Novel Cognitive Treatment Targets for Epidiolex in Sturge- Weber Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to better understand the utility of cannabidiol (CBD/ Epidiolex) for improving the treatment of cognitive impairments in Sturge-Weber syndrome (SWS).

Detailed Description
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The investigators hope to gain an understanding of the utility of pharmaceutical grade CBD used for the treatment of cognitive impairments in SWS in this open-label study. Anecdotal evidence from a phase I trial investigating the use of CBD for medically refractory seizures suggests CBD may also have a beneficial effect on cognition, mood, and behavior. The investigators hypothesize that CBD/ Epidiolex will improve SWS brain function resulting in improved cognitive function, social interactions, mood, motor function and behavior, as well as reduced migraines. This is an open-label prospective oral drug trial of Epidiolex in 10 subjects. Assessments will be done at baseline and repeated after 6 months on study drug.

Official Title
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Novel Cognitive Treatment Targets for Epidiolex in Sturge- Weber Syndrome: A Phase II Trial

Conditions
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Sturge-Weber Syndrome

Intervention / Treatment
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* Drug: Cannabidiol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with Sturge-Weber syndrome brain involvement as defined on neuroimaging (n=10 subjects, male and female, ages 3 to 50 years of age) and the following: Cognitive impairment defined as a cognitive neuroscore greater than or equal to 2 at screening. Anti-epileptic, mood or behavioral drugs (if on) at stable doses for a minimum of 4 weeks prior to enrollment. If present, VNS must be on stable setting for a minimum of 3 months prior to enrollment. If on ketogenic or Atkins diet, must be on stable ratio for a minimum of 3 months prior to enrollment. Previous subjects who fail at any point to meet continuation criteria and withdraw early may be considered for re-enrollment under new subject ID as long as the above inclusion criteria are met. The determination of whether to re-enroll will be made by the PI and sponsor on a case-by-case basis. Re-enrollment can occur no earlier than 4 weeks after the final, post-weaning follow-up visit under the old subject ID. Written informed consent obtained from the patient or the patient's legal representative must be obtained prior to beginning treatment. Exclusion Criteria: Patients with any severe and/or uncontrolled medical conditions at randomization such as: Liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA) Uncontrolled diabetes as defined by fasting serum glucose greater than 1.5 Active (acute or chronic) or uncontrolled severe infections Active, bleeding diathesis Patients who have a major surgery or significant traumatic injury within 4 weeks of study entry, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia), or patients that may require major surgery during the course of the study. Patients who start or discontinue a seizure, mood or behavioral medication in the 4 weeks leading up to screening. Prior treatment with any investigational drug or use of any other cannabis product within the preceding 4 weeks prior to study entry. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study. This includes those in foster care, or those unable to keep follow-up appointments, maintain close contact with the Principal Investigator, or complete all necessary studies to maintain safety. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of the female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 50 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cannabidiol/ Epidiolex<br>All subjects will receive the experimental Epidiolex (cannabidiol) oral solution to be taken at home twice a day, and will be treated on an outpatient basis. The drug will be taken for 24 weeks unless the subject chooses to participate in the extension phase of the study, in which case the subject will continue to receive the drug for one additional year or until the drug is approved for clinical use for the treatment of cognitive impairments in patients with Sturge-Weber syndrome. | Drug: Cannabidiol<br>* Initiation of treatment will begin with 5 mg/kg/day given in two divided doses. The dose will be increased by 5 mg/kg/day after seven days and then by 5 mg/kg/day every seven days up to a maximum dose of 20 mg/kg/day given.<br>* Other names: CBD;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| List Sorting Working Memory Test | Data on cognitive function was collected using the List Sorting Working Memory Test from the NIH Toolbox. Data was collected on working memory performance, which was transformed into a t-score from 0 to 100 where a higher t-score indicates better performance. T-score of 50 indicates the population mean with a standard deviation of 10. Data was collected at baseline and after 6 months on study drug. | Baseline, Follow-up (6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Picture Vocabulary Test | Data on cognitive function was collected using the Picture Vocabulary subtest from the NIH Toolbox. Single words are presented via an audio file, paired simultaneously with 4 screen images of objects, actions, and/or depictions of concepts. The task is to pick the picture that matches the spoken word. Performance on the task was transformed into a t-score from 0 to 100 where a higher t-score indicates better performance. T-score of 50 indicates the population mean with a standard deviation of 10. Data was collected at baseline and after 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Seizure Frequency | Change in seizure frequency by seizure score at pre-treatment baseline and after six months. The seizure score is taken from the Sturge-Weber Neuroscore on a scale of 0 to 4 where 0=none, 1=1+. but controlled, 2=Breakthrough, 3=monthly, 4=Weekly+. Higher scores indicate worse outcome. | Baseline, Follow-up (6 months) | 
| Migraine Severity | Data on migraine severity will be collected using patient responses to questions on a standard six-point scale. Data will be collected on the frequency of an event (e.g. feelings of frustration, performance of daily activities) which will be transformed into a score from 0 to 100 where higher scores indicate a less migraine severity and better outcomes. Data will be collected at baseline and after 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Modified House Classification Scores | Data on motor function was collected using a Modified House Classification. Data was collected on the ability to complete a task with the subject's non-dominant hand which was transformed into a score from 1 to 8 and 0 to 32 where higher scores indicate better motor function. Data was collected at baseline and after 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Erhardt Developmental Prehension Assessment Scores | Data on motor function was collected using the Erhardt Developmental Prehension assessment. Data was collected on the ability to complete a task with each hand, which was scored as age equivalence of task performance (in months). Higher scores indicate better motor function. Data was collected at baseline and after 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Pediatric Evaluation of Disability Inventory Computer Adapted Test | Data on motor function was collected using the Pediatric Evaluation of Disability Inventory Computer Adapted Test. Data was collected on the subject's ability to complete tasks involved in daily activities, mobility, and social/ cognitive activities. The data was transformed into scaled scores ranging from 20 to 80, where higher scores indicate better motor function. Data was collected at baseline and after 6 months on study drug. | Baseline, Follow-up (6 months) | 
| ABILHAND Questionnaire | Data on motor function was collected using the ABILHAND questionnaire, a measure of manual ability for adults with upper limb impairments. Data was collected on the subject's ability to complete daily activities that involve the upper limbs. Score was collected as a patient measure with scores ranging from -10 to 10. Higher scores indicate better motor function. Data was collected at baseline and after 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) or Wechsler Adult Intelligence Scale (WAIS-IV) | Data on cognitive function was collected using selected subtests, from either the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) or the Wechsler Adult Intelligence Scale (WAIS-IV). For the WISC-V and WAIS-IV subtests selected, scaled scores were derived from the normative data which account for age and demographic information. The selected WISC-V/WAIS-IV subtests were as follows: Digit Span, Symbol Search, Coding and Processing Speed; the first three subtests were scored from 0-10, the fourth subtest from 0-100, and for all subtests higher score is better. The selected subtests, from the WISC-V and the WAIS-IV, were combined to increase statistical power. Statistically rare changes in individual test scores were determined using a reliable change index methodology based upon normative information for these assessments. | Baseline, Follow-up (6 months) | 
| Pediatric Neurological Quality of Life (Neuro-QoL) | Data on cognitive function was collected using Neurological Quality of Life scales from the NIH Toolbox. Data on frequency of an event (e.g. forgetting schoolwork) was collected and transformed into a t-score from 0 to 100 where higher t-scores indicate worse anger, worse anxiety, worse pain, better social relationships, worse stigma, worse depression, better cognitive function, and worse fatigue. T-score of 50 indicates the population mean with a standard deviation of 10. Data was collected at baseline and 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) | Data on executive function was collected using the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2). Data on the frequency of an event (e.g. becomes upset too easily) was collected and transformed into a t-score. The following BRIEF-2 subtests were evaluated: Behavioral Regulation Index, Emotional Regulation Index, Cognitive Regulation Index, and Global Executive Composite. For each BRIEF-2 subtest, t-scores range from 0 to 100; a score of 50 indicates the population mean with a standard deviation of 10. For all BASC-3 subtests, higher scores are worse outcome. | Baseline, Follow-up (6 months) | 
| Social Responsiveness Scale, Second Edition (SRS-2) | Data on social function was collected using the Social Responsiveness Scale-Second Edition (SRS-2). Data on a child's ability to engage in emotionally appropriate reciprocal social interactions in naturalistic settings was collected and transformed into a t-score from 0 to 100 where higher scores indicate greater impairment in social function. T-score of 50 indicates the population mean with a standard deviation of 10. Data was collected at baseline and 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Behavioral Assessment System for Children, Third Edition (BASC-3) | Data on behavioral function was collected using the Behavioral Assessment System for Children, Third Edition (BASC-3). Data on the frequency of a behavior (e.g. avoids eye contact) was collected and transformed into a t-score. Subscales for the BASC-3 scored were: External Problems Composite, the Internal Problems Composite, the Behavioral Symptoms Index, and the Adaptive Skills Composite. For the first three subscales, lower t-score indicates better outcome; for the fourth, a lower t-score indicates worse outcome. T-scores for all the BASC-3 subscales range from 0 to 100, and a t-score of 50 indicates the population mean with a standard deviation of 10. | Baseline, Follow-up (6 months) | 
| Screen for Child Anxiety Related Disorders (SCARED) | Data on anxiety was collected using the Screen for Child Anxiety Related Disorders (SCARED). Data on the truthfulness of a statement (e.g. I am nervous) was collected and transformed into a score from 0 to 82 where higher scores indicate greater anxiety. Data was collected at baseline and 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) | Data on quality of life was collected using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). Data on the frequency of an event (e.g. had trouble concentrating on a task) was collected and transformed into a score from 0 to 100 where higher scores reflect better quality of life. Data was collected at baseline and 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Safety of Epidiolex | Safety of Epidiolex was measured by the number of adverse events and serious adverse events that result from study drug. | Baseline, Follow-up (6 months) | 
| Neuroscore | Data on neurological function was collected using the Neuroscore. Data on frequency of seizures, extent of hemiparesis, assessment of visual field cut, and degree of cognitive functioning was transformed into a score from 0 to 15 where higher scores indicate worse neurologic function. Data was collected at baseline and 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Port-wine Birthmark Score | Data on facial port-wine birthmarks was collected using the Port-wine Birthmark Score. Data on percent of face covered, thickness of birthmark, and darkness of birthmark color was collected and transformed into a score from 0 to 43 where higher scores indicate greater severity and greater surface area involved. Data was collected at baseline and 6 months on study drug. | Baseline, Follow-up (6 months) | 
| Adult Neurological Quality of Life (Neuro-QoL) | Data on cognitive function was collected using Neurological Quality of Life scales from the NIH Toolbox. Data on frequency of an event was collected and transformed into a t-score from 0 to 100. Higher t-scores indicate better communication, better ability to participate in social activity, worse anxiety, worse depression, worse emotional and behavioral dyscontrol, worse fatigue, better positive affect, worse sleep disturbance, better lower and upper extremity functions, worse stigma, better satisfaction with social roles, and better cognitive function. T-score of 50 indicates the population mean with a standard deviation of 10. Data was collected at baseline and 6 months on study drug. | Baseline, Follow-up (6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sturge-Weber Syndrome, SWS, Cognitive impairments