Clinical trial NCT04447846
Conditions: Sturge-Weber Syndrome
Keywords: Sturge-Weber Syndrome SWS Cognitive impairments
Sponsor: Anne Comi, MD
Start date: 2019-10-14; Completion date: 2022-12-09
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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:
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.

Arms: arm 1: 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.
Interventions: intervention 1: Cannabidiol
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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Official Title of the Study: Novel Cognitive Treatment Targets for Epidiolex in Sturge-Weber syndrome: A phase II 
trial 
NCT Number: NCT 04447846 
Date of Document: 29 June, 2021 
Principal Investigator: Dr. Anne M. Comi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Date: June 29, 2021 
Principal Investigator: Anne Comi, MD 
Application Number: IRB00204427 
 
 
 
JHM IRB - eForm A – Protocol 
 
*************************************************************************************************** 
 
 
1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research. 
 
Importance: With this phase II drug trial, we hope to better understand the utility of cannabidiol 
(CBD/Epidiolex) for improving the treatment of cognitive impairments in Sturge-Weber syndrome.   
 
Problem: Sturge-Weber syndrome (SWS) is a vascular malformation disorder occurring in about 1 in 
20,000 live births, and one of the most common neurovascular disorders. Those affected have vascular 
malformations in the brain, skin and eye. SWS is associated with lifelong epilepsy and cognitive issues; 
children develop a range of cognitive impairments, including intellectual disability, ADHD, learning 
disabilities and autism. Patients often develop anxiety, depression and behavioral issues, as well as 
migraines and motor impairments.   
 
Dr. Comi led and published on an Investigator Initiated trial of Epidiolex for medically refractory seizures 
in 5 patients with Sturge-Weber syndrome (Kaplan et al, Pediatric Neurology, 2017). Three of the 5 
subjects had sustained improvement in their seizures; one became seizure-free. Interestingly, cognitive, 
mood and behavioral improvements were also noted by these patients and their families. It is possible that 
these improvements resulted from improved seizure control. However, these improvements were first seen 
between 1-3 weeks after starting Epidiolex, and occurred sooner than would be expected as a result of 
improved seizure control. In addition, these anecdotal improvements have been sustained.  The following 
clinical improvements were reported qualitatively in these subjects: 1) improved cognitive function, 2) 
improved social function, 3) improved mood and behavior, 4) improved motor function and 5) reduced 
migraine frequency and severity.  Therefore, we are interested in doing a follow up study to quantify the 
improvements noted in the initial study.   
 
Please note that Epidiolex is FDA approved for the treatment of seizures in Lennox-Gestaut syndrome and 
Dravet syndrome and is clinically used for the treatment of seizures in Sturge-Weber syndrome and many 
other medically refractory seizure disorders[1-3].  Epidiolex is no longer scheduled and can be prescribed 
clinically for patients seen remotely. We are studying Epidiolex here in Sturge-Weber syndrome for 
different indications.   
 
Hypothesis: Cannabidiol (Epidiolex) improves SWS brain function resulting in improved cognitive 
function, social interactions, mood, motor function and behavior, as well as reduced migraines.  
 
2. 
Objectives (include all primary and secondary objectives) 
 
We propose a follow up to the initial SWS Epidiolex study which suggested improvements in SWS 
cognitive, social, and behavioral function and in other neurologic issues. Primary outcome measure: 
Quantify cognition 6 months after initiation of Epidiolex compared to baseline. Secondary outcome 


 
 
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measures: The following at 6 months compared to baseline: Social function and mood, frequency and 
severity of seizures, migraine frequency and severity, and motor outcomes. 
 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
SWS is associated with cognitive impairments. By school age, cognitive impairments are common in SWS, 
even among patients that perform at or slightly below their age level. In a retrospective study of 29 SWS 
patients who underwent neuropsychological testing, 36% demonstrated no intellectual impairment, 32% 
performed in the “borderline/low average” range, and the final 32% displayed impaired intellectual 
functioning.[4] In addition, the study found that 58% displayed impaired performance in adaptive 
functioning. Adaptive functioning has been associated with executive dysfunction, externalizing and 
internalizing behavioral disorders, and borderline intellectual functioning.[5] Interestingly, hemiparesis was 
found to be independently associated with adaptive functioning. [6-8] Neuropsychological testing is 
recommended for patients that display hemiparesis in order to introduce early interventions (occupational 
therapy, cognitive rehabilitation) and accommodations (extra school support).  On MRI, increased brain 
calcification over time is associated with a longer duration of epilepsy, a younger age of seizure onset, as 
well as a lowered IQ. Additionally, neuronal loss, gliosis, and decreased perfusion often surround calcium 
deposits.[9 10] The brain-involved hemispheres, as well as half of the uninvolved lobes also displayed 
significant reductions in glucose metabolism on positron emission tomography (PET) scans.[9]   
Cognitive impairments in SWS are likely related to impaired vascular function and blood flow. In a normal 
brain, venous blood from the cerebral cortex and subcortical white matter drains through surface veins, 
whereas blood from deep white and grey matter drains through deep medullary veins.[11-13] The 
leptomeningeal venous malformations that characterize SWS induce the destruction of effective superficial 
venous pathways. As a result, venous pressure increases, prompting the blood to seek an alternate route for 
drainage. This unusual blood flow likely contributes to the strokes and stroke-like episodes observed in SWS 
patients.[14 15] Thus, modulation of blood flow in the brain may improve neurological symptoms of SWS. 
 
GNAQ and signaling in SWS. In 2013, Shirley, Comi and Pevsner et al. identified a somatic 
nonsynonymous single-nucleotide variant R183Q in GNAQ, the gene that encodes G protein subunit αq.[16] 
G αq is part of a trimeric G protein complex that binds to the cytosolic side of an inactive G-protein-coupled 
receptor (GPCR).[16],[17 18] Several important GPCRs signal through Gαq including: 5-HT2 serotonergic 
receptors, Alpha-1 adrenergic receptor, Vasopressin type 1 receptors 1A and 1B, Angiotensin II receptor type 
1, Calcitonin receptor, Histamine H1 receptor, and the Metabotropic glutamate receptor.  This mutation exists 
in SWS-related and isolated port-wine birthmarks alike, and is enriched in endothelial cells in SWS brain 
lesions and in other skin capillary malformations.[19 20]  
GPCR engagement induces the exchange of GDP to GTP on the Gα subunit, which facilitates the release of 
the G protein heterotrimer from the GPCR, as well as the dissociation of the activated Gα from the β/γ dimer. 
This process results in downstream activation of the Ras/Raf/MEK/ERK pathway, which in turn regulates the 
PI3-K/AKT/ mammalian Target of Rapamycin (mTOR) pathway.[17 18] These pathways have essential 
regulatory functions in vascular growth and organization, and are activated in endothelial cells from SWS 
capillary malformations as indicated by increased phosphorylated-S6 expression,[21] and in SWS 
leptomeningeal tissue as shown by increased p-ERK.[22] The R183Q mutation in GNAQ is predicted to 
hyperactivate downstream pathways.  
Both the Ras/RAF/MEK/ERK and PI3K/AKT/mTOR pathways modulate vascular endothelial growth factor 
(VEGF) and hypoxia-inducible factor (HIF)-1α expression, and SWS brain tissue shows increased expression 


 
 
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of these and other vascular factors. VEGF expression is increased in cortical neurons and glia underlying the 
abnormal leptomeningeal vessels, whereas VEGF receptor 2 (VEGFR2), HIF-1α, and HIF-2α expression are 
increased in endothelial cells lining the abnormal leptomeningeal vessels.[23] Expression of VEGFR2 in 
endothelial cells is mediated by activated GNAQ,[24 25] and likely drives vascular remodeling that has been 
observed in SWS.[23]  
Cannabidiol for SWS. SWS can be viewed as a model for testing the impact of Epidiolex upon Gαq, an 
important regulator of pathways downstream of crucial GPCRs.  Furthermore, if Epidiolex improves SWS 
treatment targets such as anxiety, migraine or cognitive impairments, then this drug may prove more 
generally useful for these symptoms. 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
Study Overview:  The proposed study will be a phase II trial in 10 participants with Sturge-Weber 
syndrome brain involvement and cognitive impairments at the Hunter Nelson Sturge-Weber Center at the 
Kennedy Krieger Institute, led by Dr. Comi. We may need to consent additional subjects (N=11) to meet 
our goal of 10 accrued subjects on study drug. In response to the COVID-19 Pandemic Crisis, all visits and 
assessments will now be conducted remotely by utilizing a video conference application. If medically 
required, such as for an adverse event that requires an in-person exam, the subject will be seen on-site in 
our out-patient neurology clinic. We do not anticipate needing to see subjects on-site, but include this in 
case it is medically necessary.  
 
After screening, written consent will be obtained remotely (see process below), with baseline measures 
completed before starting on the study drug.  All scheduled visits and assessments will be done remotely. 
 
Done remotely as part of routine care (but in this setting NOT billed as clinical care): History, neurological 
exam, home weight (families to be sent digit scales to be used), home blood pressure and heart rate 
(families to be sent digital blood pressure and heart rate equipment) labs (outside lab, see process below), 
SWS neuroscore, Neuropsych testing and psychiatric exam. The following will also be done remotely and 
only done for research: Port-wine score, picture taken, NeuroQoL (Neurologic Quality of Life Scale), 
quantitative measurements of motor, behavior, and social function, and migraine scale.   
 
The study drug will be initiated at the baseline visit with Dr. Comi reviewing instructions for its use. If a 
subject lives outside of Maryland, a script will be written and sent to Pharmacord, a pharmacy hub working 
with Greenwich who will ship the Epidiolex directly to the subject’s home within 1 week. If a subject 
resides in the state of Maryland, a script will be written and sent to the Johns Hopkins Investigational Drug 
Research Pharmacy, who will ship the Epidiolex directly to the subject’s home within 1 week. Receipt of 
the epidiolex will be confirmed with the subject by the research coordinator and instructions for its use 
reviewed and any questions answered by Dr. Comi if needed.  
 
Follow-up remote visits consisting of lab work (done by script to outside labs), seizure/adverse event 
reports, an exam (including home reporting of weight, blood pressure and heart rate), neuroscore, , 
NeuroQoL, and medication review will be held after 1 and 3 months on Epidiolex. After 6 months on 
Epidiolex, the subjects will undergo follow up remote repeat testing for all the above initial measurements.  
 
If the subject had significant improvements, they will have the option to continue the drug as a part of the 
extension phase. During the extension phase, the PI will have the ability to change (increase and decrease) 
dose of Epidiolex and other anti-seizure medications as clinically indicated.   The extension phase will 
involve at least 4 visits (one every 3 months) but subjects may continue on the extension phase until 


 
 
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insurance company coverage is obtained. Study drug will be provided by Greenwich Biosciences until 
insurance coverage is obtained or other arrangements made to cover the cost of the study drug.  At the end 
of one year, if insurance coverage has not been obtained then Greenwich Biosciences will work with the 
family through the Greenwich Drug Coverage Program to ensure that subjects benefitting from the drug 
can continue to receive it.  Subjects who did not improve, or do not wish to continue taking Epidiolex, will 
wean off the drug at this time. If at any point the subject leaves the study, they will be asked to have a 
follow up remote visit one month after weaning has commenced. 
 
Serious adverse events include those events that: result in death; are life-threatening; require hospitalization 
or prolongation of existing hospitalization; or create persistent or significant disability, or birth defects. 
 
An unexpected adverse event is defined as any adverse event, the specificity or severity of which is not 
consistent with the risks of information described in the protocol. 
 
Expected adverse events are those that are identified in the research protocol as having been previously 
associated with participation in the study. 
 
All reported adverse events will be classified using the current version of the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0 developed and maintained by CTEP at National Cancer 
Institute. 
 
Dosing: Epidiolex will be started at 5 mg/kg/day and titrated to maximum dose of 20 mg/kg/day, increasing 
the dose by 5 mg/kg/day weekly over the next three weeks.  The investigational drug (Epidiolex/CBD) will 
be administered as an adjunct to all current anti-epileptic drugs. 
 
Visit Schedule (see Figure): Subjects will be seen remotely for Screening Visit for Consent and initial 
studies, at Baseline Visit to start on CBD, then at 1 month, 3 months, and 6 months after initiation. Phone 
and/or email communication will take place bimonthly.  
Lab work: CBC, chemistries including LFTs, urinalysis, Cannabidiol (CBD)/ Tetrahydrocannabidiol 
(THC) ratio,  and trough levels of all seizure medications will be done at each visit. All labs tests will be 
completed remotely at an outside lab site local to the participant and charged to the study budget.  
Database: A Redcap database will be used to organize data which will be analyzed with SPSS.  
Method of administration: Cannabidiol oral solution 100 mg/ml will be administered orally. The 
participants will be treated on an outpatient basis (remotely) and will not require inpatient hospital 
admission. 
Dose / titration schedule: 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. Study drug supply will be mailed to the participants (see 
process outlined above). The dosing schedule will be as follows, as tolerated: 
Start of study: 5 mg/kg/day; subject will be evaluated here 
Week 1: Increase dose by 5 mg/kg/day for total daily dose of 10 mg/kg/day 
Week 2: Increase dose by 5 mg/kg/day for total daily dose of 15 mg/kg/day 
Week 3: Increase dose by 5 mg/kg/day for total daily dose of 20 mg/kg/day 


 
 
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Week 4: Subject will be evaluated at stable dose of Epidiolex.  If a subject has side effects thought to be 
due to study drug on 20 mg/kg/day, or a lower dose, then the dose will be decreased to the maximal dose 
tolerated in this dose range (5-20 mg/kg/day) 
Seizure Medications: The dose of concomitant seizure, mood or behavioral drugs will remain unchanged 
during CBD treatment unless there are symptoms of toxicity, significant changes in blood levels, or an 
increase in seizures requiring an increase in a seizure medication.  If seizure or mood issues require the 
addition of a seizure medication, the subject will be taken out of the study.  
Recruitment of Participants 
 
Recruitment will be from Dr. Comi’s patients at the Hunter Nelson Sturge-Weber Center database at the 
Kennedy Krieger Institute. Patients who are in research databases (NA_00043846, NA_00038014) and 
have given the study team at the Kennedy Krieger Institute permission to contact them regarding research 
will be sent information regarding the trial and invited to contact the study team for more information if 
interested.  Patients coming for clinical visits to Dr. Comi will be pre-screened for meeting inclusion 
criteria.  A log will be kept of patients pre-screened for this trial and results of the pre-screening process.   
 
Information about the pilot study will also be posted on the center websites, clinicaltrials.gov, and offered 
for posting on the websites of relevant advocacy foundations.  If interested, individuals will contact Dr. 
Comi from the website postings. Subjects may also be referred to Dr. Comi for research purposes by 
treating clinicians not on the study team. The investigational nature and objectives of this trial, the 
procedures, the treatments involved, the attendant risks, and discomforts, as well as potential alternative 
therapies, will be carefully explained to the patient or their parents or guardian if he/she is a child.  A 
signed informed consent document will be obtained after the entirety of the pilot study is explained.  
Consent will be obtained by the PI on the trial.  Where deemed appropriate by the clinician and the child’s 
parents or guardian, the child will also be included in all discussions about the trial.  Assent will be 
obtained from all children able to provide assent according to our local IRB guidelines. Our consent 
contains an assent statement on the second-to-last page.  The goal is to recruit ten participants total in this 
study.  
Retention Strategies 
 
When recruiting participants, the frequent visit schedule will be reviewed with the participants to ensure 
they are aware of the time commitment required to be in this study.  All visits will be scheduled as far in 
advance as possible and will occur remotely by utilizing a video conference application   Participants will 
receive reminders via email or phone before their appointments.  All appointments surrounding holidays 
and travel will be scheduled far in advance.  
 
Anticipated numbers of subjects to be enrolled and on study drug: 
 
 
American 
Indian or 
Alaskan 
Native 
Asian 
or 
Pacific 
Islander 
Black, 
not of 
Hispanic 
Origin 
 
Hispanic 
White, 
not of 
Hispanic 
Origin 
 
Other or 
Unknown 
 
Total 
 
Female 
0 
1 
1 
0 
3 
 
5 
 
Male 
1 
0 
0 
1 
3 
 
5 
 
1 
1 
1 
1 
6 
 
10 


 
 
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Total 
 
Written Informed Consent 
Written informed consent will be obtained from each participant before any study-specific procedures or 
assessments are done and after the aims, methods, anticipated benefits, and potential hazards are explained.  
The participant’s willingness to participate in the study will be documented in writing in a consent form, 
which will be signed by the participant or legal guardian with the date of that signature indicated.  The 
investigator will keep the original consent forms and signed copies will be given to the participants.  It will 
also be explained to the participants that they are free to refuse entry into the study and free to withdraw 
from the study at any time without prejudice to future treatment.   
Process of Consent   
The investigational nature and objectives of this trial, the procedures, the treatments involved, the attendant 
risks, discomforts, and potential benefits, as well as potential alternative therapies, will be carefully 
explained to the patient or their parents or guardian if he/she is a child.  A signed informed consent 
document will be obtained after the entirety of the pilot study is explained. Consent will be obtained by the 
co-investigator designated to obtain consent on the IRB and delegation log for the trial.  Where deemed 
appropriate by the clinician and the child’s parents or guardian, the child will also be included in all 
discussions about the trial and assent obtained where appropriate.   
 
Virtual Written Consent Process: A copy of the IRB approved Informed Consent document will be 
provided to the participant prior to the teleconsent meeting either via email, fax or previously provided 
during an in person visit.   The person conducting the consent process will conduct the process via 
telephone or video. The following is a step-by-step teleconsent / remote consent process: After the consent 
designee and participant or LAR review the consent form, the participant or LAR will be offered the 
opportunity to ask any questions and have those questions answered. The consent designee will verify the 
participant or LAR physically signed the consent document either by viewing via video conference, 
obtaining a photo of the complete signed consent document; or obtaining verbal confirmation from the 
participant that he/she signed the consent form or agreed to participate electronically. The participant or 
LAR will sign and date/time the informed consent document. The signed document will then be mailed, 
emailed or faxed to the consent designee.  If the signed consent is emailed or faxed or returned via photo, 
the participant or LAR will be asked to return the original signed document on their first in person visit. If 
the informed consent form is mailed to the consent designee by the participant or LAR, the IRB-approved 
consent designee will sign the copy which they possess after the participant has acknowledged signature on 
their copy.  Once the original is received by the consent designee the copies will be attached to make a 
single document. Once received, the IRB-approved consent designee signs, dates/times the informed 
consent document. A copy of the fully signed written consent will be sent to the participant by mail, email 
or fax.  
Estimated Time Commitments for Visits 
Baseline Evaluations- Done on Visit 1 or 2 prior to starting drug.  Can also be done between Visit 1 
and 2 if more convenient for subject.  Cognitive testing/assessments: 1 1/2 hours. Psychiatric/Mood: 3 
hours.  Neurologic Exam, history, picture, neuroscore, birthmark score: 1 hour. Labs: 30 minutes. Total=6 
hours.  
 
Visits 3 and 4. Neurologic Exam, history, and neuroscore: 1 hour. Labs: 30 minutes. Total: 1 ½ hours 
each remote visit 
 


 
 
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Final Evaluations: Done on or close to Visit 5 (within a 7-day period of time) and while still on 
Epidiolex. Cognitive testing/assessments: 1 1/2 hours. Psychiatric/Mood: 1 hour. Neurologic Exam, 
history, picture, neuroscore, birthmark score: 1 hour. Labs: 30 minutes. Total=4 hours. 
Outcome Measures 
Primary Outcome Measure: The primary outcome will be a change in cognitive function defined as change in 
score on the List Sorting Working Memory test. This cognitive test in the NIH Toolbox was suggested by our data in 
another study to yield the most actionable data. The NIH has provided guidance on the remote application of the NIH 
Toolbox Changes in cognitive function (from pre-treatment baseline to 6 months on study drug) will be assessed.  
Each subject measured at baseline will serve as his/her own control.  Other cognitive function tests (below) which 
will be measured were selected because they also assess working memory and processing speed.  
The NIH Toolbox for the Assessment of Neurological and Behavioral Function (NIH-TB).[26 27] 
Cognitive measures are computer-based tasks used for assessing a number of cognitive domains, including 
executive functioning, memory, language, etc.  Because the tests were developed and normed for use with a 
very broad age range (ages 3-89), the NIH-TB is appropriate for the range of ages proposed for this 
research application (childhood, adolescence, and early adulthood).  The NIH-TB has also been shown to 
be appropriate for use with individuals with lower or impaired cognitive functioning.[28] These are 
published tests which are widely used.  From amongst the measures of the NIB-TB Cognitive measures, 
two measures were selected for use both which we have already utilized in subjects (and patients) with 
SWS:  
The List Sorting Working Memory subtest is a test of working memory which will be used to assess the 
study outcome of working memory. Approximate time:  10 minutes 
Secondary Outcome Measures 
Change in other cognitive outcomes: The Picture Vocabulary subtest is a single-word receptive 
vocabulary/auditory comprehension task.  When administered: 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.77 This subtest was selected as one less likely to be 
treatment responsive, as compared to the other two above. Approximate time: 10 minutes 
In addition, subscales were selected from several other assessments which also assess working memory and 
processing speed from the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) (Wechsler, 
DL. (2015). Wechsler Intelligence Scale for Children, Fifth Edition (Fifth). San Antonio, TX: The 
Psychological Corporation.).  Subtests from the WISC-V will be used to assess working memory and 
processing speed in all participants ages 6 to 15. Specific subtests will be used to measure primary outcome 
variables of this study. (1) The Digit Span subtest is verbal working memory task that presents participants 
with requirements to repeat digit strings verbatim, repeat digit strings backwards, and sequence digit strings 
numerically and alphabetically. (2) The Coding subtest is a nonverbal processing speed task that presents 
the participant with speeded visual scanning and discrimination requirements, and requires a degree of 
pencil control and visuo-motor coordination. (3) The Symbol Search subtest is also a nonverbal processing 
speed task that requires speeded visual scanning and discrimination, but has lesser visuo-motor 
coordination requirements relative to the coding subtest. The Wechsler Adult Intelligence Scale, Fourth 
Edition (WAIS-IV) (Wechsler, DL. (2008). Wechsler Adult Scale is similar.  Administration time: 10 
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NeuroQoL (NIH Tool Box Neurological Quality of life scale) has been shown in SWS that the cognitive 
function quality of life domain is significantly lower than in controls and that it is associated with extent of 
brain involvement and age of seizure onset (manuscript in preparation). Time: 15 minutes 
Checklists: The following symptom-report checklists are outcome measures that will be completed (while 
waiting for procedures/visits) by parents/caregivers in order to more fully assess executive function, social 
function and behavior:   
Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2; Gioia, G., Isquith, P., 
Guy, S., & Kenworthy, L. (2015), Behavior Rating Inventory of Executive Function, Second Edition.  Lutz, 
FL: WPS.) is a caregiver report questionnaire designed to assess the behavioral manifestations of executive 
functions in children ages 5-18 years. Raters assess the child’s behavior on a 3-point Likert scale and scores 
are obtained on the scales such as: Initiate, Working Memory, Plan/Organize, Organization of Materials, 
Self-Monitor, Task-Monitor, Inhibit, Shift, and Emotional Control. Administration time: 10 mins.   
The Social Responsiveness Scale, Second Edition (SRS-2; Constantino, J. N., & Gruber, C. P. (2012). 
Social Responsiveness Scale–Second Edition (SRS-2). Torrance, CA: Western Psychological Services) 
enquires about a child’s ability to engage in emotionally appropriate reciprocal social interactions in 
naturalistic settings and includes items that ascertain social awareness, social information processing, 
capacity for reciprocal social responses, social anxiety/avoidance, and characteristic autistic 
preoccupations/traits.  The SRS-2 generates a singular score that can be used as a measure of severity of 
social function and which can be used to screen for ASD. Approximate time: 15 – 20 minutes.   
Change in Migraine Severity: Change in migraine severity is a secondary outcome measure for this trial. 
At pre-treatment baseline and after 6 months on the study drug, the subject will complete the “Migraine 
Specific Quality of Life Questionnaire,” reflecting on how migraines affect their daily living. The MSQ has 
14 questions and been shown to be a psychometrically valid tool that can be used to reliably measure the 
impact of migraine among chronic migraine patients.[29] Administration time: 10 minutes 
Psychiatric Evaluations: Subjects will undergo baseline behavioral assessments including a semi-
structured diagnostic interview in order to obtain DSM-V diagnoses.  The diagnostic interview instrument 
will be tailored for the age and cognitive level of the participant.  For pediatric participants, the Kiddie 
Schedule for Affective Disorders and Schizophrenia (KSADS) will be used.  The KSADS is a semi-
structured diagnostic interview well established in clinical psychiatric research as the standard method for 
objectively identifying DSM diagnoses, suitable for clinical research purposes.   
Baseline behavioral profiles will also be obtained by using age-appropriate, well-established standardized 
instruments commonly used in neuropsychiatry clinical practice.  These instruments may include the 
Behavioral Assessment System for Children (BASC), The Screen for Child Anxiety Related Disorders 
(SCARED) or Children’s Depression Rating Scale (CDRS).  A quality of life scale is also expected to be 
obtained such as the Quality of Life in Epilepsy Scale for adolescents (QOLIE-ad-48).   
The use of these instruments will reveal a sophisticated behavioral and psychiatric profile that is the state of 
the art in clinical behavioral science research.  Baseline behavior function and psychiatric diagnoses will be 
well established prior to treatment and compared to ratings from behavioral profile scales obtained at a 
follow up stage (Approximate time-3 hours at baseline, 1 hour at follow-up).   


 
 
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Safety of Epidiolex: as measured by the number of adverse events and serious adverse events resulting 
from study drug.   
Change in Seizure Severity: All seizure types will be classified before study entry (most common seizure 
type are partial motor and partial with impaired consciousness). Seizure frequency for each seizure type 
will be recorded retrospectively for the month prior to enrollment and at each visit during the study using 
diaries. In addition, at each visit the parents/caregivers will report the following secondary outcome 
measures: seizure duration by seizure type, number of episodes of status epilepticus (defined as convulsive 
seizure lasting longer than 10 minutes), number of uses of rescue medication, and the number of ER visits/ 
hospitalizations. 
 
Change in motor function, as defined by Modified House Classification and selected scales from EDPA 
and parent-report measures: PEDI-CAT and ABILHAND/ABILHAND-KIDS (as previously 
described).[30] Video recordings of the Modified House Classification and selected scales from EDPA will 
be taken for each subject at baseline and at six months follow-up. The video recordings will be reviewed 
and scored blind by a study team occupational therapist. Administration time: 20 minutes 
Laboratory tests and clinical procedures 
1) Weight and vitals will be monitored at baseline and at each remote visit. (Routine care).  
2) Neuroscores (as previously described)[31-33] will be assigned at each visit by Dr. Comi as per her 
clinical routine. The SWS neuroscore is comprised the frequency of seizures, extent of hemiparesis, 
assessment of visual field cut, and degree of cognitive functioning with a total score of 15 possible points.  
Neurologic exam and general physical exam will also be performed remotely at each visit. (Routine care) 
3) Participants will be asked at each remote visit about any change in neurologic symptoms. (Routine care) 
4) For subjects with a facial port-wine birthmark, frontal and profile photograph will be taken under 
standardized conditions with scoring of the port-wine birthmark (Port-wine birthmark score) for percent 
of face covered, thickness of birthmark, and darkness of birthmark color. Families will be mailed a color 
chart (see appendix) to hold up next to the subject while photos are being taken.  Subjects without any 
facial port-wine birthmark will only need photographs taken at a single visit to confirm the lack of 
birthmark. (Research, See Study Visit Table). 


 
 
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Table of 
Remote Visits 
Screening 
 
Baseline 
 
Core Phase 
Endpoint 
6 months 
Visit Number 
1 
2 
3 
4 
5 
Study Week 
-2 
0 
 
 
4 
12 
24 
Consent 
X 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
Neuroscore 
X 
X 
X 
X 
X 
Neuro QoL 
X 
X 
X 
X 
X 
Incl/Excl 
Criteria 
X 
X 
X 
X 
X 
Past Medical 
History 
X 
 
 
 
 
Diagnosis of 
SWS 
X 
 
 
 
 
Seizure Hx 
X 
X 
X 
X 
X 
Previous AED 
Hx 
X 
 
 
 
 
Current Med 
Hx 
X 
X 
X 
X 
X 
Picture Taken 
 
X 
 
 
X 
Rescue Meds 
X 
X 
X 
X 
X 
AEDs 
X 
X 
X 
X 
X 
Motor, NP, 
psychiatric 
Assessments 
 
 
 
 
X ± 7 days 
Labwork 
 
 
 
 
 
AED Levels 
X 
 
X 
X 
X 
CMP (renal, 
hepatic) 
X 
 
X 
X 
X 
CBC 
X 
 
X 
X 
X 
CBD/THC Ratio 
 
 
X 
X 
X 
Urinalysis 
X 
 
X 
X 
X 
Pregnancy Test 
(if applicable) 
X 
 
X 
X 
X 
Safety 
 
 
 
 
 
Adverse 
Events check 
 
X 
X 
X 
X 
Safety Calls:  
 
 
 
 
 
Continue or 
Remove? 
X 
X 
X 
X 
X 
Patient 
Reported 
Outcomes 
 
 
X 
X 
X 
 
 
 
 
 
 
 
± 7 days 
± 14 days 
Bi-monthly 


 
 
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5) CBC, LFT, BUN, creatinine levels, electrolytes, and urinalysis will be measured at each visit (screening, 
1, 3, and 6 months on drug). Concomitant AED plasma concentrations will be measured at the same visits. 
CBD/THC ratio in urine will be measured three times; at the one month visit, at the three month visit, and 
at the 6 month visit. All lab tests will be done remotely at a site local to the participant and charged to the 
study budget.  
6) hCG urine pregnancy test will be used for all female participants Tanner stage 2 and above (see Study 
Visit Table). We will tell subjects that they must be using effective birth control (for example, abstinence, 
birth control pills, contraceptive implants, condoms) and confirm that this is the case at each study visit. 
We will inform female subjects that they should not become pregnant or breastfeed a baby while on this 
study or for 12 weeks after taking Cannabidiol. We will also inform male subjects that they should not get 
their partners pregnant while on this study or for 12 weeks after taking Cannabidiol.  Anyone who becomes 
pregnant while on the study will be removed immediately. 
Case Report Forms: Forms generated for use as case report forms will also be used as source documents.  
Forms will be filled out during the study visit with data. Immediately after the visit, the form will be 
photocopied and one copy will immediately have the study subject ID# written on it (case report form). The 
other copy will immediately have the subject name written on it (source document). 
b. Study duration and number of study visits required of research participants. 
 
Duration of therapy: Study duration for subjects will be between 6 months to 2 years depending on the 
age at enrollment.  During the study, subjects will be seen at 1 month, 3 months and the every 3 months 
until they are 2 years of age.  Therefore the number of study visits will range from 4 to 8, again depending 
on the age at enrollment.  Total length of study for completion of all subjects will be 4 years as outlined in 
the Milestones Table attached. Once the optimal dose is found (20 mg/kg/day or maximal tolerated dose; 
expected to be reached within 4 weeks), participants will continue on the Core Phase until 2 years of age.  
At the end of the core phase, cognitive and all other testing will be repeated. Total duration for each 
subject= until 2 years of age, a minimum of 6 months and 5 visits.  
 
Study Visit 1: Screening Visit- Informed consent process, eligibility criteria reviewed. The following tests 
are done at visit one, or at or before visit 2 (maximum of two weeks between visits 1 and 2): baseline 
developmental testing, baseline labs sent, neurological exam, and baseline motor testing, Quality of life 
measures, motor testing video, Neuroscore and Port-wine birthmark score.  
 
Study Visit 2: Baseline Visit- Confirm eligibility and begin drug at dose 1 (see Visit Table and Dose 
Schedule). Provide study drug dosing record and instruct on use. History, exam, Quality of life measurs, 
have picture taken, and Port-wine birthmark score.  
 
During visits 3 and beyond (see Visit Table)- the participants will undergo clinical neurologic assessments, 
blood draws for laboratory tests, study drug accountability, concomitant medication survey, adverse event 
reporting, and study drug administration (see Visit Table for details). Also, Quality of life measures and 
neuroscore. 
 
Final Study Visit- Repeat all assessments- developmental testing, labs, neurological exam, motor testing, 
Quality of life measures, motor testing video, Neuroscore, have picture taken, and Port-wine birthmark 
score. Determine whether subject will continue on Epidiolex or will be weaned off.  
 
Clinical Follow Up: Subject will be seen one month later for clinical follow up whether on or off Epidiolex.  
 


 
 
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An additional blood draw will also be necessary within 72 hours of a previous blood draw if the most 
recent result indicates a clinically significant (>3xULN) elevation of ALT or AST. At minimum, the 
following tests will be repeated: ALT/AST, total bilirubin, and alkaline phosphatase. A GGT test will also 
be performed at that time. This bloodwork (ALT/AST, total bilirubin, and alkaline phosphatase and GGT 
test) will also be necessary if: 1) the dose of the study drug dose is increased after the escalation phase, 2) 
another drug which affects liver function is added, stopped, or has a dose change, or 3) the subject has one 
or more of the following symptoms without another explanation: fatigue, encephalopathy, nausea, 
vomiting, right upper quadrant pain or tenderness, abdominal pain or distension, fever, excessive bruising, 
excessive nose or gum bleeds, or petechia. All trial subjects with elevated LFTs will be followed closely 
until all abnormalities return to the baseline state as assessed by the investigator with AST/ALT < 3x ULN 
and will be followed until ALT/AST have normalized and symptoms resolve. 
 
Sharing of test results: This study involves tests, labwork, that could be useful for the clinical care of the 
subject. We will share this information with the subject if clinically significant abnormalities are seen. If 
for example, if the labwork is significantly abnormal, then Dr. Comi will contact the subject tell them what 
to do.  If the evaluation of mood suggests that urgent treatment is required, then Dr. Salpekar or Dr. Comi 
will speak with them about what the next step should be.  The other research tests are not expected to 
produce results that would be relevant for clinical care, so we will not share these results with the subject.   
 
Data Management 
The trial PI will review the study progress weekly.  Patients entered on the trial and adverse events will be 
reviewed to ensure that the study is implemented as outlined in the protocol.  Data will be collected on case 
report forms.  Monthly reports will be generated to assess completeness of data.  There will be monthly 
phone conferences to address quality assurance (QA) issues.  
 
The trial database will use a system of coded identifiers to protect participant confidentiality and safety.  
Each participant enrolled will be assigned a research identifier by the KKI.  
 
Study Records Retention 
Patient files will be kept until at least seven years after completion of the study. 
 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
During this phase II trial, where the primary objectives are to assess novel treatment targets and tolerability, 
blinding is not appropriate. 
 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
 
Participants will otherwise receive routine care and will not have to stop any of their current 
anticonvulsants or other medications.  They will be clinically managed by Dr. Comi who will respond to 
side effects or worsening of the participants’ care in a manner consistent with the participants’ best interest, 
including the removal of the participant from the trial. 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
Not applicable for this trial. 
 
f. Definition of treatment failure or participant removal criteria. 
 


 
 
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Early stopping rules: If a participant experiences a significant health decline or a loss of seizure control 
(defined as a need to add a new seizure medication), ending assessments will be done, and the subject 
removed. If the subject experiences a temporary increase in seizures, Dr. Comi may take the temporary 
nature of the increase into account. If the subject has had other benefits to mood, behavior, or neurologic 
exam that outweigh the risk of an increase in seizures, then Dr. Comi may decide to decrease the dose of 
the study drug since it has been observed that some subjects do well at doses lower than 20 mg/kg/day. 
Other removal criteria include: death, lost to follow-up, withdrawal of consent for any further data 
submission, or any other reason the patient, parent, PI or caring physicians think that the subject should be 
removed. Early withdrawals within the first two months will be replaced.  
 
Study cessation rules. The study will be stopped if any of the following occur: (1) more than 4 subjects 
drop out because of adverse events probably or definitely due to study drug or (2) more than two subjects 
experience a SAE probably or definitely due to study drug. If any subject has a major unexpected negative 
event (serious injury or death) attributable to the drug, this information will be shared with the other 
subjects who will have the choice to come off the drug and further enrollment will cease while the event is 
being fully assessed. 
 
Treatment will continue until any of the following take place: 
 
1. Loss of seizure control defined as need to add another seizure medication or other seizure treatment (diet 
or surgery). 
 
2. Intolerable toxicity. 
 
3. Pregnancy. 
 
4. Withdrawal of consent. 
 
5. Six month treatment duration completed as per protocol.  
 
6. Laboratory results indicate that the subject’s liver function test (ALT or AST) has increased in any of the 
following ways: 
 >8xULN 
 >5xULN for more than 2 weeks 
 >3xULN and either (TBL >2xULN or INR >1.5) 
 >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%) 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
 
Extension Phase:  
Those who do not demonstrate a clear benefit after six months of treatment will be weaned off of the study 
drug over a month, and seen back for one final follow-up visit one month later. All subjects removed early 
from the study will be requested to complete the end of study assessments while still on study drug; but 
only if safely possible and with subject consent. 
 
At study’s end, any patient doing well on Epidiolex and demonstrating improvement on cognitive, 
neurologic, mood and/or behavioral assessments may continue on the drug (extension study). Every effort 
will be made to obtain insurance authorization based on the cognitive and medical improvements 


 
 
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demonstrated by the trial; if required the drug will be provided free of cost to the subject until the drug is 
approved for clinical use for the treatment of cognitive impairments (or other measured indications) in 
patients with Sturge-Weber syndrome. 
 
They will then be followed and seen about every 3 months, at which time interim history, including 
evaluation of side effects and patient reported outcomes, neuroscore, photographs of the port wine 
birthmark, and the Neuroquality of Life questionnaire will be collected. During the extension phase, the PI 
will have the ability to change dose (increase and decrease) dose of Epidiolex and other anti-seizure 
medications as clinically indicated. The maximum dose of Epidiolex will not exceed 20 mg/kg/day. The 
extension study will consist of at least 4 visits, with the option to remain on the extension study until 
insurance company approval is obtained for Epidiolex. Study drug will be provided by Greenwich 
Biosciences until insurance coverage is obtained.  The study coordinator will contact the family once per 
month to ensure the subject is taking the Epidiolex. The study coordinator will ask how much of the 
Epidiolex the subject has remaining and will ask to see the bottle(s) to confirm.  
 
Lab work (CBC, anticonvulsant levels, and chemistries about every 3 months) will be done as part of 
clinical care. At all extension study visits, there will be a urine pregnancy test. If the subject is under the 
age of 18, these results will be given to the parents.  
 
Every six months, an interim analysis will be done of adverse events and outcome measures.  Results will 
be discussed by the Research Investigators and a summary sent to Greenwich Biosciences. 
Study cessation rules. Consideration for stopping the study will occur if any of the following occur. (1) 
more than 4 subjects drop out of the extension study because of adverse events probably or definitely due 
to study drug, (2) more than two subjects experience a SAE probably or definitely due to study drug. All 
subjects will be informed of any SAE due to the study drug.  
For those discontinued specifically due to elevated liver function tests, they will continue to be followed 
until all abnormalities return to the baseline state as assessed by the investigator with AST or ALT 
<3xULN.  Any patient removed early from the study, and all participants at the end of the study wishing to 
remain Dr. Comi’s patient, will continue to be cared for by Dr. Comi and seen at the Hunter Nelson Sturge-
Weber Center. 
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion criteria: Participants with Sturge-Weber syndrome brain involvement as defined on 
neuroimaging (n=10 subjects enrolled and on study drug, male and female, ages 3 to 50 years of age) and 
the following: 
 
1. Cognitive impairment defined as a cognitive neuroscore of ≥2 at screening.  
 
2. Anti-epileptic, mood or behavioral drugs (if on) at stable doses for a minimum of 4 weeks prior to 
enrollment.  
 
3. If present, VNS must be on stable settings for a minimum of 3 months prior to enrollment. 
 
4. If on ketogenic or Atkins diet, must be on stable ratio for a minimum of 3 months prior to enrollment. 
 
5. Previous subjects who fail at any point to meet continuation criteria and withdraw early may be 
considered for re-enrollment under a 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. 


 
 
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6. Written informed consent obtained from the patient or the patient’s legal representative must be obtained 
prior to beginning treatment. 
 
Exclusion Criteria: 
 
1. Patients with any severe and/or uncontrolled medical conditions at randomization such as: 
 
a. Liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. 
quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA) 
 
b. Uncontrolled diabetes as defined by fasting serum glucose > 1.5 
 
c. Active (acute or chronic) or uncontrolled severe infections 
 
d. Active, bleeding diathesis 
 
2. Patients who have had 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. 
 
3. Patients who start or discontinue a seizure, mood or behavioral medication in the 4 weeks leading up to 
screening. 
 
4. Prior treatment with any investigational drug or use of any other cannabis product within the preceding 4 
weeks prior to study entry. 
 
5. 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 Principal Investigator, or complete all 
necessary studies to maintain safety. 
 
6. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory test. 
 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Epidiolex is a pharmaceutical grade purified version of cannabidiol which has been extensively studied in 
many in vivo and in vitro models. Dr. Comi has previously studied use of Epidiolex in Sturge-Weber 
patients with medically refractory seizures. 3 of the 5 patients in this cohort had sustained improvement in 
their seizures, with one patient achieving seizure freedom. Of interest, these patients and their families also 
noted cognitive, mood, and behavior improvements.[1] Other studies suggest anti-depressant like 
effects,[34] and reduced social anxiety symptoms[35] associated with Cannabidiol use. In addition, other 
studies suggest cannabidiol has neuroprotective benefit,[36] effects on abnormal angiogenesis,[37] and 
anti-inflammatory effects;[38] these effects would be expected to be beneficial in SWS.  
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 


 
 
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Epidiolex is currently FDA approved only for treatment of medically refractory seizures in Lennox-Gastaut 
syndrome, Dravet syndrome with a dose range of 5-20 mg/kg/day. It is no longer a scheduled drug.  
 
An earlier study of Epidiolex for medically refractory seizures in Sturge-Weber syndrome suggested 
improvement in cognition, social, and behavioral outcomes. The side effects experienced were mild and 
transient.  
 
The proposed trial will be assessing the impact of Epidiolex upon cognitive impairment in Sturge-Weber 
patients. 
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
 
Not applicable.  
  
7. 
Study Statistics 
a. Primary outcome variable. 
 
Change in cognitive impairment: Combined score of  two NIH Toolbox subtests. 
 
b. Secondary outcome variables. 
 
Change in the following: 
SWS neuroscore  
Port-wine score  
Adverse Events 
Seizure severity 
Social, behavioral, and mood function  
Migraine severity 
Motor function 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
Statistical Plan: Results of the above tests will be compared to age normed values.  In addition, the 
difference in results between final test results and initial test results will be obtained for the cognitive 
functioning score of each subject.  Mean and standard deviation of this difference for all 10 subjects on 
study drug will be calculated.  These results will be used to determine whether individuals and the group as 
a whole demonstrated age normed changes in their cognitive functioning over the course of the six month 
trial. There is no control group in this study of subjects who are not receiving study drug.  The published 
test-retest standard deviations will be used to determine whether changes in testing results exceed expected 
test-retest changes in results.  
 
Sample Size Calculation: Since these outcomes will be done for the first time with this drug in SWS, a 
sample size calculation was not done. Rather, we are estimating that 10 subjects enrolled and on study drug 
will be sufficient to do the proposed pilot trial and show improvements (or trends for improvement) 
sufficient to design a future larger clinical trial, or to guide clinical care.  This estimate is based on our 
experience with another trial using the same primary outcome measure. 
Interim data analysis: Every week Dr. Comi and the study coordinator study will review data for safety. 
Each month, a formal review of recruitment, safety, data completion and study progress will be made.  An 


 
 
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assessment of progress as it relates to study milestones (see Milestone Table below) will be made, and a 
summary report prepared for Greenwich Biosciences.  
 
One year into the study, an interim analysis will be done of adverse events and outcome measures.  Results 
will be discussed by the Research Investigators and a summary sent to Greenwich Biosciences. 
 
d. Early stopping rules. 
 
Study cessation rules. The study will be stopped, if any of the following occur: (1) more than 4 subjects 
drop out because of adverse events probably or definitely due to study drug, (2) more than two subjects 
experience a SAE probably or definitely due to study drug, or (3) if sufficient milestones are not being 
met.  If any subject has a major unexpected negative event (serious injury or death) attributable to the drug, 
this information will be shared with the other subjects who will have the choice to come off the drug and 
further enrollment will cease while a full analysis is completed and a decision is made whether to continue 
the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Milestone Table.  Including new timeline because of COVID shutdown.  
 
Milestones 
By 
June 
2019 
Aug 
2019 
Oct 
2019 
Dec 
2020 
Feb 
2020 
Oct  
2020 
Dec 
2020 
Feb 
2021 
Aug  
2021 
Sept. 
2021 
Oct 
2021 
Nov 
2021 
Contract signed 
  
X 
  
  
  
  
  
  
  
  
  
  
  
Protocol  
approved  
  
X 
  
  
  
  
  
  
  
  
  
  
  
Subject 1 
consented and on 
drug 
  
X 
  
  
  
  
  
  
  
  
  
  
Subjects 2&3 
consented and on 
drug 
  
  
X 
  
  
  
  
  
  
  
  
  
Subjects 
4&5consented 
and on drug 
  
  
  
X 
  
  
  
  
  
  
  
  
Interim Analysis 
Completed 
(Subjects 1-5) 
Go/No Go 
decision made 
  
  
  
  
X 
  
  
  
  
  
  
  
Subjects 6&7 
consented  
  
  
  
  
  
X 
  
  
  
  
  
  
Subjects 8&9 
consented  
  
  
  
  
  
  
X 
  
  
  
  
  
Subjects 10 &11 
consented 
 
 
 
 
 
 
 
X 
 
 
 
 
All subjects  
Completed 
(subjects 1-11) 
  
  
  
  
  
  
  
X 
  
Data Analysis 
Completed  
  
  
  
  
  
  
  
  
  
X 
  
  
Write NIH/DOD 
Grant 
applications  
  
  
  
  
  
  
  
  
  
  
X 
  
Submit Abstract 
and prepare 
Manuscript 
  
  
  
  
  
  
  
  
  
  
  
X 
 
 
 
 
8. 
Risks 


 
 
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a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
Epidiolex: As a part of Dr. Comi’s first Investigator Initiated trial of Epidiolex for treatment of medically 
refractory seizures in SWS, 5 patients with Sturge-Weber syndrome used Epidiolex to reduce the frequency 
and severity of seizures. All adverse events reported in this trial were transient, and resolved on their own 
or with adjustments to their anticonvulsant or CBD doses. The adverse events considered possibly related 
to CBD in this initial study were: a temporary increase in seizures (n= 1), transient behavioral issues (n=2), 
transient increased aspartate aminotransferase liver function test (n=1, indirectly related), tiredness (n=1) 
and transient exotropia/redness of the right eye (n=1).  
 
Other side effects, which have been previously reported in other populations using CBD, are also generally 
mild and tolerable. They include: diarrhea, fatigue, pneumonia, drowsiness, increased levels of aspartate 
aminotransferase, gamma glutamyl transferase, alanine aminotransferase, and transamines, abnormal liver 
function tests, weight loss and decrease in appetite, lethargy, drooling, irritability, aggression, trouble 
sleeping, hypersensitivity reactions sometimes requiring the use of corticosteroids, and rashes.  
 
Risks to Pregnancy: The effects of Cannabidiol on an embryo or fetus are not known. Subjects able to 
become pregnant or to father a child will be instructed to avoid pregnancy.  
 
Drug Interactions: Epidiolex can interact with other medications, particularly with valproate and with 
clobazam in our patients with SWS.  Being on these seizure medications can increase the risk of having 
adverse events such as increased liver function tests, and sedation.  Subjects who are also on these seizure 
medications will be monitored closely and may have the dose of their seizure medication or their Epidiolex 
decreased by Dr. Comi.  
 
Blood draws: Also included is the taking of peripheral blood samples, which is part of the routine care of 
these participants. Blood draws may result in discomfort, bruising, or transient pain at the site of needle 
entry into the vein. There is a remote risk of fainting. Infection could occur at the place where the needle 
goes into the arm.  
 
 
Incidental Findings: As a part of this research study, subjects will undergo laboratory testing. There is a 
possibility that while reviewing the labs results we may see and unexpected abnormality called and 
“incidental finding.” We will let subjects know if we see such an incidental finding, and will contact them 
by mail, email, or phone. In the case of a potential serious emergency, someone may go to their home.  An 
incidental finding may cause the subject to feel anxious.  A report of the incidental finding will be part of 
the subject’s medical record, it will be available to those accessing your medical record for their clinical 
care, and may affect their current or future life or health insurance coverage. The costs for any care that may 
come from the incidental finding, such as the need to see a doctor to diagnose or treat an incidental finding, will not 
be paid for by this research study. These costs would be responsibility of the subject or their insurance company. 
Other Assessments: Procedures involved in this study include cognitive testing, motor, mood, behavior, 
and social function evaluations, assessment of migraine severity. All of the above procedures may be 
considered boring or tiring to the participant, especially children. 
 
Time Commitment: There is a time commitment for participants attending the required appointments and 
maintaining seizure diary/records. The first two appointments will take about 3 hours, follow up visits 1-2 
hours and the final visit 3-4 hours. Participants will also be asked to maintain a seizure diary and study drug 
dosing record, requiring a time commitment of about 5-10 minutes per day.  
 


 
 
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Confidentiality: There is also the risk of loss of confidentiality in allowing us to see medical information 
and use it for research purposes. 
 
b. Steps taken to minimize the risks. 
 
PI Oversight: The Principal Investigator, Dr. Anne Comi, will review all data relating to safety and 
tolerability throughout the study. The study will benefit from her two decades of experience treating 
participants with Sturge-Weber syndrome as the director of the Hunter Nelson Sturge-Weber Center. The 
investigator will be available by telephone, text, or email throughout the entire study.  
 
Training: Training will be provided by Dr. Comi and the other clinician investigators to all nursing and 
research staff who will be involved in the drug trial.  This training will be documented and updated as 
needed.  
 
Managing Adverse Events: Dr. Comi will work closely with Greenwich Biosciences, and the participants, 
to both anticipate any possible side effects, and ensure that side effects are reported, evaluated, and do not 
inordinately compromise the health of the patient. The participants will be closely monitored for side 
effects during the titration and treatment period and the dose and/or frequency may be adjusted as 
appropriate. Any subject experiencing significant side effects or medical concerns during the course of 
study treatment will be responded to appropriately by Dr. Comi. Additional clinic visits with Dr. Comi 
required for medical reasons during the study will be provided at no cost to the subject.  Appropriate 
referrals for evaluations will be made as needed.  If the subject is not doing well and the patient, parent or 
Dr. Comi thinks that it is in the best interest of the subject to stop the study drug, they will be removed 
from the study. Subjects will have Dr. Comi’s cell phone number, email and office numbers and will be 
encouraged to contact her directly with any concerns.  
 
Study Oversight: Dr. Comi will meet with study staff weekly to review clinical trial subjects, issues and 
concerns.  Trial oversight will be provided by compliance and quality assurance monitors who perform 
periodic reviews of all study documents to ensure the study is being carried out as stated in the protocol. In 
addition, monthly review of the data with all trial Investigators will be made by meeting/conference call to 
review recruitment, subject issues and safety, and review data analysis and completion.  A summary of 
these meetings/calls and data will be provided to Greenwich Biosciences.   
 
Data Safety and Monitoring Plan: The Study Chair (Anne Comi, MD) has primary oversight 
responsibility of this clinical trial. Dr. Comi and the sub-investigators will comprise the Safety Monitoring 
Committee. The Safety Monitoring Committee will review accrual, patterns and frequencies of all adverse 
events, and protocol compliance every month. They will review data together every month for this small 
pilot trial by 1) Reviewing and analyzing the progress of the study; 2) Monitoring the safety of the study 
treatments and diagnostic procedures; 3) Ensuring data quality; 4) Recommending early stopping or 
continuation of the trial (if applicable); and 5) Reviewing recruitment and event rates. They will assess the 
proportion of enrolled versus projected enrollment and proportion of subjects who have completed the trial. 
The Study Chair will provide Safety Monitoring Committee reports and meeting summaries to Greenwich 
Biosciences regarding the continuation status of the protocol. 
 
The research coordinator at will make safety calls and/or email/text contact with each participant bimonthly 
to ensure follow-up and assessment of any adverse events.  Also, subjects will be asked to keep daily 
diaries of any side effects or concerns and asked to email or fax them in on a bimonthly basis.  If any 
adverse events have occurred, the PIs will be notified immediately and corrective actions will take place.  
While patients with Sturge-Weber syndrome can have serious medical issues, we do not expect any serious 
adverse events (SAEs) directly attributable to the study drug. Occurrence of an SAE directly attributable to 
the study drug will trigger a review to consider stopping the participant on the study within one month of 


 
 
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the event.  Based on a prior study, an adverse event rate of approximately 1 event /subject/month is 
expected.  An adverse event rate more than double this event rate will trigger an in-depth review to 
consider whether to consider continuing the participant on the study; an important consideration in this 
decision will be whether the adverse events are considered to be due to the study drug or not.  
 
The trial PIs and clinical coordinators will review the study progress regularly.  Adverse events will be 
reviewed to ensure the safety of the patients.  Internal reviews carried out quarterly by clinical trials 
specialists to ensure that all protocol specifications are being followed and issues addressed promptly.  
Quarterly reports will be generated by KKI to assess completeness of data.   
 
Data provided must be treated with the strictest confidence.  No information provided from individual 
patient’s records may be discussed with anyone other than those individuals mentioned in the collaborative 
research agreement.  Data may not be released in any form except as provided in the agreement. 
 
Each subject enrolled will, from that point forward, be identified by a unique identifier. All records 
generated will be stored in a locked office area, only accessible to study personnel.  Clinical information 
will be accessed, according to HIPAA requirements, by study personnel to complete study documents, as 
needed. 
 
Managing Pregnancy Risks: Subjects will be instructed that if they become pregnant, father a child, or 
breastfeed while on this research study there is the potential for very serious harmful effects to an embryo 
or fetus or infants. Female subjects will be told not become pregnant or breastfeed a baby while on this 
study or for 12 weeks after taking Epidiolex.  If they become pregnant during the study they will have to 
leave the study and we ask to will follow the progress of the pregnancy and its outcome. Subjects able to 
become pregnant or make someone become pregnant will be instructed to us effective birth control (for 
example, abstinence, birth control pills, contraceptive implants, condoms) in order to avoid pregnancy 
during the study and for at least 12 weeks after the last dose of Epidiolex. 
 
Professional Staff: All testing and medical procedures will be conducted by nurses and trained 
professional staff at Kennedy Krieger and Johns Hopkins or at outside lab  facilities (for blood draws). This 
will greatly reduce the chances of pain, infection, or bruising associated with the blood draw and any other 
assessments.  Efforts will be made to make potentially stressful tests, a comfortable experience for the 
subjects, including using of child life staff as applicable.  
 
 
Scheduling: We realize that participation in this study is a significant time commitment for subjects; 
therefore we will do our best to schedule at their convenience. For the convenience of families, paper 
evaluations for mood, behavior, and social function will be mailed to the families to complete, and then 
will be reviewed with them at the time of their visits. Breaks for food or relaxing will be taken into 
consideration during scheduling for the baseline and 6 month visits to reduce subject stress and fatigue. 
 
Protection of Confidentiality: All subject information will be de-identified prior to being shared with 
Greenwich Biosciences or collaborators, or organized into research databases for analysis and publication. 
Research data will be kept in locked cabinets or on a password protected computer in a locked office.  All 
members of the research team have been trained in confidentiality law and methods. If the subject asks to 
have their photographs destroyed at the end of the study, we will digitally delete all electronic files and 
shred all hard copies.  
 
Drug Interactions: CBD is an inhibitor of CYP 2C196, CYP 2C97, and other cytochrome P450s 
belonging to the 2C and 3A subfamilies. CBD/THC ratio in urine will be measured at study visits (see Visit 
Table). Concomitant anti-epileptic drug plasma levels will be measured at all visits. Anti-epileptic drug 


 
 
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doses will be adjusted as needed based on signs and symptoms of toxicity and / or changes in drug levels 
(routine care). Epidiolex can interact with other medications, particularly with valproate and with 
clobazam.  Being on these seizure medications can increase the risk of having adverse events such as 
increased liver function tests, and sedation.  Subjects who are also on these seizure medications will be 
monitored closely and may have the dose of their seizure medication or their Epidiolex decreased by Dr. 
Comi. 
 
The medical risks associated with joining the study are believed to be similar to continuing clinical care. 
All medications used to treat Sturge-Weber syndrome have associated risks and side effects. 
 
c. Plan for reporting unanticipated problems or study deviations. 
 
Adverse Events: All adverse events, unanticipated problems, protocol deviations or other concerns will be 
promptly reported to the principal who will have primary responsibility for notifying the IRB, the KKI 
Office of Research Compliance and the sponsors.  
 
Reporting Timeline: 
 
 Within 24 hours (of learning of the event), investigators must report any reportable Serious Adverse 
Event (SAE) that: 
1. Is considered life-threatening/disabling or results in death of subject 
-OR- 
2. Is Unexpected/Unanticipated  
 Investigators must report all other reportable SAEs within 5 working days (of learning of the event). 
 All other (suspected) reportable AEs must be reported within 14 working days of the notification of 
the event or of the site becoming aware of the event. 
 
Local institutional reporting requirements to IRBs, any GCRC oversight committee and the FDA, if 
appropriate, remain the responsibility of the treating physician and the Study Chair. 
 
Protocol deviations: that constitute unanticipated problems involving risks require prompt reporting to the 
JHM IRB.  Protocol deviations which impact data results or integrity will also be reported to Greenwich 
Biosciences.  
 
A protocol deviation that constitutes an “unanticipated problem involving risks to subjects or to others” for 
the definition of an unanticipated problem) must be reported promptly to the IRB, as follows: 
a. Emergency deviations:  When a deviation occurs in an emergency situation, such as when a 
departure from the protocol is required to protect the life or physical well-being of a 
participant.  The sponsor and the reviewing IRB must be notified as soon as possible, but not 
later than 5 days after the  emergency situation occurred. The PI must submit a report to the 
JHM IRB. 
 
b. Major, non-emergent deviations without prior approval:  A planned deviation that is non-
emergent and represents a major change in the protocol as approved by the IRB.  The IRB 
must approve the request before the proposed change is implemented.  The PI must submit 
non-emergent deviations to the IRB for review in eIRB under the Further Study Action 


 
 
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activity, and use the Change in Research activity; for paper studies, submit a Change in 
Research form.   
 
Protocol deviations that are only minor or administrative 
 
At JHM, minor or administrative protocol deviations are defined as those which do not “affect the scientific 
soundness of the research plan or the rights, safety, or welfare of human subjects.”  If a protocol deviation 
occurs which meets this definition, the deviation should be reported to the JHM IRB at the time the 
continuing review application is submitted.  In eIRB and for paper studies, we use the Protocol Deviation 
Summary Sheet (R.F. 4) to report these deviations.  Examples of minor or administrative deviations could 
include:  follow up visits that occurred outside the protocol required time frame because of the participant’s 
schedule, or blood samples obtained at times close to but not precisely at the time points specified in the 
protocol. 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
All proper steps will be taken to maintain subject confidentiality and to make the subject feel comfortable 
and aware of any risks. All subjects will be encouraged to ask her any questions they may have.  Data on 
mood and behavior will be gathered.  All research databases created with this data will not include subject 
name or other identifying information.  
 
Photographs will be stored in a digital, locked research database. Participants will have the option to select 
on the consent form between having these photographs destroyed at the end of the study, once all data has 
been analyzed and published, or allowing the photographs to be relocated to our general longitudinal SWS 
IRB-approved research database (NA_00043846), for use in future studies examining extent of the port-
wine birthmark and its correlation to other clinical outcomes. 
 
e. Financial risks to the participants. 
 
In the event that this study leads to complications requiring hospitalization or medical treatment outside of 
being seen by Dr. Comi, the participants, parents, or their insurance company will be responsible for any 
further treatment that may result from being involved in study. The subject/family is responsible for costs 
related to travel for visits. There are no other financial risks in this study.  
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
The enrolled subjects have cognitive impairments that affect their ability to independently receive 
education or to work.  Epidiolex may have positive effects on SWS cognitive problems, social 
impairments, mood, migraines, or motor function. If successful, this study would lay the foundation for a 
completely new treatment option for patients with SWS and cognitive impairment. It is likely that this 
study will result in new information regarding the usefulness of Epidiolex for Sturge-Weber syndrome 
cognitive impairments and other neurologic issues.  
 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
 


 
 
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There will not be any financial remuneration for subject participation in this phase II trial. There will also 
not be any penalty for not completing the study. Any decisions to not participate or to withdraw will not 
affect the patient’s care. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
 
The study drug and study funding will be provided by Greenwich Biosciences. The costs of the motor 
testing will be covered by funding provided by the Faneca 66 Foundation.. 
Limitations: The main limitations of this study are its size and lack of a placebo group.  However at this 
point, when the best outcome measures for assessing the improvements need to be ascertained, the 
proposed trial is most appropriate.  A larger, randomized, placebo-controlled trial can be done after this 
trial is completed.  All of the outcome measures proposed are familiar to the investigators; most of them 
have previously been utilized here in subjects with SWS.  Dr. Comi has previously successful drug trials in 
SWS and is expected to successfully complete the proposed drug trial.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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