted to the CBD Treatment Approval Committee for review.

• Hemoglobin <10 or Hematocrit <30 or White Blood Cell (WBC) < 2000, as seen in participant's laboratory results submitted to the CBD Treatment Approval Committee for review.

• In Investigator's judgement, active medical condition/treatment that impacts study activities.

• Unable to provide consent (and no LAR),

• Unable/Failure to comply with study visits/requirements and/or instructions.

• Confirmed diagnosis for Dravet Syndrome or Lennox-Gastaut Syndrome that qualifies the patient for a Greenwich (GW) Dravet Syndrome or Lennox-Gastaut Syndrome randomized controlled clinical trial for which the patient is eligible pursuant to the GW clinical trial enrollment criteria unless

• (a) there is no study that is either actively open for enrollment of patients at The University of Alabama at Birmingham (UAB) or that is expected to actively begin enrolling patients at UAB within two (2) months of the date on which the patient is screened for the UAB Pediatric CBD Program or UAB Adult CBD Program. Primary residence in a State different than Alabama.

• Subjects with contraindications to MRI/fMRI at 3 Tesla (e.g., metallic artifact) will not be offered participation in the optional sub-study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233

Sponsors and Collaborators

• University of Alabama at Birmingham

Investigators

• Principal Investigator: Martina Bebin, MD, Neurology Chair Office - University of Alabama at Birmingham

Study Documents (Full-Text)

• Statistical Analysis Plan - Feb 25, 2020
• Study Protocol - Dec 18, 2017

More Information

Additional Information:

• UAB Cannabidiol Program

Publications

• Duncan JS, Sander JW. The Chalfont Seizure Severity Scale. J Neurol Neurosurg Psychiatry. 1991 Oct;54(10):873-6.
• Pinheiro, J.C. and Bates, D.M. (2000). Mixed-Effects Models in S and S-Plus. Springer, Verlag, New York

• Responsible Party: Martina Bebin, Professor, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT02695537
• Other Study ID Numbers: IRB-140905010
• First Posted: Mar 1, 2016
• Last Update Posted: Apr 10, 2020
• Last Verified: Mar 1, 2020

• 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: Seizures; Cannabidiol

Study Results

Participant Flow

Recruitment Details	Participants with treatment-resistant epilepsy in the state of Alabama were enrolled. Their primary treating neurologist provided the UAB CBD Treatment Approval Committee with the required information (found on www.uab.edu/cbd) to review. The committee either "approved/recommended" or "disapproved/not recommended" them for treatment in the study.
Pre-assignment Detail	Of the total 141 participants with epilepsy ages 1-19 screened, 89 were enrolled in this single-center, open-label study. This study was not randomized.

Arm/Group Title	Epidiolex
Arm/Group Description	The participants (or their caregivers) self-administered CBD 100mg/mL oral solution at a starting dose of 5 mg/kg/day in twice daily dosing and titrated by 5 mg/kg/2 weeks up to 25 mg/kg/day. Additional increases in dosing, by 5 mg/kg/day up to a maximum of 50 mg/kg/day, was instituted at the discretion of the treating PI.
Period Title: Overall Study
STARTED	89
COMPLETED	51
NOT COMPLETED	38

Baseline Characteristics

Arm/Group Title	Epidiolex
Arm/Group Description	The participants (or their caregivers) self-administered CBD 100mg/mL oral solution at a starting dose of 5 mg/kg/day in twice daily dosing and titrated by 5 mg/kg/2 weeks up to 25 mg/kg/day. Additional increases in dosing, by 5 mg/kg/day up to a maximum of 50 mg/kg/day, was instituted at the discretion of the treating PI.
Overall Participants	89
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.7978 (4.9087)
Sex: Female, Male (Count of Participants)
Female	48 53.9%
Male	41 46.1%
Race/Ethnicity, Customized (Count of Participants)
Asian	3 3.4%
Black or African American	14 15.7%
White	72 80.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Severe Adverse Events (Increase in Seizure Frequency by More Than 100% Leading to Emergency Room Visit or Hospitalization).
Description	Severe adverse events (SAEs) were defined as increase in seizure frequency by more than 100% leading to emergency room visit or hospitalization. During study clinic and phone visits, adverse and severe adverse event monitoring and reporting were assessed among all participants. Data was recorded and stored in the UAB RedCap System.
Time Frame	For 1 Year following Enrollment

Outcome Measure Data

Analysis Population Description

Per protocol, after all participants have been enrolled and followed for 1 year.

Arm/Group Title	Epidiolex
Arm/Group Description	The participants (or their caregivers) self-administered CBD 100mg/mL oral solution at a starting dose of 5 mg/kg/day in twice daily dosing and titrated by 5 mg/kg/2 weeks up to 25 mg/kg/day. Additional increases in dosing, by 5 mg/kg/day up to a maximum of 50 mg/kg/day, was instituted at the discretion of the treating PI.
Measure Participants	89
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	Number of Participants With Change in Resting Blood Pressure or Heart Rate by 25% if Considered Significant by Managing Neurologist.
Description	During study clinic visits, participant vital signs, including blood pressure and heart rate, were collected. Data was recorded and stored in the UAB RedCap System. Clinically significant was determined by using the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. Adverse events categorized as a grade 3 or above were considered clinically significant. Adverse events grade 4 or above were considered severe adverse events.
Time Frame	For 1 Year following Enrollment

Outcome Measure Data

Analysis Population Description

Per protocol, after all participants have been enrolled and followed for 1 year.

Arm/Group Title	Epidiolex
Arm/Group Description	The participants (or their caregivers) self-administered CBD 100mg/mL oral solution at a starting dose of 5 mg/kg/day in twice daily dosing and titrated by 5 mg/kg/2 weeks up to 25 mg/kg/day. Additional increases in dosing, by 5 mg/kg/day up to a maximum of 50 mg/kg/day, was instituted at the discretion of the treating PI.
Measure Participants	89
Blood Pressure	0 0%
Heart Rate	0 0%

3. Primary Outcome

Title	Number of Participants With Change in Laboratory Tests Considered by Managing Neurologists as Clinically Significant.
Description	During study clinic visits, participants received laboratory testing to assess for side effects and toxicity. Data was recorded and stored in the UAB RedCap System. Laboratory testing included Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP; included Liver Function Tests (LFTs) mainly looking at alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), Urine Analysis (UA), and Antiepileptic Drug (AED) levels. Clinically significant was determined by using the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. Adverse events categorized as a grade 3 or above were considered clinically significant. Adverse events grade 4 or above were considered severe adverse events.
Time Frame	For 1 Year following Enrollment

Outcome Measure Data

Analysis Population Description

Per protocol, after all participants have been enrolled and followed for 1 year.

Arm/Group Title	Epidiolex
Arm/Group Description	The participants (or their caregivers) self-administered CBD 100mg/mL oral solution at a starting dose of 5 mg/kg/day in twice daily dosing and titrated by 5 mg/kg/2 weeks up to 25 mg/kg/day. Additional increases in dosing, by 5 mg/kg/day up to a maximum of 50 mg/kg/day, was instituted at the discretion of the treating PI.
Measure Participants	89
CBC: White Blood Cell (WBC) Count	4 4.5%
CBC: Red Blood Cell (RBC) Count	1 1.1%
CBC: Hemoglobin	2 2.2%
CBC: Hematocrit	2 2.2%
CBC: Platelet	3 3.4%
CBC: Absolute (ABS) Neutrophils	2 2.2%
CBC: ABS Lymphocytes	1 1.1%
CBC: ABS Monocytes	1 1.1%
CBC: Neutrophils	1 1.1%
CBC: Lymphocytes	0 0%
CMP: Serum Creatinine	0 0%
CMP: Creatinine Clearance	0 0%
CMP: ALT (SGPT)	11 12.4%
CMP: AST (SGOT)	8 9%
CMP: Total Bilirubin	0 0%
CMP: Direct Bilirubin	0 0%
CMP: Blood Urea Nitrogen (BUN)	1 1.1%
CMP: Albumin	0 0%
CMP: Alkaline Phosphate	1 1.1%
CMP: Glucose	0 0%
CMP: Calcium	0 0%
CMP: Carbon Dioxide	0 0%
CMP: Chloride	0 0%
CMP: Potassium	1 1.1%
CMP: Sodium	2 2.2%
UA: Specific Gravity	0 0%
UA: PH	0 0%
UA: Leukocyte Esterase	27 30.3%
UA: Nitrite	3 3.4%
UA: Protein	21 23.6%
UA: Glucose	5 5.6%
UA: Ketones	27 30.3%
UA: Urubilinogen	21 23.6%
UA: Bilirubin	4 4.5%
UA: Blood	18 20.2%
AED: Phenobarbital Level	1 1.1%
AED: Primidone Level	0 0%
AED: Klonopin Level	0 0%
AED: Clobazam Level	0 0%
AED: Desmethylclobazam Level	0 0%
AED: Lorazepam Level	0 0%
AED: Phenytoin Level	0 0%
AED: Carbamazepine Level	0 0%
AED: Clorazepate Level	0 0%
AED: Valproate Level	0 0%
AED: Felbamate Level	1 1.1%
AED: Gabapentin Level	0 0%
AED: Lamotrigine Level	0 0%
AED: Levetiracetam Level	0 0%
AED: Oxcarbazepine Level	0 0%
AED: Ethosuximide Level	1 1.1%
AED: Tiagabine Level	0 0%
AED: Topiramate Level	0 0%
AED: Vigabatrin Level	0 0%
AED: Zonisamide Level	0 0%
AED: Eslicarbazepine Level	0 0%
AED: Ezogabine Level	0 0%
AED: Pregabalin Level	0 0%
AED: Perampanel Level	0 0%
AED: Rufinamide Level	0 0%
AED: Brivaracetam Level	0 0%
AED: Lacosamide Level	0 0%
AED: Diazepam Level	0 0%

4. Secondary Outcome

Title	Change in Seizure Frequency as Measured in Total Number of Seizures Per Month.
Description	Participants were given seizure diary logs and dairy data collection was done at study clinic visits. Data was recorded and stored in the UAB RedCap System. The analysis plan was to assess the pattern of change in seizure frequency over time, relative to baseline, following CBD exposure. Since the baseline measure was reported at the time of screening, there was some tendency to overestimate the frequency of seizures in the historically reported interval. This was examined by comparing the initial study visits improvement versus the pattern of control over time, and was assessed using graphic techniques and summary statistics.
Time Frame	For 1 Year following Enrollment

Outcome Measure Data

Analysis Population Description

Per protocol, after all participants have been enrolled and followed for 1 year. Number of participants analyzed differed because: 1) Those who responded to a certain CBD dose had fewer monthly visits; 2) Those who decided to continue on the same CBD dose had fewer monthly visits; or 3) Withdrawal prior to 1 year following enrollment.

Arm/Group Title	Epidiolex
Arm/Group Description	The participants (or their caregivers) self-administered CBD 100mg/mL oral solution at a starting dose of 5 mg/kg/day in twice daily dosing and titrated by 5 mg/kg/2 weeks up to 25 mg/kg/day. Additional increases in dosing, by 5 mg/kg/day up to a maximum of 50 mg/kg/day, was instituted at the discretion of the treating PI.
Measure Participants	89
Month 1 vs Baseline	0.63
Month 2 vs Baseline	0.44
Month 3 vs Baseline	0.38
Month 4 vs Baseline	0.38
Month 5 vs Baseline	0.4
Month 6 vs Baseline	0.41
Month 7 vs Baseline	0.42
Month 8 vs Baseline	0.41
Month 9 vs Baseline	0.41
Month 10 vs Baseline	0.39
Month 11 vs Baseline	0.38
Month 12 vs Baseline	0.36

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epidiolex
	Comments	Null hypothesis is that there was no change in seizure frequency between any two assessment time points during this period of analysis. Alternative hypothesis is that there were two or more assessment time points for which change in seizure frequency was different from zero.
	Type of Statistical Test	Other
	Comments	Single group.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value reported above is the global test for change in seizure frequency over a 12-month period.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon signed rank test with Bonferonni multiple comparison correction was used as a post-hoc analysis to indicate direction of change.
Other Statistical Analysis		Generalized least squares statistical techniques were used for modeling longitudinal data after normality of seizure frequency outcome measures were achieved through log-transformations methods. The following baseline clinical variables were adjusted for: AEDs, AEDs tried, epileptic surgery, and gender. Reported results were geometric least squares mean and its associated 95% Confidence Interval. Percentage reduction in seizure frequency relative to baseline were obtained by subtracting from 1 and then multiplying by 100 at all post-baseline timepoints.

5. Secondary Outcome

Title	Change in Seizure Severity Measured by the Chalfont Seizure Severity Scale (Duncan & Sander, 1991, JNNP).
Description	Seizure severity was collected during study clinic and phone visits using the Chalfont Seizure Severity Scale (CSSS) (Duncan & Sander, 1991, JNNP) through verbal reporting. The CSSS measured components of seizures most disturbing or disruptive to the participants. The total scores for a given seizure type was its severity score. High scores indicated high severity of the seizures (no fixed maximum value), while a score of zero indicated low severity. Scores were recorded and stored in the UAB RedCap System. The analysis plan was to assess the pattern of change in seizure severity scores over time, relative to baseline, following CBD exposure. Since the baseline measure was reported at the time of screening, there was some tendency to overestimate the severity of seizures in the historically reported interval. This was examined by comparing the initial study visits improvement versus the pattern of control over time, and was assessed using graphic techniques and summary statistics.
Time Frame	For 1 Year following Enrollment

Outcome Measure Data

Analysis Population Description

Per protocol, after all participants have been enrolled and followed for 1 year. Number of participants analyzed differed because: 1) Those who responded to a certain CBD dose had fewer monthly visits; 2) Those who decided to continue on the same CBD dose had fewer monthly visits; or 3) Withdrawal prior to 1 year following enrollment.

Arm/Group Title	Epidiolex
Arm/Group Description	The participants (or their caregivers) self-administered CBD 100mg/mL oral solution at a starting dose of 5 mg/kg/day in twice daily dosing and titrated by 5 mg/kg/2 weeks up to 25 mg/kg/day. Additional increases in dosing, by 5 mg/kg/day up to a maximum of 50 mg/kg/day, was instituted at the discretion of the treating PI.
Measure Participants	89
Month 1 vs Baseline	0.66
Month 2 vs Baseline	0.47
Month 3 vs Baseline	0.37
Month 4 vs Baseline	0.35
Month 5 vs Baseline	0.36
Month 6 vs Baseline	0.4
Month 7 vs Baseline	0.43
Month 8 vs Baseline	0.44
Month 9 vs Baseline	0.45
Month 10 vs Baseline	0.46
Month 11 vs Baseline	0.46
Month 12 vs Baseline	0.46

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epidiolex
	Comments	Null hypothesis is that there was no change in seizure severity scores between any two assessment time points during this period of analysis. Alternative hypothesis is that there were two or more assessment time points for which change in seizure severity scores was different from zero.
	Type of Statistical Test	Other
	Comments	Single group.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value reported above is the global test for change in seizure severity scores over a 12-month period.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon signed rank test with Bonferonni multiple comparison correction was used as a post-hoc analysis to indicate direction of change.
Other Statistical Analysis		Generalized least squares statistical techniques were used for modeling longitudinal data after normality of seizure severity score outcome measures were achieved through log-transformations methods. The following baseline clinical variables were adjusted for: AEDs, AEDs tried, epileptic surgery, and gender. Reported results were geometric least squares mean and its associated 95% Confidence Interval. Percentage reduction in seizure severity relative to baseline were obtained by subtracting from 1 and then multiplying by 100 at all post-baseline timepoints.

Adverse Events

Time Frame	For 1 Year following Enrollment
Adverse Event Reporting Description	Adverse events and severe adverse events were collected and reported in all enrolled participants who received study drug. The Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03 was used to determine clinical significance. Adverse events categorized as a grade 3 or above was considered clinically significant. Adverse events grade 4 or above was considered severe adverse events.
Arm/Group Title	Epidiolex
Arm/Group Description	The participants (or their caregivers) self-administered CBD 100mg/mL oral solution at a starting dose of 5 mg/kg/day in twice daily dosing and titrated by 5 mg/kg/2 weeks up to 25 mg/kg/day. Additional increases in dosing, by 5 mg/kg/day up to a maximum of 50 mg/kg/day, was instituted at the discretion of the treating PI.
All Cause Mortality
	Epidiolex
	Affected / at Risk (%)	# Events
Total	0/89 (0%)
Serious Adverse Events
	Epidiolex
	Affected / at Risk (%)	# Events
Total	15/89 (16.9%)
Blood and lymphatic system disorders
Abnormal liver funtion panel	1/89 (1.1%)	2
Gastrointestinal disorders
Fecal impaction	1/89 (1.1%)	1
General disorders
Hospital admission	6/89 (6.7%)	8
Hepatobiliary disorders
Nausea	1/89 (1.1%)	1
Metabolism and nutrition disorders
Dehydration	1/89 (1.1%)	1
Nervous system disorders
Dysphagia	1/89 (1.1%)	2
Increased seizure frequency	3/89 (3.4%)	3
Renal and urinary disorders
Urinary tract infection	1/89 (1.1%)	2
Respiratory, thoracic and mediastinal disorders
Aspiration pneumonia	1/89 (1.1%)	2
Pneumonia	1/89 (1.1%)	2
Obstructive sleep apnea	1/89 (1.1%)	1
Skin and subcutaneous tissue disorders
Rash	1/89 (1.1%)	2
Surgical and medical procedures
Spinal fusion for scoliosis	1/89 (1.1%)	1
Gastrostomy tube (G-tube) placement	1/89 (1.1%)	1
Elective endoscopy	1/89 (1.1%)	1
Other (Not Including Serious) Adverse Events
	Epidiolex
	Affected / at Risk (%)	# Events
Total	82/89 (92.1%)
Blood and lymphatic system disorders
Abnormal CBC values	4/89 (4.5%)	28
Abnormal liver function panel	8/89 (9%)	37
Anemia	1/89 (1.1%)	9
Thrombocytopenia	2/89 (2.2%)	3
Hyponatremia	2/89 (2.2%)	8
Hypokalemia	1/89 (1.1%)	1
Leukopenia	1/89 (1.1%)	6
Ear and labyrinth disorders
Otitis media	5/89 (5.6%)	6
Eye disorders
Sty	1/89 (1.1%)	11
Conjunctivitis	1/89 (1.1%)	4
Gastrointestinal disorders
Diarrhea	31/89 (34.8%)	156
Constipation	5/89 (5.6%)	26
Loose stool	1/89 (1.1%)	66
Gastroesophageal reflux disease (GERD)	2/89 (2.2%)	19
General disorders
Hospital admission	1/89 (1.1%)	1
Weight gain	2/89 (2.2%)	10
Hair loss	1/89 (1.1%)	3
Concussion	1/89 (1.1%)	1
Hepatobiliary disorders
Anorexia	2/89 (2.2%)	14
Increased appetite	1/89 (1.1%)	12
Decreased appetite	4/89 (4.5%)	42
Malnutrition	1/89 (1.1%)	6
Distended gallbladder	1/89 (1.1%)	7
Abdominal pain	6/89 (6.7%)	28
Nausea	11/89 (12.4%)	33
Infections and infestations
Flu	4/89 (4.5%)	5
Viral gastroenteritis	4/89 (4.5%)	5
Tonsilitis	1/89 (1.1%)	1
Common cold	7/89 (7.9%)	11
Ear infection	7/89 (7.9%)	16
Tooth abscess	1/89 (1.1%)	1
Fever	5/89 (5.6%)	7
Upper respiratory tract infection	6/89 (6.7%)	12
Strep pharyngitis	1/89 (1.1%)	1
Strep throat	6/89 (6.7%)	7
Sinusitis	6/89 (6.7%)	8
Injury, poisoning and procedural complications
Fracture (seizure-related)	1/89 (1.1%)	1
Musculoskeletal and connective tissue disorders
Upper body pain	2/89 (2.2%)	6
Nervous system disorders
Sedation	39/89 (43.8%)	260
Insomnia	10/89 (11.2%)	61
Dizziness	6/89 (6.7%)	20
Sleep disturbance	2/89 (2.2%)	20
Ataxia	4/89 (4.5%)	17
Double vision	1/89 (1.1%)	3
Lethargic	2/89 (2.2%)	13
Dysphagia	1/89 (1.1%)	2
Loss of motor control	1/89 (1.1%)	8
Memory loss	1/89 (1.1%)	1
Psychiatric disorders
Depression/mood issues	13/89 (14.6%)	104
Behavior changes	7/89 (7.9%)	48
Homicidal thoughts	1/89 (1.1%)	2
Renal and urinary disorders
Urinary retention	1/89 (1.1%)	1
Urinary tract infection	2/89 (2.2%)	4
Proteinuria	1/89 (1.1%)	2
Reproductive system and breast disorders
Menorrhagia	4/89 (4.5%)	5
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/89 (1.1%)	1
Croup	1/89 (1.1%)	1
Hypoxemia	1/89 (1.1%)	1
Nasal congestion	1/89 (1.1%)	1
Seasonal allergies	1/89 (1.1%)	1
Nosebleeds	2/89 (2.2%)	16
Pharyngitis	1/89 (1.1%)	1
Skin and subcutaneous tissue disorders
Rash	5/89 (5.6%)	9
Hematoma	1/89 (1.1%)	2
Acne	1/89 (1.1%)	1
Eczema	1/89 (1.1%)	17
Cellulitis	1/89 (1.1%)	1
Ecchymosis	2/89 (2.2%)	3
Ingrown toenail	1/89 (1.1%)	1
Lacerations	3/89 (3.4%)	3
Diaper rash	1/89 (1.1%)	1
Surgical and medical procedures
Ear tube placement	1/89 (1.1%)	1
Port placement	1/89 (1.1%)	1
Wisdom teeth extraction	1/89 (1.1%)	1
Vascular disorders
Headaches	4/89 (4.5%)	5

Limitations/Caveats

Flexible dosing schedule; Over- or underreporting of seizure frequency and severity that may reflect patients' or caregivers' desires to qualify or remain in the study; Non-normality of the data; Early withdrawal of participants.

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.