An Open-Label Tolerability and Efficacy Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With 22q11.2 Deletion Syndrome
Phase: PHASE2
Conditions: 22Q11.2 Deletion Syndrome
Sponsor: Harmony Biosciences Management, Inc.

 
 
Confidential Information 
 
ZYN002 
An Open-Label, Tolerability and Efficacy Study of ZYN002 Administered as a 
Transdermal Gel to Children and Adolescents with 22q11.2 Deletion Syndrome 
(INSPIRE) 
Original Protocol Number: 
 
ZYN2-CL-031 
Protocol Amendment Number: 
.05 
Protocol Date: 
11 April 2019 
Protocol Amendment .01 Date: 
16 October 2019 
Protocol Amendment .02 Date: 
14 February 2020 
Protocol Amendment .03 Date: 
26 October 2020 
Protocol Amendment .04 Date 
17 December 2020 
Protocol Amendment .05 Date 
17 August 2021 
Phase: 
2 
IND Number: 
130876 
Sponsor: 
 
Zynerba Pharmaceuticals Pty., Ltd. 
2 Riverside Quay 
Southbank, VIC 3006 Australia 
 
Zynerba Pharmaceuticals, Inc. 
80 W. Lancaster Ave., Suite 300 
Devon, PA 19333 United States of America 
Medical Monitor: 
, MD  
  
 
CONFIDENTIAL INFORMATION 
The information contained in this document is the property of Zynerba Pharmaceuticals Pty., Ltd. 
(Zynerba) and is confidential.  It is intended solely for the use of Zynerba employees and contracting 
consultants and regulatory agencies.  Reproduction or disclosure of the information contained herein 
in whole or in part is forbidden to persons not involved in the clinical investigation of Zynerba, unless 
such persons are bound by a confidentiality agreement with Zynerba. 
PPD
PPD
PPD

Protocol ZYN2-CL-031.05 
17 August 2021 
 
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1. 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure Edition 8 dated 23 October 2020 and the 
Interim Supplement .01 to the IB dated 23 March 2021 for ZYN002.  I have read the 
ZYN2-CL-031.05 protocol dated 17 August 2021 and agree to conduct the study as outlined.  I 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
 

Protocol ZYN2-CL-031.05 
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Email Address and Telephone Number 
Responsible Physician 
, 
MD 
 
 
PPD
PPD

Protocol ZYN2-CL-031.05 
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2. 
SYNOPSIS 
Name of Sponsor/Company:  
Zynerba Pharmaceuticals Pty. Ltd./Zynerba Pharmaceuticals, Inc. 
Name of Investigational Product: ZYN002 
Name of Active Ingredient: Cannabidiol (CBD) 
Title of Study:  An Open-Label Tolerability and Efficacy Study of ZYN002 Administered as a 
Transdermal Gel to Children and Adolescents with 22q11.2 Deletion Syndrome 
Study Centers: Australia and the United States 
Children’s Health Queensland Hospital and Health Services 
Lady Cilento Children’s Hospital 
501 Stanley St. 
South Brisbane, QLD 4101 
Australia 
 
And 
Genetics Clinics Australia 
263 Glen Eira Rd, 
Nth Caulfield, VIC 3161  
 
And  
Greenwood Genetic Center – Greenville 
14 Edgewood, Drive 
Greenville, SC 29605 
Principal Investigator:   
, MBBS, FRACP, MRCPCH, PGCAP, DM 
Children’s Health Queensland Hospital and Health Services 
Lady Cilento Children’s Hospital 
501 Stanley St. 
South Brisbane, QLD 4101 
Australia 
 
Study Period:  
Estimated date first patient enrolled:  February 2020  
Estimated date last patient enrolled:  October 2021  
Estimated date last patient completed:  May 2022 
Phase of Development: 2 
 
Objectives:  
Primary: 
To evaluate the safety and tolerability of ZYN002 administered as a transdermal gel formulation, for 
up to 38 weeks, in patients ages 4 to < 18 years, in the treatment of 22q.11.2 Deletion Syndrome 
(22qDS). 
 
PPD

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Secondary: 
• 
To evaluate the efficacy of ZYN002 in the treatment of symptoms of 22qDS 
• 
To evaluate cannabidiol (CBD) and tetrahydrocannabinol (THC) plasma level exposure 
Exploratory: 
The identification of plasma levels of CBD metabolite(s) may be conducted. 
Methodology:  
This is an open-label study to assess the safety, tolerability and efficacy of CBD administered as 
ZYN002, a transdermal gel, for the treatment of child and adolescent patients with 22qDS.  Male and 
female patients with 22qDS will be treated in Period 1 for 14 weeks.  Patients with less than a 25% 
improvement from baseline in the ABC-C irritability subscale, the investigator may increase the total 
daily dose at Week 6.  Patients that have made a ≥35% improvement on the ABC-C irritability sub-
scale will be allowed to continue to Period 2 for an additional 24 weeks of treatment.  At the end of 
study, patients taking anti-epileptic drug (AED) medication(s) will have an additional one or two 
week Taper Period, unless they are transitioning to receive drug through Special Access, if available.  
Approximately 20 male and female patients, ages 4 to < 18 years, will receive ZYN002. 
 
Study Screening: 
Prior to any Screening procedures being performed, the parent/caregiver will provide written 
informed consent and, if applicable, the patient will provide assent.  During the Screening Period, the 
site staff will review the eligibility criteria, review any medications including over-the-counter (OTC) 
medications the patient is taking, obtain the patient’s medical history including their 22qDS diagnosis, 
confirm epilepsy diagnosis (if applicable), collect demographic detail, obtain vital signs, perform an 
electrocardiogram (ECG), perform a physical and neurological exam, skin assessment, obtain blood 
for safety laboratory tests and presence of ethanol, collect urine for urinalysis and a drug screen, and 
administer assigned scales.  Blood samples will be taken for hematology, serology and chemistry 
testing, and pregnancy testing (females only, if applicable).  At Screening, patients will also have a 
blood sample drawn for CBD/THC PK exposure and valproic acid levels (for patients receiving 
valproate or valproic acid).   
Note:  only one ECG to be collected prior to starting treatment (Screening or Visit 2), provided that 
ECG is normal or has a finding that is not clinically significant. 
The scales administered at Screening include: 
• 
Aberrant Behavior Checklist (ABC-C) 
• 
Autism Diagnostic Observation Schedule®-2 (ADOS®-2) (Note: is not administered at 
Screening if it has been administered in the prior 6 months and the results are available)  
• 
Clinical Global Impression-Severity (CGI-S) 
• 
Columbia-Suicide Severity Rating Scale – Children’s version (C-SSRS) 
• 
Anxiety, Depression and Mood Scale (ADAMS) 
• 
Qualitative Caregiver Reported Behavioral Problems Survey 
• 
Children’s Sleep Habits Questionnaire (CSHQ) 
• 
Pediatric Anxiety Rating Scale-Revised (PARS-R) 
14-Week and 24-Week Extension Open Label Treatment Period:  
Following the Screening Period, eligible patients will receive ZYN002 on Study Day 1 (Visit 2).  
There must be at least 7 days between Visit 1 (Screening) and Visit 2 (Day 1).   
Patients and parents/caregivers will be required to visit the clinic at Day 1/Visit 2, Week 6/Visit 3, and 
Week 14/Visit 4, for the collection of: vital signs, ECG, concomitant medication review, physical and 

Protocol ZYN2-CL-031.05 
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neurological exam, pregnancy tests, skin assessment exam (Day 1) and skin irritation examination 
(Visits 3 and 4), adverse event (AE) review, and questionnaire and scale completion.   
Blood samples for laboratory tests, CBD/THC PK exposure, and valproic acid (for patients taking 
valproate or valproic acid) will be collected at Week 6/Visit 3, Week 14/Visit 4 and Week 38/Visit 7 
EOS/ET.  
In addition, there will be a follow-up telephone visit at Week 10 for patients who had their dose 
adjusted at Week 6.   
Patients that complete Visit 4 and have made a ≥35% improvement on the ABC C irritability subscale 
will be allowed to continue to Period 2 for an addition 24 weeks of treatment.  Period 2 will have 
additional Visits at Week 22/Visit 5, Week 30/Visit 6, and Week 38/Visit 7 EOS/ET.  Refer to the 
Schedule of Assessments (Table 5 and Table 6) for all activities to be completed at each study Visit.   
Note:  only one ECG to be collected prior to starting treatment (Screening or Visit 2), provided that 
ECG is normal or has a finding that is not clinically significant. 
At Visit 2, parents/caregivers will be instructed on proper application of the study drug.  Patients will 
be permitted to shower or clean the arm area up to 30 minutes prior to the study dose.   
Parents/caregivers will use gloves supplied by the Sponsor to apply the study drug.  Parents/caregivers 
will apply all study drug to clean, dry, intact skin, thoroughly massaging it into the right and/or left 
upper arms and shoulders until the area is dry.  The study drug will be rubbed in completely and must 
be dry prior to dressing.   
Patients should keep the application site dry for six hours but may apply an approved moisturizing 
lotion (Cetaphil), provided by the Sponsor, two hours after dosing.  The application site should be 
covered to minimize sun exposure when going outside during the day.  Sunscreen at the application 
site may be used two hours after dosing.  If excessive skin irritation occurs at the application site, the 
parent (after consultation with the Investigator) may switch the application site temporarily to the 
upper thighs.   
Patients who weigh ≤ 35 kg will receive 125 mg CBD Q12H (every 12 hours) (± 2 hours); for a total 
daily dose of 250 mg CBD.  Patients who weigh > 35 kg will receive 250 mg CBD Q12H (±2 hours); 
for a total daily dose of 500 mg CBD.  All patients will remain on their assigned dose through Week 
6.  At Week 6, if the patient has less than a 25% improvement from baseline in the ABC-C irritability 
subscale, the investigator may increase the dose, as follows: 
- 
Patients who weigh ≤ 35 kg receiving a total daily dose of 250 mg CBD may increase to a 
daily dose of 500 mg.   
Patients who weigh > 35 kg receiving a daily dose of 500 mg CBD may increase the dose to 
750 mg/day. 
The following questionnaires and scales will be administered at Visit 2, Visit 3, Visit 4, Visit 5, Visit 
6, and Visit 7 EOS/ET, unless an exception is noted:  
• 
ABC-C 
• 
CGI-S 
• 
Clinical Global Impression-Improvement (CGI-I) (not completed on Visit 2, Day 1) 
• 
ADAMS 
• 
C-SSRS 
• 
Qualitative Caregiver Reported Behavioral Problems Survey (not completed at Visit 2) 
• 
Children’s Sleep Habit Questionnaire (Visit 4 and Visit 7 EOS/ET only) 
• 
PARS-R 
 
 
 

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End of Study (EOS) / Early Termination Visit (ET): 
Patients not on AEDs who are prematurely discontinued or do not qualify for Period 2, will complete 
the early termination procedures at Visit 4 EOS/ET.  
Patients taking valproate or valproic acid for the treatment of seizures or epilepsy, including patients 
who prematurely discontinue, will taper their current study dose in the following manner beginning at 
Visit 7 EOS/ET.  Should patients taking AEDs at the EOS continue to receive drug through Special 
Access (if available) they will not taper their dose. 
• 
Participants who weigh 35 kg or less and were receiving 250 mg daily dose of ZYN002, will 
be reduced to 125 mg daily dose over one week.  Only one sachet will be applied each day 
around the same time in the evening.  After the taper, the participants will discontinue from 
the study at Week 40.   
o If the participant’s dose was increased at Week 6 to 500 mg daily dose of ZYN002, 
the dose will be reduced to 250 mg daily dose over one week with 2 sachets applied 
each day around the same time in the evening.  After the taper, the participants will 
discontinue from the study at Week 40.   
• 
Participants who weigh 35 kg or more and were receiving 500 mg daily dose of ZYN002, will 
be reduced over two weeks.  During the first week the dose will be reduced to 125 mg two 
times a day (applied 12 hours apart) which will make the total daily dose 250 mg. This is one 
sachet in the morning and one sachet in the evening.  During the second week, the dose will 
decrease to 125 mg daily dose, which means one sachet each day for a week applied each day 
around the same time in the evening.  After the taper, the participants will discontinue from 
the study at Week 41.   
If the participant’s dose was increased at Week 6 to 750 mg daily dose of ZYN002, the dose 
will be reduced to 375 mg daily dose during the first week with one sachet applied in the 
morning and 2 sachets applied every evening.  During the second week, the dose will 
decrease to 250 mg daily dose, which means 2 sachets each day for a week applied each day 
around the same time in the evening.  After the taper, the participants will discontinue from 
the study at Week 41.  
 
• 
Patients tapering their dose will have all Visit 4 EOS/ET assessments completed. 
• 
At Week 38, patients will have their original dose in the morning and will have their evening 
dose as their new tapered dose. 
• 
Patients will return on Week 40 or 41 and have the following assessments completed: 
o Concomitant medication review 
o Vital signs 
o Targeted physical exam if investigator deems clinically relevant 
o Pregnancy test (females only) 
o C-SSRS administered 
o Collection and review of Skin Irritation Diary 
o Skin irritation examination 
o Adverse event review 
Patients having a skin irritation score > ‘0’ at Visit 7, or Weeks 40 or 41 (for patients taking AEDs ) 
will continue to be followed through Unscheduled Visits until the skin irritation score is recorded as 
‘0’ (no erythema). 
 
 
 
 

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Safety Monitoring: 
Patient safety will be monitored at each study visit using standard measures, including physical and 
neurological exams, examination of skin at application sites for irritation, vital signs (including oral, 
infrared forehead or tympanic temperature), 12- lead ECGs, the C-SSRS, safety laboratory tests 
(Screening, Week 6, Week 14, and Week 38), urinalysis (Screening, Week 6, Week 14, and Week 
38), and AE monitoring.   
In addition, there will be a follow-up telephone visit at Week 10 for patients who had their dose 
adjusted at Week 6.   
At Screening, patients will have an epilepsy diagnosis confirmed by the Investigator, if applicable.  
The parents/caregivers of patients with a current epilepsy and/or seizure diagnosis will be asked at 
each study visit if there has been any increase in frequency or severity of the patient’s seizures.  If an 
increase in frequency or severity is noted, this will be recorded as an adverse event (AE) in the case 
report form (CRF). 
Parents/caregivers will be provided a diary to complete a daily skin irritation examination.  Every 
evening from Day 1 through discharge from the study, parent/caregivers will record the skin irritation 
score in the daily skin irritation diary.  When skin redness is noted, parents/caregivers should apply 
the gel to a non-red area of the upper arms and shoulders.  If the skin irritation score is higher than ‘2’ 
(moderate erythema) at any time, the parent/caregiver will contact the study site to determine if an 
Unscheduled Visit is required. 
The Investigator will use discretion in suspending dosing for patients with a skin irritation score of ‘4’ 
but will, in all cases, immediately (within 24 hours) complete an adverse event report and contact 
their study Clinical Research Associate (CRA) and the Zynerba Medical Monitor.  A de-identified 
photograph of the skin irritation (or area) of interest may be taken after consultation with and approval 
of the Sponsor.  Digital photographs will be retained for information purposes only.  In place of 
suspending the dosing due to skin irritation, the Investigator may instruct the parent/caregiver to 
temporarily change the application site to the upper thigh. 
 
Plasma Samples for CBD, THC and Valproic Acid: 
Blood samples for plasma levels of CBD and THC will be collected at Screening (Visit 1 baseline), 
Week 6/Visit 3, Week 14/Visit 4, and Week 38/Visit 7 EOS/ET.   
In addition, blood samples for valproic acid levels (for patients taking valproate or valproic acid) for 
treatment of seizures or epilepsy, will be collected at Screening, Week 6/Visit 3, Week 14/Visit 4, and 
Week 38/Visit 7 EOS/ET.  The time of blood sample collection, as well as the time of last 
valproate/valproic acid dose, if applicable, and study drug dose will be recorded.   
Plasma samples will be analyzed by a validated high-performance liquid chromatography (HPLC), 
with tandem mass spectrometry (MS/MS) detection for the determination of CBD and THC.  Plasma 
samples for valproic acid will be analyzed through a local laboratory.  
 
Number of Patients (Planned): 
Approximately 20 male and female patients will be enrolled.  Patients who prematurely discontinue 
after Visit 2 will not be replaced. 
 
 
 
 
 

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Diagnosis and Main Criteria for Inclusion:   
Patients must qualify based on meeting all of the inclusion and none of the exclusion criteria to be 
eligible to enroll. 
Inclusion Criteria: 
1. Male or female children and adolescents aged 4 to <18 years, at the time of Screening. 
2. Judged by the Investigator to be in generally good health at Screening based upon the results 
of a medical history, physical examination, and clinical laboratory test results.  Laboratory 
results outside of the reference range must be documented as not clinically significant by the 
Investigator.   
3. Patients must have a diagnosis of 22qDS confirmed by genetic testing, with or without 
autistic features. 
4. Patients have a CGI-S score of 4 or higher at Screening and Visit 2. 
5. Patients must have a severity score on the PARS-R of 10 or higher at Screening and Visit 2. 
6. Patients with a history of seizure disorders must currently be receiving treatment with a stable 
regimen of one or two AEDs, or must be seizure-free for one year if not currently receiving 
AEDs. 
7. If patients are receiving non-pharmacological behavioral and/or dietary interventions, they 
must be stable for three months prior to Screening. 
8. Patient has demonstrated stable calcium levels for one year prior to Screening. 
9. Patients have a body mass index between 12–35 kg / m2 (inclusive). 
10. Females of childbearing potential must have a negative pregnancy test at the Screening Visit 
and a negative pregnancy test at all designated study visits. 
11. Patients and parents/caregivers agree to abide by all study restrictions and comply with all 
study procedures. 
12. Patients and parents/caregivers must be adequately informed of the nature and risks of the 
study and give written informed consent (and assent if applicable) prior to Screening. 
13. Parents/caregiver(s) must provide written consent to assist in study drug administration. 
14. In the Investigator’s opinion, patients and parents/caregivers are reliable and willing and able 
to comply with all protocol requirements and procedures. 

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Exclusion Criteria: 
Any of the following is considered criterion for exclusion: 
1. Females who are pregnant, nursing, or planning a pregnancy; females of childbearing 
potential and male patients with a partner of childbearing potential who are unwilling or 
unable to use an acceptable method of contraception as outlined below for the duration of 
therapy and for three months after the last dose of study medication. 
a. Standard acceptable methods of contraception include abstinence or the use of a 
highly effective method of contraception, including hormonal contraception, 
diaphragm, cervical cap, vaginal sponge, condom, vasectomy, or intrauterine device. 
2. History of significant allergic condition, significant drug-related hypersensitivity, or allergic 
reaction to any compound or chemical class related to ZYN002 or its excipients. 
3. Exposure to any investigational drug or device ≤ 30 days prior to Screening or at any time 
during the study. 
4. Patient has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin levels ≥ 2 times the upper limit of normal (ULN) or has alkaline phosphatase levels 
≥ 3 times the ULN as determined from Screening safety laboratories. 
5. Use of cannabis or any THC or CBD-containing product within three months of Screening 
Visit or during the study. 
6. Patient has a positive drug screen for sympathomimetic amines (amphetamines (unless 
prescribed); benzodiazepines; buprenorphine; cannabinoids; methadone; cocaine 
(metabolites); and opiates; (excludes barbiturates used as AED medication), including 
ethanol. 
7. Patient is using the following AEDs: clobazam, phenobarbital, ethosuximide, felbamate, 
carbamazepine, phenytoin or vigabatrin. 
8. Patient is using any strong inhibitor/inducer of CYP3A4 or sensitive substrate for CYP3A4 
including but not limited to the following medications: midazolam, oral ketoconazole, 
fluconazole, nefazadone, rifampin, alfentanil, alfuzosin, amiodarone, cyclosporine, dasatinib, 
docetaxol, eplerenone, ergotamine, everolimus, fentanyl, halofantrine, irinotecan, lapatinib, 
levomethadyl, lumefantrine, nilotinib, pimozide, quinidine, ranolazine, sirolimus, tacrolimus, 
temsirolimus, toremifene, tretinioin, vincristine, vinorelbine, St. John’s Wort, and grapefruit 
juice/products. 
9. Patient with diagnosis of known genetic disorder, other than 22qDS (i.e. Prader-Willi 
Syndrome, Angelman Syndrome, Fragile X Syndrome, Rett Syndrome etc.). 
10. Patient has diagnosis of DiGeorge or Velocardiofacial syndrome without the presence of 
22qDS. 
11. Patient has a primary psychiatric diagnosis other than 22qDS or anxiety, including bipolar 
disorder, psychosis, schizophrenia, post-traumatic stress disorder (PTSD) or major depressive 
disorder.  
12. Patients is on stable treatment of >6 months of not more than two psychoactive medications at 
screening or throughout the study (with the exception of one psychoactive medication 
prescribed for sleep).  
13. Patient has an advanced, severe, or unstable disease that may interfere with the study outcome 
evaluations. 
14. Patient is expected to initiate or change pharmacologic or non-pharmacologic interventions 
during the course of the study. 
15. Patient has an acute or progressive neurological disease, or any psychiatric disorder or severe 
mental abnormalities that are likely to require changes in drug therapy or interfere with the 
objectives of the study or ability to adhere to protocol requirements. 
16. Patient has a positive result for the presence of HBsAg, HCV, or HIV antibodies. 
17. Patients at risk of needing cardiovascular surgical repair within the upcoming 12 months. 

Protocol ZYN2-CL-031.05 
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18. Patient has unstable cardiovascular disease, such as advanced arteriosclerosis, 
cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, cardiac 
conduction problems, exercise-related cardiac events including syncope and pre-syncope, risk 
factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long 
QT Syndrome), other serious or other clinically unstable cardiac problems as indicated by 
history, physical examination, or ECG. 
19. Any clinically significant condition or abnormal findings at the Screening Visit that would, in 
the opinion of the Investigator, preclude study participation or interfere with the evaluation of 
the study medication. 
20. Any skin disease or condition, including eczema, psoriasis, melanoma, acne, contact 
dermatitis, scarring, imperfections, lesions, tattoos, or discoloration, that may affect treatment 
application, application site assessments, or absorption of the study drug. 
21. History of treatment for, or evidence of, drug abuse within the past year. 
22. Patient responds “yes” to Question ‘4’ or ‘5’ on the C-SSRS (Children) during Screening or at 
any time on study. 
Investigational Product, Dosage, and Mode of Administration:  
Treatment Period: 
This study has a 14-Week Treatment Period and a 24-Week Extension Period, dosing is as follows: 
• 
Patients weighing ≤ 35 kg will receive 125 mg CBD applied Q12H (± 2 hours); total daily 
dose of 250 mg CBD. Each application will consist of one sachet of ZYN002 CBD 4.2% 
concentration, containing 2.98 g of gel.  At Week 6, if the patient has less than a 25% 
improvement from baseline in the ABC-C irritability subscale, the investigator may increase 
the dose as follows: 
o Patients weighing ≤ 35 kg receiving a total daily dose of 250 mg CBD may increase 
to a daily dose of 500 mg.  Each application will consist of two sachets of ZYN002 
CBD 4.2% concentration, containing 2.98 g of gel 
 
Patients weighing > 35 kg will receive 250 mg CBD applied Q12H (±2 hours); total daily 
dose of 500 mg CBD.  Each application will consist of two sachets of ZYN002 CBD 4.2% 
concentration, each sachet containing 2.98 g of gel.  At Week 6, if the patient has less than a 
25% improvement from baseline in the ABC-C irritability subscale, the investigator may 
increase the dose as follows: 
o Patients who weigh > 35 kg receiving a daily dose of 500 mg CBD may increase the 
daily dose to 750 mg.  Each application will consist of three sachets of ZYN002 CBD 
4.2% concentration, containing 2.98 g of gel. 
Should the weight of the patient change from visit to visit the dose may be adjusted, at the discretion 
of the investigator. 
Duration of Treatment:  
Parents/caregivers will apply study drug twice daily for 14 weeks in Period 1 and up to 24 weeks in 
the extension Period 2.  Patients on AEDs will have an additional one or two weeks of treatment to 
taper off study drug, unless they transition to receive drug through Special Access at the EOS. 
 
Reference Therapy, Dosage and Mode of Administration:  
N/A Open-Label Study 
 
 
 

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Safety and Pharmacokinetic Analyses:  
Safety Analyses:  
Safety assessments will include collection of AEs including seizure assessment if applicable, physical 
and neurological examination, 12-lead ECG, clinical laboratory assessments (hematology, chemistry, 
and urinalysis), vital signs, C-SSRS, and findings from the skin irritation examinations following 
treatment.  All patients who receive at least one dose of study drug will be included in the safety 
analysis. 
 
Plasma Concentrations of CBD/THC: 
Plasma concentrations for CBD and THC will be summarized by treatment group and by Screening 
and treatment time points.  As only sparse samples will be collected, pharmacokinetic (PK) 
parameters for CBD will not be calculated; however, observed plasma concentrations will be 
compared to simulated exposures based on population PK modeling. 
 
Plasma Concentrations - Valproic Acid: 
The following data will be summarized separately for each AED medication: 
• 
Plasma concentration at Screening, pre-dose Week 6, Week 14 and Week 38 EOS/ET.  
• 
Elapsed time between last valproate/valproic acid dose and the time of plasma sample 
collection. 
Descriptive statistics (arithmetic mean, median, SD, minimum, maximum, coefficient of variation, 
geometric mean [plasma concentration]) for the valproic acid plasma trough concentrations and elapse 
time will be presented at each nominal PK sampling time. 
 
Statistical Methods: 
Descriptive statistics (mean, median, standard deviation, minimum, and maximum) for 
continuous data and number (n) and percentage (%) for categorical data will be presented for all 
efficacy and safety parameters. 
All efficacy assessments will be summarized at Weeks 6, 14, 22, 30, and 38 EOS/ET.  
Vital sign assessments (actual and change from screening) taken at study Day 1, Weeks 6, 14, 22, 30 
and 38 and will be summarized using descriptive statistics and presented by maintenance dose.   
ECGs (actual and change from Screening) will be summarized by actual treatment group. ECG results 
including any clinically significant findings will be summarized at each study visit. 
Safety laboratory and urinalysis assessments taken at Week 6, Week 14, and Week 38 EOS/ET (actual 
and change from Screening) will be summarized by treatment at the time of the assessment. 
Application site irritation will be summarized using counts and percentages at each respective   site 
irritation score (0, 1, 2, 3, or 4) by dose at the time of assessment. 
AEs will be tabulated by the actual treatment dose of study drug received at the time of initiation of 
the adverse event and classified by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA).  Additionally, AEs will be tabulated overall (total 
number of AEs and total number of patients with AEs). 
 

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3. 
TABLE OF CONTENTS AND LIST OF TABLES 
TABLE OF CONTENTS 
1. 
INVESTIGATOR’S AGREEMENT ............................................................................2 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Background Information .............................................................................................20 
5.2. 
Nonclinical Summary .................................................................................................23 
5.3. 
Clinical Summary .......................................................................................................27 
5.3.1. 
ZYN002 Phase 1 Studies ............................................................................................27 
5.3.2. 
ZYN002 Phase 2 Studies ............................................................................................29 
5.3.3. 
Ongoing ZYN002 Clinical Studies .............................................................................32 
5.3.4. 
Completed Clinical Studies in Literature ...................................................................33 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................35 
6.1. 
Primary Objective .......................................................................................................35 
7. 
INVESTIGATIONAL PLAN .....................................................................................36 
7.1. 
Overall Study Design ..................................................................................................36 
7.2. 
Number of Patients .....................................................................................................36 
7.3. 
Dose Rationale ............................................................................................................36 
7.4. 
Treatment Assignment ................................................................................................37 
7.5. 
Dose Adjustment Criteria ...........................................................................................37 
7.6. 
Study Assessments......................................................................................................37 
7.6.1. 
Screening Period .........................................................................................................37 
7.6.1.1. 
14-Week and 24-Week Extension Open Label Treatment Period ..............................38 
7.6.2. 
Informed Consent .......................................................................................................47 
7.6.3. 
22q.11.2 Deletion Syndrome Diagnosis .....................................................................47 
7.6.4. 
Demographics .............................................................................................................47 
7.6.5. 
Vital Signs ..................................................................................................................47 
7.6.6. 
Medical History ..........................................................................................................47 
7.6.7. 
Concomitant Medication Review ...............................................................................47 
7.6.8. 
Review Adverse Events ..............................................................................................47 

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7.6.9. 
Complete Physical/Neurological Examinations .........................................................47 
7.6.10. 
Targeted Physical Examination ..................................................................................48 
7.6.11. 
Electrocardiogram .......................................................................................................48 
7.6.12. 
Investigator Skin Assessment Examination ................................................................48 
7.6.13. 
Investigator Skin Irritation Examination ....................................................................48 
7.6.14. 
Patient Skin Irritation Diary........................................................................................49 
7.6.15. 
Clinical Laboratory Testing ........................................................................................49 
7.6.15.1. 
Screening (Days -28 to -8) Laboratory Tests .............................................................50 
7.6.15.2. 
Week 6, Week 14, and Week 38 (±3 days) Laboratory Tests ....................................50 
7.6.15.3. 
End of Study Visit or Early Termination ....................................................................50 
7.6.16. 
Unscheduled Visits .....................................................................................................51 
7.6.17. 
Hepatitis/HIV Screen ..................................................................................................51 
7.6.18. 
Pregnancy Test ............................................................................................................51 
7.6.19. 
Toxicology Screen ......................................................................................................51 
7.6.20. 
Blood Samples for Valproic Acid...............................................................................51 
7.6.21. 
Blood Sample for CBD/THC PK ...............................................................................52 
7.6.22. 
Telephone Follow-up at Week 10 ...............................................................................52 
7.7. 
Study Questionnaires and Scales ................................................................................52 
7.7.1. 
Assessments of 22qDS Symptomatology ...................................................................52 
7.7.2. 
Aberrant Behavior Checklist-Community (ABC-C) ..................................................52 
7.7.3. 
Autism Diagnostic Observation Schedule® (ADOS®-2) ............................................52 
7.7.4. 
Clinical Global Impressions Scale-Severity and Improvement ..................................53 
7.7.5. 
Columbia Suicide Severity Rating Scale (Children’s Version) ..................................53 
7.7.6. 
Anxiety, Depression, and Mood Scale (ADAMS) .....................................................53 
7.7.7. 
Qualitative Caregiver Behavioral Problems Survey ...................................................54 
7.7.8. 
Children’s Sleep Habit Questionnaire (CSHQ) ..........................................................54 
7.7.9. 
Pediatric Anxiety Rating Scale – Revised (PARS-R) ................................................54 
7.8. 
End of Study / Early Termination Visit ......................................................................55 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................57 
8.1. 
Patient Inclusion Criteria ............................................................................................57 
8.2. 
Patient Exclusion Criteria ...........................................................................................58 
8.3. 
Randomization Criteria ...............................................................................................59 
8.4. 
Patient Withdrawal Criteria ........................................................................................59 

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9. 
TREATMENT OF PATIENTS ..................................................................................60 
9.1. 
Description of Study Drug ..........................................................................................60 
9.2. 
Concomitant Medications ...........................................................................................60 
9.2.1. 
Concomitant Medications Allowed ............................................................................60 
9.2.2. 
Concomitant Medications Not Allowed .....................................................................61 
9.3. 
Duration of Treatment ................................................................................................61 
9.4. 
Treatment Compliance ................................................................................................61 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................63 
10.1. 
Study Drug ..................................................................................................................63 
10.2. 
Study Drug Packaging and Labeling ..........................................................................63 
10.3. 
Study Drug Storage .....................................................................................................63 
10.4. 
Study Drug Preparation ..............................................................................................63 
10.5. 
Administration ............................................................................................................63 
10.6. 
Study Drug Accountability .........................................................................................64 
10.7. 
Study Drug Handling and Disposal ............................................................................64 
11. 
ASSESSMENT OF SAFETY .....................................................................................65 
11.1. 
Safety Parameters .......................................................................................................65 
11.2. 
Adverse and Serious Adverse Events .........................................................................65 
11.2.1. 
Definition of Adverse Events .....................................................................................65 
11.2.1.1. 
Adverse Event .............................................................................................................65 
11.2.1.2. 
Serious Adverse Event ................................................................................................66 
11.3. 
Relationship to Study Drug ........................................................................................67 
11.4. 
Adverse Event Severity ..............................................................................................67 
11.5. 
Reporting Adverse Events ..........................................................................................67 
12. 
PHARMACOKINETIC ASSESSMENTS .................................................................69 
12.1. 
Blood Sample Collection ............................................................................................69 
12.2. 
Sample Analysis .........................................................................................................69 
13. 
STATISTICS ..............................................................................................................70 
13.1. 
Determination of Sample Size ....................................................................................70 
13.2. 
Analysis Populations ..................................................................................................70 
13.2.1. 
Intent-to-Treat Population ..........................................................................................70 
13.2.2. 
Safety Population ........................................................................................................70 
13.2.3. 
Pharmacokinetic Population .......................................................................................70 

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13.3. 
Efficacy Analysis ........................................................................................................70 
13.4. 
Pharmacokinetic Analyses ..........................................................................................70 
13.4.1. 
PK Sample for Determination of CBD/THC ..............................................................70 
13.4.2. 
PK Sample Determination of  Valproic Acid .............................................................71 
13.5. 
Statistical Methods ......................................................................................................71 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................72 
14.1. 
Study Monitoring ........................................................................................................72 
14.2. 
Audits and Inspections ................................................................................................72 
15. 
DATA QUALITY ASSURANCE ..............................................................................73 
16. 
ETHICS ......................................................................................................................74 
16.1. 
Human Research Ethics Committee (HREC) .............................................................74 
16.2. 
Ethical Conduct of the Study ......................................................................................74 
16.3. 
Patient Information and Informed Consent ................................................................74 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................75 
17.1. 
Inspection of Records .................................................................................................75 
17.2. 
Retention of Records ..................................................................................................75 
18. 
PUBLICATION POLICY ..........................................................................................76 
19. 
LIST OF REFERENCES ............................................................................................77 
20. 
APPENDICES ............................................................................................................83 
20.1. 
Application of ZYN02 Gel Instructions .....................................................................84 
20.2. 
Skin Irritation Diary ....................................................................................................85 
 
 
 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
Summary of 22qDS Patient Phenotypic Features .......................................................22 
Table 4: 
Schedule of Assessments – Screening (Visit 1) .........................................................40 
Table 5: 
Period 1 Schedule of Assessments – 14-Week Treatment Period ..............................41 
Table 6: 
Period 2 Schedule of Assessments – 24-Week Extension Treatment ........................44 
Table 7: 
Skin Irritation Scale ....................................................................................................49 
 
LIST OF FIGURES 
Figure 1: 
Phenotypic Manifestations of 22qDS by Age Range .................................................21 
 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation 
Definition 
2-AG 
Arachidonoylclycerol 
22q11.1 or 22qDS 
22q11.2 Deletion Syndrome 
5-HT 
Serotonin 
ADAMS 
Anxiety, Depression and Mood Scale 
ADOS®-2 
Autism Diagnostic Observation Schedule®-2 
AE 
Adverse event 
AEA 
Anandamide  
AED 
Anti-epileptic drug 
AIM 
Autism Impact Measure 
ALT 
Alanine transaminase  
API 
Active Pharmaceutical Ingredient 
ASD 
Autism Spectrum Disorder 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BID 
Twice daily 
CB1 
Cannabinoid receptor type 1 
CB2 
Cannabinoid receptor type 2 
CBD 
Cannabidiol 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CFR 
Code of Federal Regulations  
Cmax  
Maximum observed concentration 
CNS 
Central nervous system 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CSHQ 
Children’s Sleep Habit Questionnaire 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
e.g. 
For example 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C virus antibodies 
HDL 
High density lipoprotein  
HIV 
Human immunodeficiency virus 
HPLC 
High-performance liquid chromatography 
HREC 
Human Rights Ethics Committee 
ICF 
Informed consent form 
ITT 
Intent-to-treat 
IV 
Intravenous 

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Table 2: 
Abbreviations and Specialist Terms 
Abbreviation 
Definition 
Kg 
Kilogram 
LDL 
Low density lipoprotein 
MAPK1 
Mitogen-activated protein kinase 1 
MedDRA 
Medical Dictionary for Regulatory Affairs 
Mg 
Milligram 
MS/MS 
Tandem mass spectrometry 
N 
Number  
Ng 
Nanogram 
NOAEL 
No-observed-adverse-effect-level 
NONMEM 
Nonlinear mixed effects model 
OA 
Osteoarthritis 
OTC 
Over-the-counter 
PARS-R 
Pediatric Anxiety Rating Scale-Revised 
PK 
Pharmacokinetic 
PND 
Post-natal day 
PTSD 
Post traumatic stress disorder 
Q12 H 
Every 12 hours 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
TBX1 
T-Box Protein 1 
TdP 
Torsades de pointes 
THC 
Δ9-tetrahydrocannabinol 
ULN 
Upper limit of normal 
UV 
Ultraviolet 
WBC 
White blood cell 
w/w 
Weight/weight 
 

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5. 
INTRODUCTION 
5.1. 
Background Information 
The Drug Product ZYN002 is a transdermal cannabidiol (CBD) gel.  CBD is the primary non-
euphoric cannabinoid contained in the Cannabis sativa L plant.  The CBD contained within 
ZYN002 is a pharmaceutically produced Active Pharmaceutical Ingredient (API) that is 
chemically identical to the CBD present in Cannabis.   
Cannabis has low affinity for CB1 and CB2 receptors, and CBD produces multiple effects, 
including blocking the equilibrative nucleoside transporter, the orphan G-protein receptor GPR 
55, and the transient receptor potential of ankyrin type 1 channel, and regulating the intracellular 
effects of calcium.  The influence of CBD on these targets, each of which is known to play a role 
in neuronal excitability, is the scientific basis for its antiepileptic potential.  The expectation of a 
wide margin of safety in humans was founded on the results of well-controlled studies in which 
CBD has exhibited high tolerability across several modes of administration. 
ZYN002 is being developed as a clear, transdermal gel to provide consistent, controlled 
cannabidiol (CBD) delivery with twice daily (every 12 hours [Q12 H]) dosing.  Because CBD is 
virtually insoluble in water, ethanol and propylene glycol are used as solubilizing agents and 
diethylene glycol monoethyl ether (brand name: Transcutol® HP) is used as a permeation 
enhancer.   
22q11.2 deletion syndrome, (also referred to as 22qDS) is the most common (yet under-
diagnosed) microdeletion syndrome affecting 1 in 2,000 to 1 in 4,000 live births.  Approximately 
50 genes are affected resulting in effects on multiple body systems. 22q11.1DS is inherited as 
autosomal dominant but 90-95% cases are spontaneous (McDonald-McGinn et al, 2015).  
Patients usually harbor a 1.5 to 3 Mb hemizygous deletion at chromosome 22q11.2, resulting in 
pathognomonic T-Box Protein 1(TBX1), adaptor protein CRKL and/or mitogen-activated protein 
kinase 1 (MAPK1) haplo-insufficiency.   
The TBX1 gene provides instructions for making a protein called T-box 1.  Genes in the T-box 
family play important roles in the formation of tissues and organs during embryonic 
development.  To carry out these roles, proteins produced from these genes bind to specific areas 
of DNA.  The proteins attach to critical regions near genes and help control the activity of those 
genes.  T-box proteins are called transcription factors on the basis of this action.  The T-box 1 
protein appears to be necessary for the normal development of muscles and bones of the face and 
neck, large arteries that carry blood out of the heart, structures in the ear, and glands such as the 
thymus and parathyroid.  Although the T-box 1 protein acts as a transcription factor, researchers 
have not determined which genes are regulated by this protein (Antshel, et al., 2018).  Mortality 
in infancy is 5% mostly due to severe cardiac abnormalities. 
DiGeorge syndrome was initially described in the 1960’s in patients with cardiac defects, 
immunodeficiency, cleft lip/plate and hypoparathyroidism without knowledge of the 
chromosomal defect.  In the 1980’s the link of these findings to a chromosome defect was 
identified.  Velocardiofacial syndrome was independently described in the 1970’s as abnormal 
development of the parathyroid glands, thymus, and conotruncal region of the heart.  “DiGeorge” 
now applies only to those with DiGeorge syndrome who do not have the 22q deletion.  Thirty 

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five to 90% of patients diagnosed as DiGeorge syndrome and 80 to100% of patients diagnosed 
with velocardiofacial syndrome have 22qDS (Sullivan, K E, 2011).  
The clinical presentations of 22qDS are highly variable within and between families, even in 
identical twins.  Each patient presents their own unique profile of symptoms and signs.  Males 
and females are equally affected.  Undiagnosed older children and adults are often only 
ascertained due to behavioral problems or school performance.  In some cases, adults are only 
diagnosed when they have an affected child.  Over 180 clinical features have been described in 
association with 22qDS, none of which in isolation is considered pathognomonic for the 
condition (Koczkowska et al, 2017). 
The most common medical problems include congenital heart defects (primarily conotruncal 
abnormalities such as Tetralogy of Fallot), facial and palatal abnormalities, immunodeficiency, 
and hypocalcemia.  There is a very wide range in the severity of these effects from life 
threatening to very minimal or symptomatic and undiagnosed.  The neurocognitive profile is 
highly variable (both inter- and intra-individual).  Typically, early in infancy motor delays 
(hypotonia) and speech and language delays are evident.  The majority of patients fall into an IQ 
range of 70 to 84.  These patients are also at an increased risk to develop ADHD, autism 
spectrum disorder (ASD), anxiety and mood disorders as well as psychotic disorders and 
schizophrenia.  This complex behavioral/psychiatric phenotype changes across ages particularly 
with the risk of development of schizophrenia as seen in Figure 1 (Swillen, 2015).   
 
Figure 1: 
Phenotypic Manifestations of 22qDS by Age Range 
 
 
 

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Table 3 summarizes phenotypic features from a large cohort of 22qDS patients (n=906) 
(McDonald-McGinn, 2011).  The incidence of autism in this analysis is lower than that reported 
by others in which rates over 40% have been found (Antshel, 2007). 
Table 3: 
Summary of 22qDS Patient Phenotypic Features 
System 
Percent (%) 
Cardiac 
77 
Immune 
77 
Velopharyngeal 
43 
Submucous Cleft Palate 
16 
Overt Cleft Palate 
11 
Cleft Lip and Palate 
2 
Esophageal Dysmotility 
36 
Hypocalcemia 
49 
Feeding/Swallowing Issues 
35 
Generalized Anxiety 
8 
Phobias 
42 
ADHD 
54 
Autism 
14 
 
Behavioral Effects 
The most common behavioral/psychiatric diagnoses in children with 22qDS are attention deficit 
hyperactivity disorder (ADHD), ASD and anxiety.  These behaviors each occur in approximately 
40% of patients.  Cross-sectional studies have shown that children with 22qDS are withdrawn, 
have problems with social interaction, attention and anxiety in comparison to patients with 
speech/language delays or children with simple clefts (Swillen, 2015).  The presence of autism in 
children with 22qDS is not linked to the subsequent risk of developing schizophrenia.  These two 
conditions are independent phenotypic expressions of 22qDS (pleiotropy) 
(Vorstman, et al, 2013).  However, there is a link between ADHD, particularly with inattentive 
symptoms, in childhood and an increased risk for later development of psychotic disorder 
(Niarchou, et al, 2018.  Cognitive decline in childhood also is associated with an increased risk 
of schizophrenia. 
Psychosis 
The incidence of psychiatric disorders in children with 22qDS is similar to that in children with 
other developmental disorders but this changes as the children age (Swillen, 2015).  One percent 
of patients with schizophrenia carry the 22qDS gene.  Up to 30% of the patients with 22q11.2DS 
will develop schizophrenia or schizo-affective disorder.  Schizophrenia is the most common 
psychiatric disorder in adults with 22qDS.  The relative risk for the development of 
schizophrenia in patients with 22qDS is 20 to 25 times that of the normal population.  The only 
patients with a higher relative risk for schizophrenia are children of parents who both have 
schizophrenia or monozygotic twins of an affected individual (Basset, 2008).  The major 

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symptoms of schizophrenia seen in patients with 22qDS are essentially the same as those in 
patients without the deletion.  These two groups do differ on intelligence quotient (IQ), however 
with those with 22qs having lower IQ (70 to 84) compared with patients without the 22qDS.  
Niarchou et al., (2018) compared the emergence of psychotic symptoms and psychotic disorders 
in patients with 22qDS with and without inattention symptoms or diagnosed ADHD.  Patients 
with inattention symptoms at the mean age of 11 had a relative risk of 1.2 for the development of 
psychotic symptoms at 14 years.  Patients diagnosed with ADHD at age 11 had a relative risk of 
4.5 for having a psychotic disorder at age 14.  There is no increased risk for psychotic symptoms 
or disorder with the presence of hyperactivity-impulsiveness symptoms. 
Intelligence 
There is a wide range in the effect of 22qDS on intelligence.  The effect has been summarized as 
a 30- point leftward shift in the normal distribution of IQ scores (Swillen, 2015).  Approximately 
55% have borderline to normal intelligence (FSIQ > 70), approximately 45% have mild to 
moderate intellectual disability (FSIQ 55 to 70) and a minority experience moderate to severe 
intellectual disability (Swillen, 2015).  There is considerable variability in changes in IQ scores 
as children age.  In a recent longitudinal study, average children with 22qDS showed a cognitive 
decline of 7 FSIQ-points or 9 VIQ-points with increasing age (Vorstman et al., 2015).  In the 
subgroup that developed psychotic symptoms, this decline was significantly steeper.  A relatively 
low initial IQ (below 75) measured at or before the onset of adolescence was found to be an 
independent risk factor for psychosis in 22qDS.  The association between the decline in VIQ and 
increased risk of schizophrenia is consistent with what has been described in the general 
population (Vorstman et al., 2015).  By late adolescence and early adulthood approximately 30% 
of patients with 22qDS will develop psychotic disorders, most often schizophrenia or 
schizo-effective disorders. 
5.2. 
Nonclinical Summary 
To support the clinical development of ZYN002, Zynerba will rely upon: 
• Data from nonclinical safety studies conducted by Zynerba with ZYN002, ZYN002 
placebo gel, or CBD, the active ingredient in ZYN002,  
• Publicly available information about the toxicity/safety of CBD and the excipients in 
ZYN002, and 
• Clinical safety data generated by Zynerba with CBD and ZYN002. 
Published nonclinical studies with CBD indicate that it does not produce adverse effects on 
nervous system, respiratory, or gastrointestinal function, although it does exhibit beneficial 
activity in some nervous system disorders (e.g., anti-convulsant and anxiolytic activity) and 
gastrointestinal disorders (e.g., anti-inflammatory activity).  In a GLP-compliant study conducted 
by Zynerba, CBD did not affect cardiovascular system function even at an estimated plasma 
concentration (4350 ng/mL) that is 256 times greater than the expected plasma Cmax in patients 
over a 14-day period (17 ng/mL).  Based on this information, human subjects using ZYN002 are 
unlikely to experience adverse effects on nervous system, cardiovascular, respiratory, or 
gastrointestinal function. 

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ZYN002 was devoid of systemic toxicity in animals given topical doses applied to 10% of their 
body surface area daily for up to 26 weeks (rats) or twice a day for up to 13 weeks (minipigs).  
These studies identified CBD no-observed-adverse-effect-levels (NOAELs) of 100 and 17 
mg/kg/day, respectively, which are both equivalent to approximately 970 mg/day in a 60-kg 
human subject.  After the last dose at these NOAELs, plasma CBD exposure was much greater in 
rats than minipigs.  Cmax values were 584 ng/mL in male rats and 2680 ng/mL in female rats but 
only 8 ng/mL in minipigs of both sexes.  AUC0-24h values were 8790 h*ng/mL in male rats and 
38900 h*ng/mL in female rats but only 140 h*ng/mL in minipigs of both sexes.   
In 26- and 13-week, repeat-dose studies, ZYN002 produced evidence of local irritation at the 
application site in both rats and minipigs that was CBD concentration-related, and rats were 
more sensitive than minipigs.  For rats, the 26-week NOAEL for local irritation was considered 
to be the low dose level, where the CBD concentration was 1.0% (10 mg/mL) and the local CBD 
dose was 0.15 to 0.18 mg/cm2/day.  Local irritation was reversible when dosing stopped.  In 
minipigs, local irritation was transient, limited to erythema, and resolved despite continued twice 
daily application of ZYN002.  Therefore, the 13-week NOAEL for local irritation was 
considered to be the high-dose level, where CBD concentration was 7.5% (75 mg/mL) and the 
local CBD dose was approximately 0.62 mg/cm2 twice daily (BID).   
Zynerba has conducted studies of daily administration of ZYN002 to rabbits and rats (up to the 
highest dose of 100 mg/kg/day) to evaluate the effects of CBD on reproductive function and 
developmental toxicity, as follows: 
• Male rat fertility study (ZYN2-NC-37) concluded reproductive function was not affected 
at any dose level; there were no effects on the fertility/conception rate, number of days to 
mating, or the number of corpora lutea, implantation sites, live and dead embryos, 
resorptions, pre- or post-implantation losses or live embryos index.  There also were no 
effects on sperm concentration, motility, or quality and no histopathologic findings in the 
testis at any dose level. 
• Results from a pregnant rabbit embryo-fetal development study (ZYN2-NC-40) indicated 
that ZYN002 did not affect the number of corpora lutea, implantation sites, live and dead 
fetuses, sex ratio, resorptions, pre- and post-implantation losses, or gravid uterus weight.  
There were also no major malformations or minor external or internal anomalies, skeletal 
anomalies or skeletal variants that were considered related to study treatment.  ZYN002 
was considered to have had no effect on embryo-fetal development. 
• A female rat fertility study (ZYN2-NC-36) concluded reproductive function was not 
affected at any dose level; there were no effects on estrous cycling, mating, the 
fertility/conception rate, number of days to mating, or the number of corpora lutea, 
implantation sites, live and dead embryos, resorptions, pre- or post-implantation losses, 
or live embryos index.  There also were no effects on ovarian or uterine weight at any 
dose level. 
• A pregnant rat embryo-fetal development study (ZYN2-NC-38) executed during the 
period of major organogenesis did not affect maintenance of pregnancy or fetal survival, 
growth.   
Zynerba has also conducted a 10-week juvenile rat toxicity study (ZYN2-NC-34) where rats 
tolerated daily doses of CBD up to 80 mg/kg/day for 10 weeks, administered by SC injection in 

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sesame oil from post-natal day (PND) 12 to 20 (study Days 1-9) and then by transdermal 
application of ZYN002 from PND 21 to 81 or 82 (study Days 10-70/71).  The only adverse 
effect was on retinal development: 
• Chorioretinal dysplasia was identified at a higher rate in ZYN002 rats (18/298 or 6%) 
compared to the control group (1/200 rats or 0.5%).  The finding was not clearly dose 
related and was higher than historical background incidence (0.4%). (Tanaka et al. 1993: 
Hubert et al. 1994; Stein et al. 2017). 
• Based on the results of the study, pregnant women or women planning to become 
pregnant should not receive CBD due to the CBD-related increase in the incidence of 
chorioretinal dysplasia found in juvenile rats.  The chorioretinal dysplasia seen in rats 
would be irrelevant for human subjects exposed after birth because of species differences 
in ocular development.  Briefly, in humans, the eyelids fuse during the third month of 
gestation and open during the sixth month of gestation.  The human retina is largely 
morphologically mature at birth.  In contrast, in rats the eyelids fuse by pre-natal Day 17 
(third trimester) and open at approximately post-natal Day 14; consequently, rats are born 
with fused eyelids and eyes that are not fully developed.  In other words, the CBD-related 
increase in the incidence of chorioretinal dysplasia in juvenile rats was a consequence of 
exposure to CBD during a period of choroid and retinal development that occurs prior to 
birth in humans. 
Repeat-dose toxicity studies in rats and minipigs with ZYN002 have revealed no effects on 
endocrine systems or reproductive organs in either species.  Published information suggests that 
CBD has the potential to affect reproductive function in animals, at least in males, possibly 
secondary to effects on sex hormone levels (Dalterio et al. 1984; Dalterio and deRooij, 1986).  
Published information also suggests that administration of CBD to pregnant mice has the 
potential to affect development of offspring, at least to males (Dalterio et al. 1984; Dalterio and 
deRooij 1986). 
CBD does not absorb UV or visible light over 290-700 nm (Hazekamp et al. 2005) and so 
ZYN002 does not present a potential phototoxicity hazard to human subjects.   
ZYN002 did not induce contact hypersensitivity in a mouse local lymph node assay and so is 
considered not to pose a risk of inducing contact sensitization in human subjects. 
Because of its high ethanol content (> 50%), ZYN002 caused irritation when placed into the eyes 
of rabbits and would be expected to do so if it accidentally contacts the conjunctiva or cornea of 
human subjects.  Irritation was reversible within 7 days. 
In the completed clinical pharmacology studies, ZYN002 was not associated with any 
impairment in critical areas of cognitive functioning often impacted by CNS drugs, including 
divided attention and working memory and focused attention after single or repeat doses of 
ZYN002 at doses up to 250 mg as a single or BID dose.  Assessments of psychological health 
also demonstrated no changes in depression and anxiety symptoms, or positive and negative 
affect, following administration of ZYN002.  Results from three completed Phase 1 studies, 
along with a population pharmacokinetic (PK) model, which includes results from ZYN2-CL-03, 
ZYN2-CL-004 and ZYN2-CL-005, have adequately described the PK of CBD following 

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application of ZYN002 transdermal gel.  Pharmacokinetic conclusions for these studies are as 
follows: 
• The plasma CBD concentration-time profiles after transdermal administration of 
ZYN002 were consistent with slow transcutaneous absorption, extensive distribution 
(with volume of distribution >20 L/kg), extensive metabolism, and a slow terminal 
phase half-life (t1/2) of approximately 4-12 days. 
• THC was not quantifiable in either plasma or urine. 
• There is adequate animal NOAEL:human exposure ratios for AUC and Cmax.   
Population pharmacokinetic analyses indicate approximately 85% of steady-state is reached by 
Day 14. 
Because CYP3A4 and CYP2C19 are the major isoforms responsible for CBD metabolism, 
concomitant administration of drugs that inhibit these enzymes may result in higher exposure to 
CBD and drugs that induce these enzymes may result in lower exposure to CBD; therefore, 
strong inhibitors or inducers of CYP3A4 may increase or decrease the plasma concentrations of 
CBD and should be administered with caution. 
As a potential perpetrator, CBD would not cause a clinically significant induction of CYP 
isoenzymes.  However, CBD exhibited time-dependent inhibition of CYP2D6 and CYP1A2, 
which was reversible, and of CYP3A4, which was irreversible.  Sensitive CYP3A4 substrates 
with a narrow therapeutic index or risk for severe toxicity should be avoided until this risk has 
been assessed with ZYN002.  CBD did not inhibit human efflux and uptake transporters.  
Overall, these results support further clinical development of ZYN002 transdermal gel. 
 
 

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5.3. 
Clinical Summary 
CBD studies completed with oral, inhaled, and intravenous (i.v.) formulations support a 
favorable tolerability and efficacy profile in several disease states.  These efficacy and 
tolerability data provide a rationale for development of the transdermal delivery of synthetic 
CBD which is not subject to gastric acid degradation and first pass metabolism in the liver, and 
may achieve consistent blood levels for the treatment of child and adolescent patients. 
5.3.1. 
ZYN002 Phase 1 Studies 
Five Phase 1 studies (ZYN2-CL-01, ZYN2-CL-02, ZYN2-CL-008, ZYN2-CL-011, and 
ZYN2-CL-014) of ZYN002 (CBD) administered via a transdermal delivery system have been 
conducted in healthy subjects and patients with epilepsy.  In addition, one placebo study 
(ZYN2-CL-06) was conducted to evaluate the skin tolerability of the excipients in the ZYN002 
formulation.  
These efficacy and tolerability data provide a rationale for development of a transdermal delivery 
of synthetic CBD which is not subject to first pass metabolism and may achieve consistent blood 
levels for the treatment of patients with 22qDS, ASD, FXS, and epilepsy.  
A summary of the safety results from the Zynerba studies further supports the development of 
ZYN002.  Five Phase 1 safety and tolerability study results are as follows:  
• ZYN2-CL-01, a single rising-dose study in healthy subjects (n=32) and patients with 
epilepsy (n=10) receiving ZYN002 (50, 100, 125, and 250 mg) or placebo showed that 
ZYN002 was safe and well tolerated at all doses.  The incidence of treatment-emergent 
adverse events (TEAEs) associated with ZYN002 was similar to placebo in healthy 
volunteers.  There were no serious adverse events (SAEs), no clinically significant changes 
in ECGs, vital signs or clinical laboratory results.  ZYN002 had good skin tolerability, and 
there was no post-dosing erythema at 24, 48, 72, and 96 hours.  
• ZYN2-CL-02, a seven-day repeat application, multiple rising dose study of healthy subjects 
(n=24) receiving ZYN002 (200, 250, 500 mg/day), and patients with epilepsy (n=12), 
receiving 500 mg/day showed that ZYN002 was safe and well tolerated at all doses. One 
subject receiving placebo discontinued due to an SAE, a device related infection (catheter) 
not related to study drug.  Most TEAEs were mild in intensity and there was only one severe 
TEAE of back pain in a healthy subject administered ZYN002 500 mg.  Most TEAEs were 
considered related to study drug and either resolved or were resolving.  Application site 
disorders were the most frequently reported TEAEs for both healthy subjects and epilepsy 
patients.  The most frequently reported TEAEs were application site dryness and application 
site pruritus.  Headache was the most frequently reported TEAE that was not associated with 
the application site.  There were no clinically significant changes in ECGs or vital signs.  
• ZYN2-CL-06, a 14-day repeat application study in healthy subjects (n=5) receiving placebo 
which tested the skin tolerability of the excipients used in the ZYN002 formulation but did 
not contain the active ingredient of CBD.  There were no AEs or SAEs reported in this study. 
The majority of skin irritation erythema scores were ‘0’ (no erythema), and when erythema 
was recorded it was scored as a ‘1’ (minimal erythema).  There were no clinically significant 
changes in ECGs, laboratory testing, physical examinations, or vital signs.  

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• ZYN2-CL-008, a 14-day repeat application study in healthy subjects (n=42) receiving 
ZYN002 (394.8, 500, and 504 mg/day) or placebo showed that ZYN002 was safe and well 
tolerated at all doses.  Most TEAEs were mild in intensity.  Most TEAEs were considered not 
related to study drug and either resolved or were resolving at the time of database lock.  No 
SAEs were reported and no subjects discontinued from the study due to a TEAE.  Headache 
and upper respiratory tract infection were the most frequently reported TEAEs and occurred 
in similar incidence for both ZYN002 and placebo.  Application site dryness, application site 
pain, and application site pruritus were the next frequently reported TEAEs.  
• ZYN2-CL-011, a 14-day repeat application study in 39 healthy male and female subjects.  
This study was an open-label study where subjects were all administered 250 mg BID for a 
total daily dose of 500 mg/day.  Three application sites were evaluated; upper thighs 
(Treatment A), upper back (Treatment B) and the upper arms/shoulders (Treatment C).  
Twenty-nine of the 29 (74.4%) treated subjects had at least one TEAE.  There were no deaths 
reported in the study.  The majority of the events were mild (95.3%) in severity and none 
were reported as severe.  Most TEAEs were reported as related to study treatment (91.9%).  
One subject 
 discontinued treatment on Day 5 due to an AE of an allergic reaction 
of skin rash to the upper arms, chest, and forearms.  This AE was considered probably related 
to study treatment.  There were no serious adverse events reported. 
• ZYN2-CL-014 was a randomized, placebo-controlled, double-blind, multiple-dose, parallel-
group, relative bioavailability study to evaluate the relative bioavailability of ZYN02 CBD 
gel applied to the right and left upper arms/shoulders and the right and left upper 
arms/shoulders and right and left upper thighs.  Treatment was administered BID for 13 
consecutive days with only a morning dose on Day 14, to healthy male and female subjects.   
This study evaluated the safety and tolerability of a daily dose of 780 mg where the CBD 
concentration administered was either 7.5% or 4.2% in healthy subjects.   
Safety results from this 14-day repeat application study in healthy subjects receiving 
ZYN002 780 mg/day with two CBD concentrations (4.2% and 7.5%) showed that ZYN002 
was safe and well tolerated at all application sites (upper right and left thighs and upper 
arms/shoulders).  Thirty five (88%) of the treated subjects had at least one TEAE.  There 
were no deaths due to adverse events.  The majority of the events were mild (81%), 18% 
were considered moderate and one (1%) was reported as severe (subject R011 reporting 
increased lipase).  Most TEAEs were reported as probably related to study treatment (60%).  
There were no serious adverse events reported.  The most frequently reported treatment 
related TEAE was application site dryness reported by 21 (53%) subjects.  All application 
site TEAEs were considered related to study drug.  ZYN002 was well tolerated at all 
application sites with most erythema being recorded as a score of ‘0’ (no erythema) or ‘1’ 
(minimal erythema).  There were no clinically significant changes in ECGs or vital signs.  
There were no clinically significant abnormalities observed in group laboratory parameters. 
In the completed clinical pharmacology studies, ZYN002 was not associated with any 
impairment in critical areas of cognitive functioning often impacted by central nervous 
system (CNS) drugs, including divided attention and working memory and focused attention 
after single or repeat doses of ZYN002 at doses up to 250 mg as a single or BID dose.  
Assessments of psychological health also demonstrated no changes in depression and anxiety 
symptoms, or positive and negative affect, following administration of ZYN002. 
PPD

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5.3.2. 
ZYN002 Phase 2 Studies 
Seven Phase 2 studies have been completed in patients with epilepsy (ZYN2-CL-03, 
ZYN2-CL-004), osteoarthritis (OA) (ZYN-CL-005), FXS (ZYN2-CL-009, ZYN2-CL-016), 
DEE (ZYN2-CL-025), and Autism Spectrum Disorder (ASD) (ZYN2-CL-030). 
1. ZYN2-CL-03, a randomized, double-blind, placebo-controlled, multiple-dose study was 
conducted at 10 sites in Australia and 4 sites in New Zealand, to assess the efficacy and 
safety of ZYN002 administered as a transdermal gel to patients with focal epilepsy.  The 
results showed ZYN002 to be safe and well tolerated with a safety profile consistent with 
previous studies.  A total of 188 patients were randomized to receive either 195 or 
390 mg/day of ZYN002 or placebo for 12 weeks.  AEs were reported by 26 of 63 (41.3%) of 
placebo-treated patients, 31 of 63 (49.2%) of patients randomized to 195 mg/day of ZYN002 
and 32 of 62 (51.6%) of patients randomized to 390 mg/day of ZYN002. For each dosing 
group, the majority of AEs were mild to moderate in intensity.  The TEAE that occurred 
more frequently in patients on drug than those on placebo and occurred in at least 2% of 
patients included: fatigue, headache, nausea, application site dryness, anxiety, urinary tract 
infection, diarrhea, application site pruritus, thermal burn (secondary to seizure related 
accident), ataxia, oropharyngeal pain and erythema.  
2. ZYN2-CL-005, a randomized, double-blind, placebo-controlled, multiple center, multiple 
dose study, was conducted at 10 sites in Australia, to assess the efficacy and safety of a 
12 week repeat application in patients diagnosed with OA of the knee.  The results showed 
ZYN002 to be safe and well tolerated with a safety profile consistent with previous studies. 
A total of 320 patients were randomized to receive ZYN002 at 250 or 500 mg/day or placebo 
for 12 weeks.  Patients experiencing at least one treatment-emergent adverse event were 
similar between those on study drug (n=106, 50%) and those on placebo (n=45, 42%).  The 
TEAEs that occurred more frequently in patients on drug than those on placebo and occurred 
in at least at 2% of patients included: headache, dizziness, application site dryness, 
application site reaction, and application site pain.  
3. ZYN2-CL-009 was an ongoing open-label study to assess the safety and efficacy of ZYN002 
administered as a transdermal gel to children and adolescents (age range 6 to <18) with 
Fragile X Syndrome (FXS).  The study was conducted at three investigative sites in 
Australia.  The 12-week treatment period included a 6-week titration period, after which the 
patient was to remain on their maintenance dose over the next 6 weeks of treatment.  
Following completion of the first 12 weeks of treatment, patients had the option of 
continuing into an extension phase of the study, which allowed for them to receive study 
drug for up to 24 additional months.  The extension phase of the study has concluded and is 
in the process of preparing results.  
Twenty-two patients were screened for the study and 20 were enrolled.  Of the 20 patients, 
18 completed the 12 weeks of open-label treatment and 13 of those 18 patients continued into 
the extension phase of the study.   
 
 
 

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12-week treatment period results include:  
Safety Results:  Seventeen patients reported 33 TEAEs in this 12-week open-label study.  
The majority of TEAEs were mild (25 [76%]) or moderate in intensity (8 [24%]) and were 
considered unrelated to treatment with CBD (25 [76%]).  There were no SAEs reported, and 
1 of 20 patients (5%) discontinued treatment due to a TEAE (i.e., exacerbation of eczema).  
The most common treatment emergent adverse event was mild-moderate gastroenteritis 
(6 [18%]), not related to study drug and resolved during the study period.  This was followed 
by upper respiratory tract infection, viral infection, influenza, otitis media, and tonsillitis 
(7 [21%], not related to study drug and all resolved during the study period.  One patient 
developed a moderate application rash 35 days after starting study drug.  Study drug was 
withheld for one day and the application site was changed to the thighs for 6 days while the 
rash resolved.  The rash did not recur.  This patient also had a high eosinophil count, 
considered probably related to the skin rash.  Upon a repeat laboratory test, the eosinophil 
count had decreased to just above normal.  This patient currently is in the extension phase of 
the study.  
Other adverse events considered possibly related included symptoms of FXS (e.g., sensorial 
hyperactivity, nightmares, increased bedwetting and increase in self stimulatory talk).  
There were no clinically significant changes in vital signs, ECG, clinical laboratory results 
(other than eosinophilia noted above), and no reports of suicidal ideation for any patient 
throughout the study.  
Study results for Week 51 of the extension period include: 
Through Week 51 there were no clinically significant changes in vital signs, ECGs, or 
clinical laboratory results.  Through Week 51 there were a total of 66 TEAEs reported in the 
study, all mild to moderate in severity, with the majority judged by the Investigator as not 
related to study drug. No SAEs have been reported.  Gastroenteritis and upper respiratory 
tract infections continue to be the most commonly reported adverse events.  
Efficacy Results: Eighteen patients completed the efficacy assessments through Week 12 of 
the study.  Validated clinician- and caregiver-rated FXS scales were used to measure 
Baseline symptom severity and changes in symptoms between Baseline and Week 12 of the 
treatment period in this open-label study.  
The primary endpoint was the change from Baseline to Week 12 in the total score of the 
ADAMS, a caregiver-rated scale.  Compared to the Baseline total score, the ZYN002 treated 
patients had a 45.81% reduction (p<0.0001) in the ADAMS Total Score.  Furthermore, 
ZYN002 treated patients had statistically and clinically significant improvement compared to 
Baseline in all but one of the ADAMS subscales (i.e., Manic/Hyperactive Behavior, Social 
Avoidance, General Anxiety, and Compulsive Behavior) at Week 12. A significant change 
was not observed for the Depressed Mood subscale of the ADAMS, clinically meaningful 
changes were observed for all other assessments, including in the ABC-CFXS, Pediatric 
Anxiety Rating Scale-Revised (PARS-R), and Visual Analog Scale (VAS). 
Data from the extension phase of the study highlight continued gains in the primary and key 
secondary efficacy outcomes.  The improvement observed during the initial 12-week 
treatment period has been sustained through 12 months.  A 54.4% reduction in ADAMS 

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Total Score was observed between Screening and Month 12, relative to a 48.6% reduction 
from Screening to Week 12 (among the 12 patients enrolled through Month 12 of the 
extension phase).  Similar changes were observed for Social Avoidance as measured by both 
the ADAMS (52.5% [n = 12] at Week 12 vs. 55.6% [n = 12] at Month 12) and ABC-CFXS 
(57.9% [n = 12] at Week 12 vs. 77.2% [n = 9] at Month 12). 
4. ZYN2-CL-004 was an open-label extension study to allow patients with focal epilepsy who 
completed ZYN2-CL-03 to continue to receive ZYN002.  The primary objective was to 
assess the long-term safety and tolerability of ZYN002 in adult epilepsy patients over an 
18-month period.  The secondary objective was to evaluate efficacy in this population.  
Patients had to complete the 12 weeks of study treatment on protocol ZYN2-CL-03.  
ZYN002 was administered as a transdermal gel with all patients starting on ZYN002 at doses 
equal to or higher than those used in the blinded study – CBD 195 mg every 12 hours (Q12 
H) (±2 hours) (390 mg daily), with the option that after Month 1 to either increase or reduce 
the dose of ZYN002.  The dose could be increased to 292.5 mg Q12H (±2 hours) (585 mg 
daily). After one month at the 585 mg daily dose, the Investigator had the option to increase 
the dose to 390 mg Q12H (±2 hours) (780 mg daily).  Of the patients who completed the 
blinded 12-week phase, 171 (98%) enrolled in the open-label extension study.  Seizure 
control was evaluated as a function of duration on ZYN002, regardless of initial 
randomization group or dose.  Longer exposure to ZYN002 resulted in greater improvements 
in seizure frequency, with median percent change in seizures from -25% at 3 months 
(n=171), -40% at 6 months (n=130), -48% at 9 months (n=107), -52% at 12 months (n=94), -
57% at 15 months (n=84) and -55% at 18 months (n=63).  
ZYN002 was well tolerated, with excellent skin tolerability.  The most common adverse 
events were upper respiratory tract infection (viral and bacterial; 20.4%), headache (11.7%), 
laceration (8.8%) and fatigue (5.8%).  One patient died following the Month 15 visit; the 
causality is suspected Sudden Unexplained Death in Epilepsy.  There have been no abnormal 
liver adverse events, defined as alanine aminotransferase or aspartate aminotransferase levels 
> 3 times the upper limit of normal.   
5. ZYN2-CL-025 was an open-label study to evaluate over a 26-week treatment period, (Period 
A) the safety and tolerability of ZYN002 in 48 children and adolescent patients (age range 3 
to <18 years) with developmental and epileptic encephalopathies (DEE).  Patients weighing 
≤ 25 kg received 125 mg CBD Q12H (±2 hours), for a total daily dose of 250 mg CBD (2 
sachets) for the four-week titration period.  At the week four visit (Visit 4), based on 
Investigator discretion, the dose could remain at 250 mg CBD daily or be increased to 250 
mg CBD Q12H (±2 hours), for a total daily dose of 500 mg CBD (4 sachets) for the 
remaining 22 weeks of the treatment period.  Patients weighing > 25 kg received 250 mg 
CBD Q12H (±2 hours), for a total daily dose of 500 mg CBD (4 sachets) for the four-week 
titration period.  At the week four visit (Visit 4), based on Investigator discretion, the dose 
could remain at 500 mg CBD daily or be increased to 375 mg CBD Q12H (±2 hours), for a 
total daily dose 750 mg CBD (6 sachets) for the remaining 22 weeks of the treatment period.  
No sooner than Week 10, after evaluation of the patient’s seizure diary and CBD plasma 
concentration from Weeks 4 and/or 6 the Investigator in conjunction with the Zynerba 
Medical Monitor, may determine that the patient’s dose could be increased.  An unscheduled 
visit was required in order to increase the dose.  Patients taking 500 mg CBD daily may be 
increased to 750 mg CBD daily (6 sachets) and patients taking 750 mg CBD daily could be 

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increased to 1000 mg CBD (8 sachets) daily for the remainder of the treatment period.  In 
Period B patients continued to receive ZYN002 for up to an additional 46 weeks at the same 
maintenance dose they were receiving at Week 26.   
6. ZYN2-CL-016 was a randomized, double-blind, placebo-controlled, multiple-center study to 
assess the efficacy and safety of ZYN002 for the treatment of child and adolescent (age range 
3 to <18 years) patients with FXS.  Male and female patients with FXS were treated for 12 
weeks with a two-week single-blind placebo lead-in preceding the 12-week double-blind 
treatment period.  Approximately 204 male and female patients, ages 3 to < 18 years, were be 
randomized 1:1 to either study drug or placebo.  Randomization was stratified by gender, 
weight category and region.  In a blinded fashion, ZYN002-treated patients who weigh ≤ 35 
kg received 125 mg CBD Q12H (every 12 hours) (± 2 hours); for a total daily dose of 250 
mg CBD.  Patients who weighed > 35 kg received 250 mg CBD Q12H (±2 hours); for a total 
daily dose of 500 mg CBD.  All patients  remained on their assigned dose during the 12-week 
treatment phase of the study. 
7. ZYN2-CL-030 was an open-label study of patients aged 4 to < 18 years diagnosed with 
autism spectrum disorder (ASD).  Treatment duration was 14 weeks with a 6-month 
extension.  The study has concluded and is in the process of preparing results. 
5.3.3. 
Ongoing ZYN002 Clinical Studies 
Two clinical ZYN002 studies are ongoing as follows:  
• ZYN2-CL-017 is a 52-week, ongoing, open label study for those patients that complete 
the treatment phase of studies ZYN2-CL-009, ZYN2-CL-016, and ZYN2-CL-033. 
• ZYN2-CL-031 is an open-label study of patients aged 4 to < 18 years diagnosed with 
22q.11.2 Deletion Syndrome.  Treatment duration is 14 weeks with a 6-month extension.  
The study is currently enrolling. 
 
 

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5.3.4. 
Completed Clinical Studies in Literature 
CBD has been clinically studied in healthy subjects with a variety of conditions.  Highlights of 
clinical study information are summarized below.  Additional information is provided in the 
Investigator’s Brochure. 
• Most assessments have used a 600 mg oral dose of CBD, but subjects in several trials 
have been treated with oral CBD doses of 1200 mg or more (Zuardi et al, 2010; 
Matsuyama and Fu 1981), and one study employed a 1500 mg dose (Zuardi et al. 
2006).  More recent epilepsy studies have titrated doses up to 25 – 50 mg/kg of oral 
doses in patients (age 1-30 years) (Devinsky et al. 2016, Devinsky et al. 2017).  The 
mean CBD dose at 12 weeks was 22.9 mg/kg corresponding to a 732 mg oral dose for 
an average 10-year old patient.  At the highest dose, Zynerba has studied a 1000 mg 
daily dose of CBD (ZYN002 4.2%).  This study will investigate ZYN002 at the daily 
dose of 250 or 500 mg ZYN002 (4.2% concentration). 
• Because the zero-order delivery from ZYN002 should provide a lower Cmax than oral 
or buccal routes of delivery, ZYN002 usage may result in less systemic exposure, 
placing it well below the threshold of safety in humans that has been established at 
higher systemic doses with oral, inhalation and injectable formulations. 
• The 600 mg oral dose of CBD has been monitored in multiple long-term treatment 
situations.  In at least six studies, study periods of 3 months have been used (Martin-
Santos et al. 2012; Bhattacharyya et al. 2012; Winton-Brown et al. 2011; Fusar-Poli 
et al. 2010; Bhattacharyya et al. 2010; Fusar-Poli et al. 2009; Borgwardt et al. 2008), 
and several patients have taken CBD for 4.5 months (Cunha et al. 1980). 
• Psychoactive effects associated with CBD have not been widely reported until 
recently.  Previous reports suggest the absence of psychoactive effects whether CBD 
is administered intravenously (Perez-Reyes et al. 1973) or orally (Englund et al. 2013; 
Martin-Santos et al. 2012, Bhattacharyya et al. 2012; Bhattacharyya et al. 2010; 
Zuardi et al. 2009), and pre-treatment with oral CBD 600 mg has been shown to 
inhibit the psychosis and cognitive impairment associated with intravenous THC 1.5 
mg (Englund et al. 2013 and Bhattacharyya et al. 2010).  Recent studies with 
Epidiolex (5 to 20 mg/kg/day)show high rates of somnolence (36%) and fatigue 
(20%) (Devinsky et al. 2017).  These effects could be due to drug, underlying disease, 
potential conversion of oral CBD to THC or a combination of these factors.  Previous 
work has shown that in the presence of acidic reagents, CBD isomerizes to 
tetrahydrocannabinol (Ganoi and Mecoulam, 1966).  In simulated gastric fluid, 
cannabidiol converts to Δ9-tetrahydrocannabinol, 9-α-hydroxy-hexahydrocannabinol 
and 8-hydroxy-iso-hexahydrocannabinol.  All have psychoactive activity (Merrick et 
al. 2016; Watanabe et al. 2007). 
• CBD-treated subjects in clinical studies have shown no treatment-related effects on 
key vital sign indicators, including blood pressure and heart rate (Perez-Reyes et al. 
1973; Martin-Santos et al. 2012; Hallak et al. 2011; Fusar-Poli et al. 2009; Borgwardt 
et al. 2008; Zuardi et al. 1993; Consroe et al. 1991; Zuardi et al. 1982), as well as 
electrocardiography (Guy and Flint 2003; Carlini and Cunha 1981; Cunha et al. 
1980). 

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• Findings from functional magnetic resonance imaging and behavioral studies show 
that CBD modulates function in regions not usually implicated in response inhibition.  
In terms of clinical sequelae, these data help to explain why CBD does not impair 
motor or cognitive performance and has anxiolytic effects (Borgwardt et al. 2008). 
In addition, studies completed with oral, inhaled, and intravenous (IV) CBD support an 
excellent tolerability profile and efficacy in several disease states.  These efficacy and 
tolerability data provide a rationale for development of a transdermal delivery of synthetic 
CBD which is not subject to first pass metabolism and may achieve consistent blood levels.  

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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
Primary: 
To evaluate the safety and tolerability of ZYN002 administered as a transdermal gel formulation, 
for up to 38weeks, in patients ages 4 to < 18 years, in the treatment of symptoms of 22q.11.2 
Deletion Syndrome (22qDS). 
Secondary: 
• To evaluate the efficacy of ZYN002 in the treatment of symptoms of 22qDS.  
• To evaluate CBD and THC plasma level exposure. 
Exploratory: 
The identification of plasma levels of CBD metabolite(s) may be conducted. 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an open-label study, to assess the tolerability and efficacy of CBD administered as 
ZYN002, a transdermal gel, for the treatment of child and adolescent patients with 22qDS.  Male 
and female patients with 22qDS will be treated in Period 1 for 14 weeks.  Patients with less than a 
25% improvement from baseline in the ABC-C irritability subscale, the investigator may increase the 
total daily dose at Week 6.  Patients that have made a ≥35% improvement on the ABC-C irritability sub-
scale will be allowed to continue to Period 2 for an additional 24 weeks of treatment.  Patients taking 
AED medications for treatment of seizures or epilepsy, will have an additional one or two week Taper 
Period unless they transition to receiving drug through Special Access.  Approximately 20 male and 
female patients, ages 4 to < 18 years, will receive ZYN002.  ZYN002, with a 4.2% concentration of 
CBD, will be administered as a transdermal gel according to the dosing schedule outlined in 
Section 7.4. 
Prior to any Screening procedures being performed, the parent/caregiver will provide written 
informed consent and, if applicable, the patient will provide assent.   
7.2. 
Number of Patients 
Approximately 20 male and female patients will be enrolled.  Patients who prematurely 
discontinue after Visit 2 will not be replaced. 
7.3. 
Dose Rationale 
Steady-state CBD concentrations were simulated, using a nonlinear mixed effects model 
(NONMEM, n=1000), for pediatric subjects by age group and by body weight.  Simulated 
exposures were compared, for each pediatric age group receiving ZYN002 at either 125 or 
250 mg CBD BID, to adults receiving ZYN002 250 mg CBD BID (a ZYN002 dose that has been 
demonstrated to be safe and well tolerated; Section 5.3), assuming dose proportionality.  The 
simulations suggest that dosing 125 mg CBD BID in subjects weighing ≤ 35 kg results in 
relatively similar mean AUCs (85-140%) compared to adults receiving 250 mg CBD BID and 
that dosing pediatric age groups weighing > 35 kg with 250 mg CBD BID also results in similar 
mean AUCs (96 to 123%) compared to adults. 
Therefore, a total daily dose of 250 or 500 mg CBD will be applied to patients that weigh ≤ 35 
kg and a total daily dose of 500 or 750 mg will be applied to patients that weigh > 35 kg. 
ZYN002 studies have been conducted in healthy subjects and patients using the CBD 4.2% 
concentration at similar daily dose levels as this study (250, 500 and 1000 mg/day).  ZYN002 
has shown to be safe and well tolerated in all studies (Refer to Section 5.3). 
 
 

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7.4. 
Treatment Assignment 
The last date of study treatment will be collected and recorded in the CRF.  This study has a 
14-week treatment period as follows: 
• Patients weighing ≤ 35 kg will receive 125 mg CBD applied Q12H (± 2 hours); total 
daily dose of 250 mg CBD. Each application will consist of one sachet of ZYN002 CBD 
4.2% concentration, containing 2.98 g of gel.  At Week 6, if the patient has less than a 
25% improvement from baseline in the ABC-C irritability sub-scale, the investigator may 
increase the dose as follows: 
o Patients weighing ≤ 35 kg receiving a total daily dose of 250 mg CBD may 
increase to a daily dose of 500 mg.  Each application will consist of two sachets 
of ZYN002 CBD 4.2% concentration, containing 2.98 g of gel. 
• Patients weighing > 35 kg will receive 250 mg CBD applied Q12H (±2 hours); for a total 
daily dose of 500 mg CBD.  Each application will consist of two sachets of ZYN002 
CBD 4.2% concentration, each sachet containing 2.98 g of gel.  At Week 6, if the patient 
has less than a 25% improvement from baseline in the ABC-C irritability sub-scale, the 
investigator may increase the dose as follows: 
o Patients weighing > 35 kg receiving a total daily dose of 500 mg CBD may 
increase the daily dose to 750 mg.  Each application will consist of three sachets 
of ZYN002 CBD 4.2% concentration, containing 2.98 g of gel. 
Should the weight of the patient change from visit to visit the dose may be adjusted, at the 
discretion of the investigator. 
7.5. 
Dose Adjustment Criteria 
Patients will receive their assigned dose of ZYN002 as described in Section 7.4.  Dose 
adjustments will be made for patients on AEDs for treatment of seizures or epilepsy, who will 
have a Taper Period at the end of the study, unless they are transitioning to receive drug through 
Special Access, if available (Section 7.8). 
Should the weight of the patient change from visit to visit the dose may be adjusted, at the 
discretion of the investigator. 
In addition, at Week 6 if the patient has less than a 25% improvement from baseline in the 
ABC-C irritability subscale, the investigator may increase the total daily dose. 
7.6. 
Study Assessments 
7.6.1. 
Screening Period  
During the Screening Period, the site staff will review the eligibility criteria, review any 
medications including OTC medications the patient is taking, obtain the patient’s medical history 
including their 22qDS diagnosis, confirm epilepsy diagnosis (if applicable), collect demographic 
details, obtain vital signs, perform an ECG, perform a physical and neurological exam, skin 
assessment, obtain blood for safety laboratory tests, and presence of ethanol collect urine for 
urinalysis and a drug screen, and administer assigned scales.  Blood samples will be taken for 

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hematology and chemistry testing, and pregnancy testing (females only, if applicable).  Patients 
will also have a blood sample drawn CBD/THC PK exposure and for valproic acid levels (for 
patients receiving valproate or valproic acid).  Refer to Table 4 for all Screening assessments.  
Note:  only one ECG to be collected prior to starting treatment (Screening or Visit 2), provided 
that the ECG is normal or has a finding that is not clinically significant.  The scales administered 
at Screening include: 
• Aberrant Behavior Checklist (ABC-C) 
• Autism Diagnostic Observation Schedule®-2 (ADOS®-2) (Note: is not administered at 
Screening if it has been administered in the prior 6 months and the results are available)  
• Clinical Global Impression-Severity (CGI-S) 
• Columbia-Suicide Severity Rating Scale – Children’s version (C-SSRS) 
• Anxiety, Depression and Mood Scale (ADAMS) 
• Qualitative Caregiver Reported Behavioral Problems Survey 
• Children’s Sleep Habit Questionnaire (CSHQ) 
• Pediatric Anxiety Rating Scale – Revised (PARS-R) 
In addition, an optional blood sample may be collected at the Screening Visit for analysis of the 
features of the 22qDS gene. 
7.6.1.1. 
14-Week and 24-Week Extension Open Label Treatment Period 
Following the Screening Period, eligible patients will receive ZYN002 on study Day 1 (Visit 2).  
There must be at least 7 days between Visit 1 (Screening) and Visit 2 (Day 1). 
Patients and parents/caregivers will be required to visit the clinic at Day 1/Visit 2, Week 6/Visit 
3, and Week 14/Visit 4 End of Study (EOS)/Early Termination (ET), for the collection of:  vital 
signs, ECG, concomitant medication review, physical and neurological exam, pregnancy tests, 
skin assessment examination (Day 1) and skin irritation examination (Visit 3 and 4), adverse AE 
review, and questionnaire’s and scale completion.  Blood samples for laboratory tests, 
CBD/THC PK exposure, and valproic acid (for patients taking valproate or valproic acid) levels 
will be collected at Week 6/Visit 3 Week 14/Visit 4, and Week 38/Visit 7 EOS/ET.   
In addition, there will be a follow-up telephone visit at Week 10 for patients who had their dose 
adjusted at Week 6.  Patients that complete Visit 4 and have made a ≥35% improvement on the 
ABC C irritability subscale will be allowed to continue to Period 2 for an addition 24 weeks of 
treatment.  Period 2 will have additional Visits at Week 22/Visit 5, Week 30/Visit 6, and Week 
38/Visit 7 EOS/ET.  Refer to the Schedule of Assessments (Table 5 and Table 6) for the 
activities to be completed at each study Visit. 
Note:  only one ECG to be collected prior to starting treatment (Screening or Visit 2), provided 
that ECG is normal or has a finding that is not clinically significant. 
At Visit 2, parents/caregivers will be instructed on proper application of the study drug 
(Section 20.1).  Patients will be permitted to shower or clean the arm area up to 30 minutes prior 
to the study dose.   
Parents/caregivers will use gloves supplied by the Sponsor to apply the study drug.  
Parents/caregivers will apply all study drug to clean, dry, intact skin, thoroughly massaging it 

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into the right and/or left upper arms and shoulders until the area is dry.  The study drug will be 
rubbed in completely and must be dry prior to dressing.   
Patients should keep the application site dry for six hours but may apply an approved 
moisturizing lotion (Cetaphil), provided by the Sponsor, two hours after dosing.  The application 
site should be covered to minimize sun exposure when going outside during the day.  If redness 
occurs at the application site, the parent (after consultation with the Investigator) may switch the 
application site temporarily to the upper thighs.  The following questionnaires and scales will be 
administered at Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, and Visit 7 EOS/ET:  
• ABC-C 
• CGI-S 
• Clinical Global Impression-Improvement (CGI-I) (not completed on Visit 2, Day 1) 
• ADAMS 
• C-SSRS 
• Qualitative Caregiver Reported Behavioral Problems Survey (not completed at Visit 2) 
• Children’s Sleep Habit Questionnaire (Visit 4 and Visit 7 EOS/ET only) 
• PARS-R 
Study procedures will be performed as summarized in the study schematic presented in Tables 4, 
5, and Table 6. 
 
 
 

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Table 5 Footnotes - Period 1: 
 
a. All patients will have a Week 14 Visit/ET.  All patients that do not qualify for Period 2 will have an End of Study Visit at Week 14.  AED 
patients will taper study drug for 1 or 2 weeks after the EOS Visit and return on Week 16 or 17 for final discharge from the study.   
b. For patients that do not qualify for Period 2, Week 14/Visit 4 EOS/ET patients will have both weight and height taken.  For patients taking 
AEDs and returning on Week 16 or 17 to be discharged from the study, a targeted physical examination (heart, lungs, abdomen and 
extremities) may be performed, if the investigator deems clinically relevant. 
c. Vital signs (including blood pressure, heart rate, respiratory rate, and infrared forehead or oral or tympanic temperature) will be recorded 
after the patient has been sitting for at least 5 minutes.  Vital signs will be assessed at each study visit pre-dose.   
d. One ECG to be collected prior to starting treatment (Screening or Visit 2), provided that ECG is normal or has a finding that is not clinically 
significant. 
e. A pregnancy test will be completed at Week 6, and Week 14/EOS/ET for all females of childbearing potential.  Pregnancy tests can be 
plasma or urine. 
f. Patients receiving valproate or valproic acid will have a blood sample drawn for plasma level of valproic acid.  Where possible, effort 
should be made to get a trough sample.  If not, the AED morning dose may be administered prior to the clinic visit.  The time of the prior 
dose of study drug and valproate/valproic acid, if applicable in addition to the time of each blood sample collection will be recorded.  During 
the Treatment Period valproic acid (for patients receiving valproate or valproic acid) blood samples will be taken at Week 6, and Week 14.   
g. On Day 1 the parent/caregiver will be instructed on how to complete the daily skin irritation diary.  Scoring of skin irritation will start the 
evening of Day 1 through discharge from the study by the parent/caregiver.  The site will evaluate the parent/caregiver applying the study 
treatment at each study visit and provide feedback/additional instruction as applicable. 
h. At Weeks 6, and 14 parents/caregivers will administer the dose in the clinic after they have their PK and valproic acid (for patients taking 
valproate/valproic acid) blood drawn.  At Week 14 patients who require a tapering period will be provided a 1 or 2-week supply of study 
treatment.  
i. 
A skin assessment examination will be completed by the Investigator at Day 1 pre-dose.  Shoulders and upper arms will be examined to 
determine there are no skin disease or condition, including eczema, psoriasis, melanoma, acne, contact dermatitis, scarring, imperfections, 
lesions, tattoos, or discoloration that may affect treatment application, application site assessments, or affect absorption of the study drug 
where study drug could be applied. 
j. 
Parents/caregivers will assess the application site daily and record all irritation scores in their daily skin irritation diary, starting with the PM 
dose on Day 1.  When irritation exists, efforts will be made to apply the gel to a non-irritated area of the upper arms/shoulders and/or right 
and left upper thighs.  Temporary application to the upper thighs can only be used after consultation with the investigator.  If the skin 
irritation score is greater than “2”, the patient will contact the Investigator to determine if an Unscheduled Visit is required.  
k. The investigator will perform a skin irritation examination pre-dose at study Visits 3, Visit 4/EOS/ET and Unscheduled Visits.  The 
parent/caregiver will also be asked about the patients skin irritation at the Week 10 Telephone Follow-up call. 
l. 
A Telephone Follow-Up with occur for those patients whose dose was increased at Week 6. 
 

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Table 6 Footnotes - Period 2: 
 
a. Patients who withdraw prior to Period 2 Week 38 will complete the EOS/ET at Week 38.  AED patients will taper study drug for 1 or 2 
weeks after the EOS Visit and return on Week 40 or 41 for final discharge from the study, unless they are transitioning to receive drug 
through Special Access.   
b. Patients will have both weight and height taken at EOS/ET.  For patients taking AEDs and returning on Week 40 or 41 to be discharged 
from the study, a targeted physical examination (heart, lungs, abdomen and extremities) may be performed, if the investigator deems 
clinically relevant. 
c. Vital signs (including blood pressure, heart rate, respiratory rate, and infrared forehead or oral or tympanic temperature) will be recorded 
after the patient has been sitting for at least 5 minutes.  Vital signs will be assessed at each study visit pre-dose.   
d. A pregnancy test will be completed at Week 38/EOS/ET for all females of childbearing potential.  Pregnancy tests can be plasma or urine. 
e. Patients will have a blood sample drawn for plasma level of valproic acid (for patients taking valproate or valproic acid) at Week 38/Visit 7.  
Where possible, effort should be made to get a trough sample for the valproic acid (for patients receiving valproate/valproic acid).  If not, 
the AED morning dose may be administered prior to the clinic visit.  The time of the prior dose of study drug and valproic acid (if 
applicable) in addition to the time of each blood sample collection will be recorded.   
f. Scoring of skin irritation will start the evening of Day 1 through discharge from the study by the parent/caregiver.  The site will evaluate the 
parent/caregiver applying the study treatment at each study visit and provide feedback/additional instruction as applicable. 
g. At Week 38, parents/caregivers will administer the dose in the clinic after they have their PK and valproic acid (for patients taking valproate 
or valproic acid) blood drawn.  At Week 38 patients who require a tapering period will be provided a 1 or 2-week supply of study treatment.  
h. Parents/caregivers will assess the application site daily and record all irritation scores in their daily skin irritation diary, starting with the PM 
dose on Day 1.  When irritation exists, efforts will be made to apply the gel to a non-irritated area of the upper arms/shoulders and/or right 
and left upper thighs.  Temporary application to the upper thighs can only be used after consultation with the investigator.  If the skin 
irritation score is greater than “2”, the patient will contact the Investigator to determine if an Unscheduled Visit is required.  
i. 
The investigator will perform a skin irritation examination pre-dose at study Visit 7 EOS/ET and Unscheduled Visits.  Weeks 5 and 6 the 
patient can receive their morning dose at home.

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7.6.2. 
Informed Consent 
Signed informed consent will be obtained at Screening from parent/caregivers and if applicable 
assent will be obtained from patients where developmentally appropriate.  The informed consent 
form (ICF) will be signed by the parent/caregiver and the assent by the patient (if applicable) 
before any study procedures are undertaken.  Details about how the ICF will be obtained and 
documented are provided in Section 17.3. 
7.6.3. 
22q.11.2 Deletion Syndrome Diagnosis 
Patients participating in this study will have a diagnosis of 22q.11.2 (also referred to as 22qDS) 
confirmed by genetic testing, with or without autistic features.  
7.6.4. 
Demographics 
At the Screening Visit, patient demographic information will be collected and recorded in the 
CRF. 
7.6.5. 
Vital Signs 
Vital sign determinations include sitting blood pressure, heart rate, respiratory rate, and infrared 
forehead, or oral or tympanic body temperature will be recorded.  Vital signs will be recorded 
after the patient has been sitting for at least 5 minutes. Vital signs will be assessed pre-dose at all 
study visits. 
7.6.6. 
Medical History  
A complete medical history for the previous 5 years will be obtained from each patient during 
the Screening Visit.   
7.6.7. 
Concomitant Medication Review 
Medication (prescription and OTC) use will be recorded at the Screening Visit and updated at 
Day 1 (prior to dosing).  A review of patient concomitant medication will be performed at each 
study visit, Unscheduled Visits, the Week 10 Telephone Follow-up call, and at the End of Study 
Visit. 
7.6.8. 
Review Adverse Events 
A review of AEs will be performed at Screening, and each study visit, the Week 10 Telephone 
Follow-up call, and any Unscheduled Visits.  Detailed information regarding AEs can be found 
in Section 11.2. 
7.6.9. 
Complete Physical/Neurological Examinations 
A complete physical and neurological examination, including height and weight will be 
performed at Screening and Visit 4/Week14 and Visit 7/Week 38 EOS/ET.  Only patient weight 
will be collected at Visit 4 and Visit 7 EOS/ET.  Patient weight will be collected with minimal 
clothing (e.g., no coats, shoes, jumpers or jackets). 

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A complete physical and neurological examination will be performed at Day 1, Week 6 and 
Week 38/EOS/ET. 
7.6.10. 
Targeted Physical Examination 
For patients taking AEDs and returning on Week 40 or 41 to be discharged from the study, a 
targeted physical examination (heart, lungs, abdomen and extremities) may be performed, if the 
investigator deems clinically relevant. 
7.6.11. 
Electrocardiogram 
A 12-lead resting ECG will be obtained during the Screening Visit, and at study Visits 2, 3, 4, 
and 7/EOS/ET Visits.  As applicable, ECGs will be conducted pre-dose, within 60 minutes of 
study drug application.  All ECGs will be reviewed by a central reader (Cardiologist).  The 
cardiologist will interpret, sign, and date the ECGs.  Clinical interpretations will be recorded in 
the CRF (normal or abnormal with specific abnormality noted). 
Note:  one ECG to be collected prior to starting treatment (Screening or Visit 2), provided that 
ECG is normal or has a finding that is not clinically significant. 
7.6.12. 
Investigator Skin Assessment Examination 
At the Screening Visit and Day 1 (prior to dosing), the upper arms/shoulders will be examined to 
determine there is no skin disease or condition, including eczema, psoriasis, melanoma, acne, 
contact dermatitis, scarring, imperfections, lesions, tattoos, or discoloration that may affect 
treatment application, application site assessments, or affect absorption of the study drug where 
study drug will be applied. 
7.6.13. 
Investigator Skin Irritation Examination 
The investigator will conduct a skin irritation examination pre-dose of the application site(s) at 
Week 6, Week 14, and Week 38 EOS/ET, and Unscheduled Visits.  In addition, 
parents/caregivers will be asked about skin irritation at the Week 10 Telephone Follow-up call.  
When excessive skin redness is noted, efforts will be made to temporarily apply the gel to a non-
red area of the upper arms/shoulders and/or right/left thighs at the approval of the investigator.  
The investigator will use discretion in suspending dosing for patients with a skin redness score of 
‘4’ (intense erythema) but will in all score of ‘4’ cases immediately (within 24 hours) complete 
an adverse event report and contact their study CRA and the Sponsor Medical Monitor.   
Application of ZYN002 to the right or left thigh should be viewed as a temporary alternate 
application site only until the redness on the upper arms/shoulders is reduced. 
Patients having a skin irritation score > ‘0’at Week 38 will continue to be followed through 
Unscheduled Visits until the skin irritation score is recorded as ‘0’ (no erythema).  At this time, 
the patient will be discharged from the study. 
Refer to Table 7 for the Skin Irritation Scale to be used for skin redness examinations. 

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Table 7: 
Skin Irritation Scale 
Score 
Definition 
0 
No erythema 
1 
Minimal erythema 
2 
Moderate erythema with sharply defined borders 
3 
Intense erythema with or without edema 
4 
Intense erythema with edema and blistering/erosion 
A de-identified picture of an application site may be taken at the discretion of the Principal 
Investigator.  
Should the patient experience dry skin at the application sites, moisturizing lotion (Cetaphil) 
which will be supplied by the Sponsor, may be applied two hours post gel application. 
7.6.14. 
Patient Skin Irritation Diary  
Parents/caregivers will be instructed on completion of the daily skin irritation diary at Day 1 
(Section 20.2).  Parent/caregiver scoring of skin irritation will start the evening of Day 1 (PM 
application) and will continue daily through discharge of the study.  Before each evening dose, 
parents/caregivers will record the skin score in their daily skin irritation diary.  When skin 
redness is noted, patients should apply the gel to a non-red area of the upper arms/shoulders 
and/or right and left thighs.  If the skin irritation score is higher than ‘2’ (moderate erythema) the 
parent/caregiver will contact the study site to determine if an Unscheduled Visit is required.  
Application of ZYN002 to the right or left thigh should be viewed as a temporary alternate 
application site only until the redness on the upper arms/shoulders is reduced. 
The investigator will use discretion in suspending dosing for patients with skin check score of 
‘4’ but will in all cases of a score of ‘4’ immediately (within 24 hours) complete an adverse 
event report and contact their study CRA and the Sponsor Medical Monitor.  
The patient’s skin check diary will be reviewed by the investigator at Week 6, Week 14, and 
Week 38 EOS/ET Visit, and Unscheduled Visits. 
7.6.15. 
Clinical Laboratory Testing 
All blood samples will be collected and handled in accordance with the instructions from the 
local laboratory.  For collection of laboratory samples, patients should fast for approximately 
four to eight hours prior to having blood drawn for blood laboratory analysis.  Instructions 
regarding the collection, processing, and shipping of these samples will be provided by the 
laboratory chosen for this study. 
All abnormal laboratory test results will be followed to a satisfactory resolution.   
Samples will be collected based on Table 4, Table 5 and Table 6 Schedule of Assessments.  
Routine laboratory tests (clinical chemistry, hematology, and urinalysis) will be collected at the 
Screening Visit, Week 6, Week 14, and Week 38 EOS/ET Visits.   

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7.6.15.1. Screening (Days -28 to -8) Laboratory Tests 
• 
Routine blood chemistry tests will include:  glucose, total bilirubin, serum glutamic 
oxaloacetic transaminase/aspartate transaminase (SGOT/AST), serum glutamic 
pyruvic transaminase/alanine transaminase (SGPT/ALT), alkaline phosphatase, blood 
urea nitrogen, creatinine, amylase, total protein, uric acid, sodium, chloride, 
bicarbonate, potassium, calcium, phosphorous, albumin, triglycerides, cholesterol: 
low density lipoprotein (LDL) and high density lipoprotein (HDL).   
• 
Routine hematology tests will include:  white blood cell (WBC) with differential 
count, red blood cell (RBC), hematocrit, hemoglobin, and platelet count. 
• 
Hepatitis B (HBsAg), hepatitis C (HCV-Ab) serology and human immunodeficiency 
virus (HIV) type 1 and 2. 
• 
Urine drug screen for sympathomimetic amines (amphetamines; benzodiazepines; 
buprenorphine; cannabinoids; methadone; cocaine (metabolites); opiates (except 
barbiturates for AED medication). 
• 
Blood test for the presence of ethanol. 
• 
Urine specimens will be tested for routine urinalysis (specific gravity, pH, protein, 
glucose, ketones, bilirubin, blood, leukocyte esterase and nitrite) and microscopic 
analysis if indicated.   
• 
Pregnancy test, females only (plasma or urine). 
• 
Optional:  DNA sample for genomic screening. 
7.6.15.2. Week 6, Week 14, and Week 38 (±3 days) Laboratory Tests 
• 
Routine blood chemistry tests will include:  glucose, total bilirubin, SGOT/AST, 
SGPT/ALT, alkaline phosphatase, blood urea nitrogen, creatinine, amylase, total 
protein, uric acid, sodium, chloride, bicarbonate, potassium, calcium, phosphorous, 
albumin, triglycerides, cholesterol: LDL and HDL.   
• 
Routine hematology tests will include:  WBC with differential count, RBC, 
hematocrit, hemoglobin, and platelet count. 
• 
Urine specimens will be tested for routine urinalysis (specific gravity, pH, protein, 
glucose, ketones, bilirubin, blood, leukocyte esterase and nitrite) and microscopic 
analysis if indicated. 
• 
Pregnancy test, females only (plasma or urine). 
7.6.15.3. End of Study Visit or Early Termination  
• 
Each patient will have an End of Study Visit/ET completed at Week 38.  The clinical 
laboratory testing will include the following: 
• 
Routine blood chemistry tests will include:  glucose, total bilirubin, SGOT/AST, 
SGPT/ALT, alkaline phosphatase, blood urea nitrogen, creatinine, amylase, total 
protein, uric acid, sodium, chloride, bicarbonate, potassium, calcium, phosphorous, 
albumin, triglycerides, cholesterol: LDL and HDL.   

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• 
Routine hematology tests will include:  WBC with differential count, RBC, 
hematocrit, hemoglobin, and platelet count. 
• 
Urine specimens will be tested for routine urinalysis (specific gravity, pH, protein, 
glucose, ketones, bilirubin, blood, leukocyte esterase, and nitrite) and microscopic 
analysis if indicated. 
• 
Pregnancy test, females only (plasma or urine). 
7.6.16. 
Unscheduled Visits 
If the skin irritation score is >‘0’ at Week 38, and weeks 40 or 41 for patients taking AED 
medications, the patient will have Unscheduled Visit(s) until the skin irritation score is rated as 
‘0’ (no erythema).  The following assessments will be completed at the Unscheduled Visit: 
• Concomitant medication review 
• Vital signs 
• C-SSRS 
• Site review of patient Skin Irritation Diary 
• Skin irritation examination 
• Adverse event review 
7.6.17. 
Hepatitis/HIV Screen 
At the Screening Visit patients will be screened for HBsAg, HCV-Ab serology and HIV type 1 
and type 2. 
7.6.18. 
Pregnancy Test  
Pregnancy tests will be collected at Screening, Week 6, and Week 14/EOS/ET Visits for female 
patients of child bearing potential.  Any patient that is pregnant will be excluded or discontinued 
from the study, as applicable.  Pregnancy test can be plasma or urine. 
7.6.19. 
Toxicology Screen 
Urine drug screen for sympathomimetic amines (amphetamines; benzodiazepines; 
buprenorphine; cannabinoids; methadone; cocaine (metabolites); and opiates (except barbiturates 
for AED medication) will be done at Screening.  In addition, a blood test for the presence of 
ethanol will be done at Screening.  A positive toxicology screen will result in excluding the 
patient from the study. 
7.6.20. 
Blood Samples for Valproic Acid 
At Screening, Week 6, Week 14, and Week 38 EOS/ET Visits, patients will have blood drawn 
for plasma level of their valproic acid (for patients receiving valproate or valproic acid).   
All effort should be made to obtain a trough sample for the valproate/valproic acid.  AED name, 
time taken, and amount and date of the last dose will be captured before the blood samples are 
collected.  At each monthly visit, the Investigator will review the valproic acid (for patients 
receiving valproate or valproic acid) level and the dose of concomitant AEDs in the event they 
require adjusting if the patient experiences AEs that warrant a dose change. 

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7.6.21. 
Blood Sample for CBD/THC PK 
At the Screening Visit, Week 6/Visit 3 and Week 14/Visit 4, and Week 38/Visit 7 EOS/ET, 
blood will be drawn for a trough plasma level for the determination of CBD/THC.  All PK blood 
samples will be collected pre-dose.   
7.6.22. 
Telephone Follow-up at Week 10 
There will be a Telephone Follow-up call at Week 10 only for patients who had their dose 
adjusted at Week 6.  The purpose of the call is to confirm the patient is tolerating the increased 
dose.  Concomitant medications and adverse events will be reviewed at the Telephone Follow-up 
call, along with enquiring about patient skin irritation. 
7.7. 
Study Questionnaires and Scales 
7.7.1. 
Assessments of 22qDS Symptomatology 
The same site rater should be used for all clinician-reported assessments across all visits.  The 
same parent/caregiver should be used for all parent/caregiver-reported assessments across all 
visits. 
7.7.2. 
Aberrant Behavior Checklist-Community (ABC-C)  
The Aberrant Behavior Checklist- Community, 2nd Edition, will be completed by the 
parent/caregiver, with support from the site staff, at Screening, Visit 2, Visit 3, Visit 4, Visit 5, 
Visit 6, and Visit 7 EOS/ET.  The ABC-C asks responders to rate behaviors from “0 - not at all a 
problem” to “3 - the problem is severe in degree” across 58 questions.  Use of the checklist has 
been validated in a variety of clinical populations.   
7.7.3. 
Autism Diagnostic Observation Schedule® (ADOS®-2) 
The ADOS (Western Psychological Services) is a semi-structured assessment of communication, 
social interaction and play or imaginative use of materials for individuals suspected of having 
22qDS or other pervasive developmental disorders from 12 months through adulthood (Lord et 
al. 2000).  The ADOS®-2 consists of various activities to allow the observation of social and 
communication behaviors related to the diagnosis of pervasive developmental disorders.  The 
ADOS®-2 includes five modules for use with different age groups and language level.  In this 
version, a Toddler Module has been included.  For this patient population, the appropriate 
module will be utilized based on age and language level.  Each subject will be administered one 
module.  The assessment is administered by a certified rater and requires 35 to 40 minutes to 
complete.  The ADOS®-2 is a diagnostic tool and this information will be used to document the 
presence of autism or other pervasive developmental disorders.  This assessment will only be 
administered at sites with qualified individuals based on the publisher’s criteria.  The ADOS®-2 
will be completed at Screening. 
 
 

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7.7.4. 
Clinical Global Impressions Scale-Severity and Improvement  
The Clinical Global Impression Scales, Severity (CGI-S) and Improvement (CGI-I), are 
commonly used in clinical trials (Leigh et al. 2013) as they allow the clinician to utilize the 
history from the caregiver and incorporate the score into a clinical rating for the severity of 
symptoms.   
CGI-S is a 7-point scale that requires the clinician to rate the severity of the patient's illness at 
the time of assessment, relative to the clinician's past experience with patients who have the 
same diagnosis.  Considering total clinical experience, a patient is assessed on severity of mental 
illness at the time of rating 1 - normal, not at all ill; 2 - borderline mentally ill; 3 - mildly ill; 4 - 
moderately ill; 5 - markedly ill; 6 - severely ill; or 7 - extremely ill.  CGI-S will be assessed at 
Screening, Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, and Visit 7 EOS/ET to judge the severity of 
the symptoms of 22qDS at the onset of and throughout the study.   
CGI-I is a 7-point scale that requires the clinician to assess how much the patient's illness has 
improved or worsened relative to a Baseline state at the beginning of the intervention and rated 
as: 1 - very much improved; 2 - much improved; 3 - minimally improved; 4 - no change; 5 - 
minimally worse; 6 - much worse; or 7 - very much worse.  Information from both the clinician 
and the parent/caregiver history are incorporated into a clinical rating.  CGI-I will be assessed at 
Visit 3 and Visit 4/EOS/ET.   
7.7.5. 
Columbia Suicide Severity Rating Scale (Children’s Version) 
The C-SSRS (Children’s version) is to be completed at Screening, all study visits including 
Unscheduled Visits.  The C-SSRS assessment will be conducted only if the patients are of an 
appropriate age (6 years or older) and capable of understanding and answering the questions in 
the Investigator’s opinion.  For patients under the age of 6 or who are not capable of 
understanding and answering the questions in the Investigator’s opinion, the Investigator will 
consider the trend in ABC-C Irritability when assessing the risk of self-harm for an individual 
patient.   
Any patient who responds Yes to Questions ‘4’ or ‘5’ on the C-SSRS will be discontinued from 
the study and the Investigator will determine if further evaluation is required.  Note that any 
completed suicide or suicidal attempt will be collected as an SAE. 
7.7.6. 
Anxiety, Depression, and Mood Scale (ADAMS)  
The Anxiety, Depression, and Mood Scale will be completed by the parent/caregiver, with 
support from the site staff, at Screening, Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, and Visit 7 
EOS/ET.  The ADAMS will be used as a comprehensive assessment of anxiety, depression, and 
mood among the FXS patients.  The ADAMS is comprised of 28 items, which are rated on a 
scale of “0 - not a problem” to “3 - severe problem.”  The ADAMS yields a total score as well as 
five subscale scores:  “Manic/Hyperactive Behavior,” “Depressed Mood,” “Social Avoidance,” 
“General Anxiety,” and “Compulsive Behavior.”  The ADAMS has been validated and has 
demonstrated good internal consistency and test-retest reliability.  Interrater reliability has been 
shown to be satisfactory (Esbensen et al. 2003). 

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7.7.7. 
Qualitative Caregiver Behavioral Problems Survey 
At the Screening Visit, the parent/caregiver will be asked the following question “What are the 
three behavioral, emotional, or social problems that most impacted your son/daughter and his/her 
family in approximately the past year?”  At Visit 3, Visit 4, Visit 5, Visit 6, and Visit 7 EOS/ET 
the parent/caregiver will be reminded of their responses at the Screening Visit in order to rate the 
three questions for improvement or worsening. 
7.7.8. 
Children’s Sleep Habit Questionnaire (CSHQ) 
The Children’s Sleep Habit Questionnaire will be completed by the parent/caregiver at Screening 
Visit 4, and Visit 7 EOS/ET.  The parent/caregiver will complete a questionnaire comprised of 
33 questions about their child’s sleep habits and possible difficulties with sleep.  They will be 
asked to think about the past week in your child’s life when answering the questions.  If last 
week was unusual for a specific reason (such as their child had an ear infection and did not sleep 
well or the TV set was broken), they will choose the most recent typical week.  They will: 
• Answer USUALLY if something occurs 5 or more times in a week. 
• Answer SOMETIMES if it occurs 2-4 times in a week. 
• Answer RARELY if something occurs never or 1 time during a week.   
 
Parent/caregiver will also indicate whether or not the sleep habit is a problem by circling “Yes”, 
“No,” or “not applicable (N/A)”. 
7.7.9. 
Pediatric Anxiety Rating Scale – Revised (PARS-R) 
The PARS-R will be completed at Screening, Weeks 14, 22, 30, and Week 38.  The patient must 
have a severity score of 10 or higher at Screening and Visit 2 in order to be eligible for 
participation. 
The PARS-R is a clinician-rated caregiver interview that covers 61 behaviors related to anxiety 
(Riddle, Ginsburg, Palapattu, &Walkup 2004, Riddle et al. 2002).  The PARS-R provides broad 
coverage of separation anxiety, social phobia, and generalized anxiety.  Symptoms are further 
categorized into Social Interactions or Performance Situations, Separation, Generalized, Specific 
Phobia, Panic Symptoms/Physical Signs, Obsessive-Compulsive, Health/Illness Concerns, and 
Other.  The interviewer assesses the severity by quantifying the frequency and degree of 
interference and avoidance in family, school and community settings.  Each of seven severity 
items is scored on a scale of 1 to 5, with 5 being the most severe and frequent.  The final score is 
the sum of five of the seven severity items.  The five item scale is recommended for use during 
treatment studies (Riddle et al. 2004, Riddle et al. 2002).  Studies show excellent inter-rater 
reliability (even across sites kappa .87-.90) and test retest reliability after 3 to 8 weeks in 49 
individuals with FXS ages 5 to 35 years of age (Russo- Ponsaran et al. 2014 AJIDD).  The 
PARS-R correlates well with other anxiety measures (Russo-Ponsaran et al. 2014) and has been 
used in clinical trials in individuals with Autism Spectrum Disorder ASD (Storch et al. 2014) and 
is currently being utilized in several trials in FXS.   

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7.8. 
End of Study / Early Termination Visit  
All patients will complete the EOS/ET Visit assessments at Week 38.  Patients not taking AEDs 
will only have a morning dose of study drug at the Week 38 Visit before discharge from the 
study.  The following will be completed at the EOS/ET Visit: 
• Laboratory and urinalysis tests as defined in Section 7.6.15.3. 
• Concomitant medication review 
• Physical/neurological examination 
• Vital signs 
• 12-lead ECG 
• Pregnancy test (females only) 
• Collection and site review of patient Daily Skin Irritation Diary (diary for AED patients 
will also be collected Week 16 or 17) 
• CBD/THC plasma sample drawn 
• Valproic acid plasma sample drawn (for patients taking valproate or valproic acid)  
• Skin irritation examination 
• Adverse event review 
• Completion of patient questionnaires and scales – refer to Table 5 and Table 6 in 
Section 7.7  
• Study drug will be applied (last dose for patients not taking AED medication, not 
applicable to ET patients) 
Patients not on AEDs who are prematurely discontinued will complete the early termination 
procedures at Visit 7 EOS/ET.  
Patients taking valproate or valproic acid for treatment of seizures or epilepsy including patients 
who prematurely discontinue, will taper their current study dose in the following manner 
beginning at Visit 7 EOS/ET.  Should patients taking AEDs at the EOS continue to receive drug 
through Special Access (if available) they will not taper their dose. 
• Participants who weigh 35 kg or less and were receiving 250 mg daily dose of 
ZYN002, will be reduced to 125 mg daily dose over one week.  Only one sachet will 
be applied each day around the same time in the evening.  After the taper, the 
participants will discontinue from the study at Week 40.   
o If the participant’s dose was increased at Week 6 to 500 mg daily dose of 
ZYN002, the dose will be reduced to 250 mg daily dose over one week with 2 
sachets applied each day around the same time in the evening.  After the taper, 
the participants will discontinue from the study at Week 40.   
• Participants who weigh 35 kg or more and were receiving 500 mg daily dose of 
ZYN002, will be reduced over two weeks.  During the first week the dose will be 
reduced to 125 mg two times a day (applied 12 hours apart) which will make the total 
daily dose 250 mg.  This is one sachet in the morning and one sachet in the evening.  
During the second week, the dose will decrease to 125 mg daily dose, which means 
one sachet each day for a week applied each day around the same time in the evening.  
After the taper, the participants will discontinue from the study at Week 41.   

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o If the participant’s dose was increased at Week 6 to 750 mg daily dose of 
ZYN002, the dose will be reduced to 375 mg daily dose during the first week 
with one sachet applied in the morning and 2 sachets applied every evening.  
During the second week, the dose will decrease to 250 mg daily dose, which 
means 2 sachets each day for a week applied each day around the same time 
in the evening.  After the taper, the participants will discontinue from the 
study at Week 41. 
• Patients tapering their dose will have all Visit 7 EOS/ET assessments completed. 
• At Week 38, patients will have their original dose in the morning and will have their 
evening dose as their new tapered dose. 
• Patients will return at Week 40 or 41 and have the following assessments completed: 
o Concomitant medication review 
o Vital signs 
o Targeted physical exam if investigator deems clinically relevant 
o Pregnancy test (females only) 
o C-SSRS administered 
o Collection and review of Skin Irritation Diary 
o Skin irritation examination 
o Adverse event review 
Patients having a skin irritation score > ‘0’ at Week38 will continue to be followed through 
Unscheduled Visits until the skin irritation score is recorded as ‘0’ (no erythema). 
 

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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
Patients must qualify based on meeting all of the inclusion and none of the exclusion criteria to be 
eligible to enroll. 
1. Male or female children and adolescents aged 4 to < 18 years, at the time of Screening. 
2. Judged by the Investigator to be in generally good health at Screening based upon the 
results of a medical history, physical examination, and clinical laboratory test results.  
Laboratory results outside of the reference range must be documented as not clinically 
significant by the Investigator.   
3. Patients must have a diagnosis of 22qDS confirmed by genetic testing, with or without 
autistic features. 
4. Patients have a CGI-S score of 4 or higher at Screening and Visit 2. 
5. Patients must have a severity score on the PARS-R of 10 or higher at Screening and Visit 
2. 
6. Patients with a history of seizure disorders must currently be receiving treatment with a 
stable regimen of one or two AEDs, or must be seizure-free for one year if not currently 
receiving AEDs. 
7. If patients are receiving non-pharmacological behavioral and/or dietary interventions, 
they must be stable for three months prior to Screening. 
8. Patients have a body mass index between 12–35 kg / m2 (inclusive). 
9. Patient has demonstrated stable calcium levels for one year prior to Screening. 
10. Females of childbearing potential must have a negative pregnancy test at the Screening 
Visit and a negative pregnancy test at all designated study visits. 
11. Patients and parents/caregivers agree to abide by all study restrictions and comply with 
all study procedures. 
12. Patients and parents/caregivers must be adequately informed of the nature and risks of the 
study and give written informed consent (and assent if applicable) prior to Screening. 
13. Parents/caregiver(s) must provide written consent to assist in study drug administration. 
14. In the Investigator’s opinion, patients and parents/caregivers are reliable and willing and able to 
comply with all protocol requirements and procedures. 
 
 

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8.2. 
Patient Exclusion Criteria 
Any of the following is considered criterion for exclusion: 
1. Females who are pregnant, nursing, or planning a pregnancy; females of childbearing 
potential and male patients with a partner of childbearing potential who are unwilling or 
unable to use an acceptable method of contraception as outlined below for the duration of 
therapy and for three months after the last dose of study medication. 
a. Standard acceptable methods of contraception include abstinence or the use of a 
highly effective method of contraception, including hormonal contraception, 
diaphragm, cervical cap, vaginal sponge, condom, vasectomy, or intrauterine 
device. 
2. History of significant allergic condition, significant drug-related hypersensitivity, or 
allergic reaction to any compound or chemical class related to ZYN002 or its excipients. 
3. Exposure to any investigational drug or device ≤ 30 days prior to Screening or at any 
time during the study. 
4. Patient has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin levels ≥ 2 times the upper limit of normal (ULN) or has alkaline phosphatase 
levels ≥ 3 times the ULN as determined from Screening safety laboratories. 
5. Use of cannabis or any THC or CBD-containing product within three months of 
Screening Visit or during the study. 
6. Patient has a positive drug screen for sympathomimetic amines (amphetamines (unless 
prescribed); benzodiazepines; buprenorphine; cannabinoids; methadone; cocaine 
(metabolites); and opiates; (excludes barbiturates used as AED medication), including 
ethanol. 
7. Patient is using the following AEDs:  clobazam, phenobarbital, ethosuximide, felbamate, 
carbamazepine, phenytoin, or vigabatrin. 
8. Patient is using any strong inhibitor/inducer of CYP3A4 or sensitive substrate for 
CYP3A4 including but not limited to the following medications: midazolam, oral 
ketoconazole, fluconazole, nefazadone, rifampin, alfentanil, alfuzosin, amiodarone, 
cyclosporine, dasatinib, docetaxol, eplerenone, ergotamine, everolimus, fentanyl, 
halofantrine, irinotecan, lapatinib, levomethadyl, lumefantrine, nilotinib, pimozide, 
quinidine, ranolazine, sirolimus, tacrolimus, temsirolimus, toremifene, tretinioin, 
vincristine, vinorelbine, St. John’s Wort, and grapefruit juice/products. 
9. Patient with diagnosis of known genetic disorder, other than 22qDS (i.e. Prader-Willi 
Syndrome, Angelman Syndrome, Fragile X Syndrome, Rett Syndrome etc.). 
10. Patient has diagnosis of DiGeorge or Velocardiofacial syndrome without the presence of 
22qDS. 
11. Patient has a primary psychiatric diagnosis other than 22qDS or anxiety, including 
bipolar disorder, psychosis, schizophrenia, post-traumatic stress disorder (PTSD) or 
major depressive disorder.  
12. Patient is on stable treatment of > 6 months of not more than two psychoactive 
medications at screening or throughout the study (with the exception of one psychoactive 
medication prescribed for sleep).  
13. Patient has an advanced, severe, or unstable disease that may interfere with the study 
outcome evaluations. 
14. Patient is expected to initiate or change pharmacologic or non-pharmacologic 

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interventions during the course of the study. 
15. Patient has an acute or progressive neurological disease, or any psychiatric disorder or 
severe mental abnormalities that are likely to require changes in drug therapy or interfere 
with the objectives of the study or ability to adhere to protocol requirements. 
16. Patient has a positive result for the presence of HBsAg, HCV, or HIV antibodies. 
17. Patients at risk of needing cardiovascular surgical repair within the upcoming12 months. 
18. Patient has unstable cardiovascular disease, such as advanced arteriosclerosis, 
cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, cardiac 
conduction problems, exercise-related cardiac events including syncope and pre-syncope, 
risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history 
of Long QT Syndrome), other serious or other clinically unstable cardiac problems as 
indicated by history, physical examination or ECG. 
19. Any clinically significant condition or abnormal findings at the Screening Visit that 
would, in the opinion of the Investigator, preclude study participation or interfere with 
the evaluation of the study medication. 
20. Any skin disease or condition, including eczema, psoriasis, melanoma, acne, contact 
dermatitis, scarring, imperfections, lesions, tattoos, or discoloration, that may affect 
treatment application, application site assessments, or absorption of the study drug. 
21. History of treatment for, or evidence of, drug abuse within the past year. 
22. Patient responds “yes” to Question ‘4’ or ‘5’ on the C-SSRS (Children) during Screening 
or at any time on study. 
8.3. 
Randomization Criteria 
Not applicable as this is a single-arm study. 
8.4. 
Patient Withdrawal Criteria 
Each patient has the right to withdraw from the study at any time without prejudice.  If a patient 
withdraws from the study after receiving study drug, the reason(s) must be stated on the CRF, 
and a final evaluation of the patient should be performed. 
The Investigator and/or Sponsor may discontinue any patient’s participation for any reason 
including (not all inclusive): any adverse event, clinically significant worsening in seizure 
frequency, adverse change in any laboratory test, or failure to comply with the protocol.  
Laboratory samples for a post-study laboratory profile and follow-up safety exams should be 
obtained as soon after patient discontinuation as possible. 
Patients who withdraw from the study will not be replaced.  All effort must be made to ensure 
that the End of Study/Early Termination Visit procedures are completed at the time of 
discontinuation. 

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9. 
TREATMENT OF PATIENTS 
9.1. 
Description of Study Drug 
ZYN002 is pharmaceutically manufactured CBD in a clear permeation-enhanced gel 
formulation.  The drug product will be supplied as a 4.2% w/w gel contained in a foil-lined 
sachet.  Each sachet is nominally filled to dispense 2.98 g of gel.  The gel will be applied to 
clean, dry, intact skin of the upper arms/shoulders and can temporarily be applied to the right and 
left thighs.  The study drug treatment dosing volumes are as follows: 
• Patients ≤ 35 kg will receive 125 or 250 mg CBD applied Q12H (± 2 hours); total daily 
dose of 250 or 500 mg CBD.  Each application will consist of one sachet or two sachets 
of ZYN002 CBD 4.2% concentration, containing 2.98 g of gel.  Dosing is up to 38 
weeks. 
• Patients >35 kg will receive 250 or 375 mg CBD applied Q12H (±2 hours); total daily 
dose of 500 or 750 mg CBD.  Each application will consist of two or three sachets of 
ZYN002 CBD 4.2% concentration, each sachet containing 2.98 g of gel.  Dosing is up to 
38 weeks. 
The last date of study drug treatment will be collected and recorded in the CRF. 
9.2. 
Concomitant Medications 
Because CYP3A4 and CYP2C19 are the major isoforms responsible for CBD metabolism, 
concomitant administration of drugs that inhibit these enzymes may result in higher exposure to 
CBD and drugs that induce these enzymes may result in lower exposure to CBD; therefore, 
strong inhibitors or inducers of CYP3A4 may increase or decrease the plasma concentrations of 
CBD and should be administered with caution. 
As a potential perpetrator, CBD would not cause a clinically significant induction of CYP 
isoenzymes.  However, CBD exhibited time-dependent inhibition of CYP2D6 and CYP1A2, 
which was reversible, and of CYP3A4, which was irreversible.  Sensitive CYP3A4 substrates 
with a narrow therapeutic index or risk for severe toxicity should be avoided until this risk has 
been assessed with ZYN002.  CBD did not inhibit human efflux and uptake transporters.  
Refer to the following site for examples of strong inhibitors/inducers of CYP 3A4 and CYP 3A4 
substrates with narrow therapeutic indexes:  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm 
9.2.1. 
Concomitant Medications Allowed 
Patients may take hormonal contraception and AEDs (not in the exclusion criteria) during study 
participation.   
Patients on a stable treatment of >6 months are allowed two psychoactive medications at 
screening or throughout the study. 
 
 

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For the purposes of the protocol, the following sedative medications, when used as a single, 
bedtime dose – need not be considered one of the two allowed psychotropic medications: 
• 
Clonidine 
• 
Guanfacine 
• 
Melatonin 
• 
Diphenhydramine or other sedating antihistamine medications 
9.2.2. 
Concomitant Medications Not Allowed 
Other prescription or OTC medications may be taken as approved in advance by the investigator 
and recorded in the CRF.   
The following medications are not allowed: any strong inhibitor/inducer of CYP3A4 or sensitive 
substrate for CYP3A4 including but not limited to the following medications: midazolam, oral 
ketoconazole, fluconazole, nefazadone, rifampin, alfentanil, alfuzosin, amiodarone, cyclosporine, 
dasatinib, docetaxol, eplerenone, ergotamine, everolimus, fentanyl, halofantrine, irinotecan, 
lapatinib, levomethadyl, lumefantrine, nilotinib, pimozide, quinidine, ranolazine, sirolimus, 
tacrolimus, temsirolimus, toremifene, tretinioin, vincristine, vinorelbine, St. John’s Wort, and 
grapefruit juice/products. 
In addition, the following AED medications are not allowed:  clobazam, phenobarbital, 
ethosuximide, felbamate, carbamazepine, phenytoin, or vigabatrin. 
9.3. 
Duration of Treatment 
All patients will complete an initial Screening Visit, and participate in Period 1, 14-week 
Treatment Period.  Patients that have made a ≥35% improvement on the ABC-C irritability 
subscale will be allowed to continue to Period 2 for an additional 24 weeks of treatment.  
Patients taking AEDs will have a Taper Period of an additional one or two weeks, unless they are 
transitioning to receive drug through Special Access, if available. 
Patients will complete an EOS Visit at Week 38.  Patients taking AEDs will return on Week 40, 
or Week 41 when they will be discharged from the study, unless the skin irritation score is > ‘0’, 
the patient will continue to be followed through an Unscheduled Visit until the skin irritation 
score is recorded as ‘0’ (no erythema).  At this time, the patient will be discharged from the 
study. 
9.4. 
Treatment Compliance 
The Investigator will keep a current and accurate inventory of all clinical supplies received from 
the Sponsor.  Any deviations from the protocol will be recorded.  
All patients will be provided with a sufficient supply of study drug during their study site visit to 
last until their next study visit.   
All parents/caregivers will be provided with a sufficient supply of study drug for the patient 
during their site visit.  Up to a 7-Day Replacement kit(s), containing the patient’s assigned study 
drug, will also be supplied at each visit, as needed during the study.  The Replacement kit(s) are 
to be returned at each study visit so that drug accountability can be performed.  The Replacement 

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kits are to be used in situations where a visit is outside the visit window and the patient requires 
additional study drug prior to a visit and/or study drug is inadvertently lost/damaged/destroyed.  
Parents/caregivers will bring the used and unused sachets, in the baggies provided, to each visit.  
The site will perform drug accountability (if all sachets were completely or partially utilized) at 
each study visit and record compliance for the previous visit. 
At Week 38, patients taking concomitant AED’s for treatment of seizures or epilepsy, will be 
provided a one or two-week supply to complete the Tapering Period (Weeks 39 and/or Week 
40), unless they are transitioning to receive drug through Special Access, if available.  Patients 
will bring their used and unused sachets to the site at each study visit.  The site will perform drug 
accountability (if all sachets were completely or partially utilized) at each visit and record if the 
patient was compliant since the last visit.  
 

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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
ZYN002 is a transdermal pharmaceutically manufactured cannabidiol gel.  It is a clear 
transdermal gel containing a 4.2% w/w concentration of CBD for topical application.  
10.2. 
Study Drug Packaging and Labeling 
ZYN002 drug product will be packaged in sachets. 
Study supplies will be labeled with a computer-generated label, which will include the following 
information:  
• Protocol Number  
• Intended Use 
• Storage Conditions 
• Labeled:  Keep out of reach of children 
• Manufacturer/Sponsor Identification 
10.3. 
Study Drug Storage 
Study drug is to be stored in ambient conditions between 15°C - 25°C / 59°F - 77°F. 
10.4. 
Study Drug Preparation 
Study drug will be applied directly from the sachets as received. 
10.5. 
Administration 
The site will instruct parents/caregivers on how to apply the gel and the first dose of study drug 
will be applied by the parent/caregiver at the Day 1 visit, and at each subsequent study visit.  
Patients will be instructed to withhold their morning dose of ZYN002 until a blood sample is 
collected at Week 6. Week 14 and Week 38 EOS/ET.   
Patients will be permitted to shower or clean the application site(s) area up to 30 minutes prior to 
the study dose.   
Parents/caregivers will use gloves (supplied by the Sponsor) to apply the study drug.  
Parents/caregivers will apply all study drug to clean, dry, intact skin, thoroughly massaging it 
into the right and/or left upper arms and shoulders until the area is dry.  The study drug will be 
rubbed in completely and must be dry prior to dressing.   
Patients should keep the application site dry for six hours but may apply an approved 
moisturizing lotion (Cetaphil), provided by the Sponsor, two hours after dosing.  The application 
site should be covered to minimize sun exposure when going outside during the day.  Sunscreen 
at the application site may be used two hours after dosing.  If redness occurs at the application 
site, the parent (after consultation with the Investigator) may switch the application site 
temporarily to the upper thighs.   

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10.6. 
Study Drug Accountability 
Patients will bring the unused and used sachets to the site at each study visit.  The site will 
perform drug accountability (if all sachets were completely or partially utilized) at each visit and 
record if the patient was compliant with study drug application since the previous visit.   
10.7. 
Study Drug Handling and Disposal 
Used sachets will be placed in baggies (provided by Sponsor).  Unused sachets should be 
returned in the way in which they were dispensed (box and/or baggies).  For drug accountability 
purposes the patient number, initials and Visit number will be written on the outside of the 
box/baggie. 
The study monitor will confirm the number of unused sachets of study drug with the research 
facility and coordinate return or disposal of the used and unused supplies.    
 
 

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11. 
ASSESSMENT OF SAFETY 
11.1. 
Safety Parameters 
Patient safety will be monitored at each study visit using standard measures, including physical 
and neurological exams, examination of skin at application sites for irritation, vital signs 
(including oral, infrared forehead or tympanic temperature), 12-lead ECGs, the C-SSRS, safety 
laboratory tests, urinalysis, and AE monitoring. 
11.2. 
Adverse and Serious Adverse Events 
Throughout the study, the Investigator will monitor each patient for evidence of drug intolerance 
and for the development of clinical and/or laboratory evidence of an AE.  An AE assessment will 
be made by the investigator on a routine basis throughout treatment and at each post-treatment 
evaluation.  In order to standardize the approach to assessing the occurrence of AEs, the 
investigator should make a judgment as to any change in condition or AEs that were not present 
before study drug administration when he obtains the parent/patient’s response to how they are 
feeling.  Patients having TEAEs will be followed until they return to normal or become 
stabilized. 
All TEAEs that occur during the course of the study must be reported in detail on the appropriate 
CRFs, patient’s source document record, and on any other report form required by National Law.  
All efforts will be made to follow-up adverse events until resolution.   
11.2.1. 
Definition of Adverse Events 
11.2.1.1. Adverse Event  
An AE is an undesirable medical occurrence (sign, symptom, or diagnosis) or worsening of a 
pre-existing medical condition (e.g., diabetes, congestive heart failure, rheumatoid arthritis, 
psoriasis) that occurs at any time after signing of the ICF whether or not it is considered to be 
related to treatment.  Worsening of an existing medical condition is when a condition present at 
the time of signing of the ICF (e.g., cancer, diabetes, gout) becomes more severe, more frequent, 
or increased in duration during the study.  Hospitalizations for pretreatment conditions (e.g., 
elective cosmetic procedures) or surgeries that were planned before entry into the study are not 
considered AEs. 
The Investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value represents for the patient a change from the time of signing of the ICF.  In 
general, abnormal laboratory findings without clinical significance (based on the Investigator's 
judgment) should not be recorded as AEs.  Clinically significant changes occurring after the 
signing of the ICF are considered AEs; however, the reported adverse event should include the 
underlying diagnosis or resulting clinical sequelae.  Patients having clinically significant AEs 
will be followed until they return to normal or become stabilized. 
Throughout the study, the Investigator will monitor each patient for evidence of drug intolerance 
and for the development of clinical and/or laboratory evidence of an adverse event.  An AE 
assessment will be made by the Investigator on a routine basis throughout the study.  All AEs 
which occur during the course of the study must be reported in detail on the appropriate CRF 

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page and on any other report form required by national law.  All TEAEs must be followed to a 
satisfactory resolution. 
All AEs will be collected from study Screening until the patient is discharged from the study. 
Application site irritation scores of 1, 2, or 3 should not be recorded as AEs but will be assessed 
and recorded as part of the skin irritation score examinations.  Skin irritation recorded with a 
score of ‘4’ (as assessed by the Investigator) will be recorded as part of the skin irritation 
examination, and will also be recorded by the Investigator as an AE.  The Investigator should 
report as an expedited AE (within 24 hours of assessment) to the Sponsor.  
If a patient reports a worsening of skin irritation after a period of improvement, the Investigator 
should assess whether the event is indicative of a delayed hypersensitivity reaction.  If in the 
opinion of the Investigator the event is a delayed hypersensitivity reaction, this will be recorded 
as an AE.  
All study drug application site signs/symptoms will be recorded as AEs.  The event term should 
specify “application site disorder - [specify sign or symptom]”. 
If a patient becomes pregnant during or after exposure to a study drug received in this study, the 
investigator will immediately discontinue the patient from the study and contact the Sponsor or 
designee.  The investigator will complete the Sponsor’s (or designee’s) Clinical Pregnancy 
Notification Form and email it to the Sponsor within two days of learning of the pregnancy.  
Diligent efforts will be made to determine the outcome for all pregnancy exposures in the 
clinical study.  Information on the status of the mother and the child will be forwarded to the 
Sponsor. 
Generally, follow-up will occur within 6 to 8 weeks following the estimated delivery date.  Any 
premature termination of the pregnancy will be reported.  Both maternal and paternal exposure 
will be collected.  For exposure involving the female partner of a male participant, the necessary 
information must be collected from the participant, while respecting the confidentiality of the 
partner. 
Although pregnancy occurring in a clinical study is not considered to be an AE or SAE, any 
pregnancy complication or elective termination of a pregnancy for medical reasons will be 
recorded as an AE or SAE and will be followed as such.  All reports of congenital 
abnormalities/birth defects are SAEs.  Spontaneous miscarriages should also be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs. 
The date of onset and resolution of the adverse event will be collected.   
11.2.1.2. Serious Adverse Event  
Any adverse event that results in one or more of the following is considered a SAE: 
• Death 
• Life Threatening - The patient was at risk of death at the time of the event.  It does 
not refer to the hypothetical risk of death if the adverse event were more severe or 
were to progress. 
• In-patient hospitalization (admission or prolongation of existing hospitalization). 

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• Persistent or significant disability / incapacity - Any AE having an outcome that is 
associated with a substantial disruption of the ability to carry out normal life 
functions.  This includes the inability to work.  This is not intended to include 
transient interruptions of daily activities. 
• Congenital abnormality or birth defect - Any structural abnormality in patient 
offspring that occurs after intrauterine exposure to treatment. 
• Other Medically Important Events - Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered a serious 
adverse event when, based upon medical judgment, they may jeopardize the patient or 
may require intervention to prevent one of the outcomes listed above. 
11.3. 
Relationship to Study Drug 
The following information will be collected for each adverse event and the relationship of the 
adverse event to the study drugs will be assessed using the following definitions: 
Related - An adverse event has a strong temporal relationship to study drug or recurs on re-
challenge, and another etiology is unlikely. 
Not related - An adverse event is due to underlying or concurrent illness or effect of another 
drug and is not related to the study drug (e.g., has no temporal relationship to study drug or has a 
much more likely alternative etiology).  The alternative etiology will be recorded on the CRF. 
11.4. 
Adverse Event Severity 
The AE term should be reported in standard medical terminology when possible.  For each AE, 
the investigator will evaluate and report the date of onset and resolution, intensity, causality, 
action taken, serious outcome (if applicable), and whether or not it caused the patient to 
discontinue the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 11.2.1.2 .  An AE of severe intensity 
may not be considered serious. 
11.5. 
Reporting Adverse Events 
If any protocol defined expedited event, or serious, life-threatening, or fatal AE occurs 
whether related to study drug or not, the Investigator must notify the Sponsor within 24 hours 
by telephone and email. 
24 Hour SAE Telephone:  
+1 919-265-4976 
Email: 
 
saereport031@zynerba.com 

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The definition for a ‘protocol defined expedited event’ for the purposes of this study is a Skin 
Irritation score of ‘4’, “intense erythema with edema and blistering/erosion” (see Table 7). 
The Investigator must complete, sign and date the SAE pages, verify the accuracy of the 
information recorded on the SAE pages with the corresponding source documents, and send a 
copy by email to the Sponsor.   
Additional follow-up information, if required or available, should all be emailed to the Sponsor 
within one business day of receipt and this should be completed on a follow-up SAE form and 
placed with the original SAE information and kept with the appropriate section of the CRF 
and/or study file. 
All SAEs (related and unrelated) will be followed from the signing of the ICF until the End of 
Study Visit, 30 days post last dose of study drug or the patient is lost to follow up (whichever 
comes last).  Any SAEs considered possibly or probably related to the investigational product 
and discovered by the Investigator up to 30 days after the study should be reported.  All SAEs 
must be reported to the Sponsor within one business day of the first awareness of the event.  The 
Investigator must complete, sign and date the SAE pages, verify the accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a PDF copy by 
email to the Sponsor.   
The Sponsor representative is responsible for notifying the relevant regulatory authorities of 
certain events.  It is the Investigator’s responsibility to notify the HREC of all SAEs that occur at 
his or her site.  Investigators will also be notified of all unexpected, serious, drug-related events 
(7/15 Day Safety Reports) that occur during the clinical study.  Each site is responsible for 
notifying its HREC of these additional SAEs. 
 

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12. 
PHARMACOKINETIC ASSESSMENTS 
12.1. 
Blood Sample Collection 
A 2-3 -mL blood sample (trough) for PK analysis of CBD/THC will be collected into sodium 
heparin tubes at Screening, pre-dose on study Visit 3/Week 6, Visit 4/Week 14, and Visit 7/Week 
38 EOS/ET Visits.   
In addition, a separate blood sample for valproic acid levels (for patients taking valproate or 
valproic acid for treatment of seizures or epilepsy) will be collected at Screening, Week 6, 14, 
and Week 38 EOS/ET Visits.  Valproic acid samples will be analyzed by a local laboratory.  For 
patients receiving valproate/valproic acid medication and having a Taper Period their final blood 
draw for PK and valproic acid levels will be taken at Week 38.   
PK blood samples for CBD/THC analysis will be placed on ice until centrifuged.  The blood 
samples will be placed in a refrigerated centrifuge within 60 minutes of collection and spun at 
high speed (2500 revolutions per minute) for 10 minutes at 4°C.  Plasma samples will be split in 
half and transferred into standard polypropylene cryovial tubes for the plasma aliquots.  The 
plasma samples will be frozen at a freezer temperature of -80°C or below (±10 C), within two 
hours after collection and will remain frozen until shipped.  Half of the plasma sample will be 
retained at the investigative site as a back-up sample.  Half of the frozen samples will be packed 
in dry ice sufficient to last the number of days applicable to transport.  Plasma samples will be 
shipped to a lab chosen by the Sponsor. 
An inventory of the samples shipped will accompany the package.   
12.2. 
Sample Analysis 
Plasma samples will be analyzed by a validated high-performance liquid chromatography 
(HPLC), with tandem mass spectrometry (MS/MS) detection for the determination of CBD/THC 
concentrations in plasma.  
Plasma samples for valproic acid will be analyzed through a local laboratory. 
All analysis will be completed to Good Laboratory Practice (GLP) standards.  Plasma PK and 
valproic acid results will be provided in a separate bioanalytical report. 
Additional analysis of collected plasma may be conducted to investigate the metabolism of CBD.  
If conducted, the results from the metabolite investigation will be reported separately in a stand-
alone report.  Additionally, quantitation of selected metabolites from collected plasma may be 
conducted. 

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13. 
STATISTICS 
13.1. 
Determination of Sample Size 
This study is exploratory in nature and as such, a formal sample size was not determined. 
13.2. 
Analysis Populations 
13.2.1. 
Intent-to-Treat Population 
All efficacy assessments taken at study Weeks 6, 14, 22, 30, and 38 will be summarized by dose 
for each patient. 
13.2.2. 
Safety Population 
All patients who receive at least one dose of study drug will be included in the safety population.  
Safety population will be used for all safety evaluations. 
13.2.3. 
Pharmacokinetic Population 
The PK population will consist of all patients who received at least one application of study drug 
and have plasma concentration obtained from at least one of the Treatment Period evaluations 
(Week 6, Week 14, and Week 38 EOS/ET). 
13.3. 
Efficacy Analysis 
Descriptive statistics (mean, median, standard deviation, minimum, and maximum) for 
continuous data and number (n) and percentage (%) for categorical data will be presented for all 
efficacy and safety parameters.  
Baseline will be defined as the last assessment prior to the first dose of ZYN002.   
All efficacy assessments will be summarized by dose for each patient.   
13.4. 
Pharmacokinetic Analyses 
13.4.1. 
PK Sample for Determination of CBD/THC 
The following PK parameters for determination of CBD/THC will be calculated/derived from the 
data.  Plasma PK will be calculated on:   
Trough: 
Steady-state plasma concentration occurring just prior to the next dose of 
ZYN002. 
 
Elapsed time between the last ZYN002 dose and time of plasma sample 
collection. 
Descriptive statistics (arithmetic mean, median, SD, minimum, maximum, coefficient of 
variation, geometric mean [plasma concentration]) for the plasma trough concentrations and 
elapsed time will be presented at ach nominal blood sampling time (Screening, pre-dose Week 6, 
14, and Week 38 EOS/ET.  Analyses for CBD metabolites are exploratory and may be 
conducted. 

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13.4.2. 
PK Sample Determination of  Valproic Acid 
The following data will be summarized separately for each AED medication: 
• Plasma concentration occurring at Screening, pre-dose Week 6, 14, and Week 38 
EOS/ET.   
• Elapsed time between last valproate/valproic acid dose and the time of plasma sample 
collection. 
Descriptive statistics (arithmetic mean, median, SD, minimum, maximum, coefficient of 
variation, geometric mean [plasma concentration]) for the valproic acid plasma trough 
concentrations and elapse time will be presented at each nominal PK sampling time. 
13.5. 
Statistical Methods 
Descriptive statistics (mean, median, standard deviation, minimum, and maximum) for 
continuous data and number (n) and percentage (%) for categorical data will be presented for all 
efficacy and safety parameters. 
All efficacy assessments will be summarized at Weeks 6, 14, 22, 30, and 38.  
Vital sign assessments (actual and change from screening) taken at study Day 1, Weeks 6, 14, 
22, 30, and 38 will be summarized using descriptive statistics and presented by maintenance 
dose.   
ECGs (actual and change from Screening) will be summarized by actual treatment group. ECG 
results including any clinically significant findings will be summarized at each study visit. 
Safety laboratory and urinalysis assessments taken at Week 6, 14, and Week 38 (actual and 
change from screening) will be summarized by treatment at the time of the assessment. 
Application site irritation will be summarized using counts and percentages for each respective 
site irritation score (0, 1, 2, 3, or 4) by dose at the time of assessment. 
AEs will be tabulated by the actual treatment dose of study drug received at the time of initiation 
of the adverse event and classified by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA).  Additionally, AEs will be tabulated overall 
(total number of AEs and total number of patients with AEs). 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
During the study, a monitor from the Sponsor or their representative will have regular contacts 
with the investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRF, and that investigational product accountability checks are 
being performed 
• Perform source data verification.  This includes a comparison of the data in the CRF with 
the patient’s medical records at the hospital or practice, and other records relevant to the 
study.  This will require direct access to all original records for each patient (e.g. clinic 
charts). 
• Record and report any protocol deviations not previously sent to the Sponsor or their 
representative. 
• Confirm AEs and SAEs have been properly documented in the CRF and confirm any 
SAEs have been forwarded to the Sponsor or their representative and those SAEs that 
met criteria for reporting have been forwarded to the HREC. 
The monitor will be available between visits if the investigator(s) or other staff have 
questions or needs information or advice. 
14.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, or HREC may visit the site to 
perform audits or inspections, including source data verification.  The purpose of a Sponsor audit 
or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice guidelines of 
the International Conference on Harmonization, and any applicable regulatory requirements.  
The investigator should contact the Sponsor and their representative immediately if contacted by 
a regulatory agency about an inspection. 
 
 

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15. 
DATA QUALITY ASSURANCE 
Original patient records such as research facility records and laboratory reports should be 
available at each site for source document review by Sponsor personnel.  Source document 
review is the verification of the information recorded on CRFs with that recorded in the original 
patient records.  In this study, source document review of specific types of information will be 
conducted for all patients. 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
the Sponsor or their representative may conduct a quality assurance audit.  Please see Section 17 
for more details regarding the audit process. 

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16. 
ETHICS 
16.1. 
Human Research Ethics Committee (HREC) 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the 
Investigator’s Brochure, the ICF, and all other forms of patient information related to the study 
(e.g., advertisements used to recruit patients) and any other necessary documents be reviewed by 
a HREC.  HREC approval of the protocol, ICF and patient information and/or advertising, as 
relevant, will be obtained prior to the authorization of drug shipment to a study site.  Any 
amendments to the protocol will require HREC approval prior to implementation of any changes 
made to the study design. 
16.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki and GCP guidelines.  
The investigator is responsible for reporting to the HREC modifications, safety updates, 
amendments, and deviations of the protocol that impact on patient safety. 
At appropriate intervals, the clinical monitor will visit the site during the clinical study and 
assure that the Investigator’s obligations are being fulfilled.  Per GCP requirement for 
confirmatory proof of patient files, a copy of all records must be retained with the files of the 
principle investigator for a minimum of 15 years.  These records include the Confidential 
Follow-up Forms and other documents such as ICFs, laboratory reports, and other source 
documents, drug accountability forms, HREC approvals, protocols, and CRFs. 
16.3. 
Patient Information and Informed Consent 
The study protocol and ICF must be approved by the investigator’s HREC and a copy of the 
approved ICF must be supplied to the Sponsor.   
The parent/caregiver will be asked to read the consent form.  If the parent/caregiver decides that 
the patient should participate in the study, the parent/caregiver will be asked to sign and date the 
form as evidence of consent.  Each parent/caregiver must voluntarily sign and date a consent 
form before participating in this study.  It is the obligation of the investigator or their 
representative to explain the nature of the study to the parent/caregiver.  The physician will 
document in the patient’s medical chart that the parent/caregiver has signed an ICF to participate 
in an investigational study, a copy of the ICF will be given to the parent/caregiver, and the 
original should be retained with the patient’s study records. 
Patient names will remain confidential.  Only the patient number, and date of birth date will be 
recorded on the CRF.  The parent/caregiver will give explicit permission for representatives of 
the regulatory authorities and the HREC to inspect their medical records to verify the 
information collected.  The parent/caregiver will be informed that all protected health 
information and clinical data are saved in a confidential manner.  
The investigator will maintain a personal patient identification list (patient and treatment 
numbers with the corresponding patient names) to enable records to be identified. 
 

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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
The Sponsor will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study.  The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, evaluation checklists, 
pharmacy dispensing and other records, recorded data from automated instruments, microfiches, 
photographic negatives, microfilm or magnetic media, and/or x-rays. 
In addition, the Investigator will permit study-related audits, HREC review, and regulatory 
inspection(s), providing direct access to source data documents. 
17.2. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of 15 years 
from study completion. If it becomes necessary for the Sponsor or the Regulatory Authority to 
review any documentation relating to the study, the Investigator must permit access to such 
records. 

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18. 
PUBLICATION POLICY 
All information concerning ZYN002 and the Sponsor’s operations, such as ZYN002 patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by the Sponsor and not previously published, is considered confidential 
information. 
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by the Sponsor in connection with the development of ZYN002.  
This information may be disclosed as deemed necessary by the Sponsor.  To allow for the use of 
the information derived from this clinical study and to ensure complete and thorough analysis, 
the investigator is obligated to provide the Sponsor with complete test results and all data 
developed in this study. 
This confidential information shall remain the sole property of the Sponsor, shall not be 
disclosed to others without the written consent of the Sponsor, and shall not be used except in the 
performance of this study. 

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Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG.  1982.  Action of cannabidiol on the anxiety 
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137. 
 

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20. 
APPENDICES 

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20.1. 
Application of ZYN02 Gel Instructions 
 
The gel application instructions are attached. 
 
 
ZYN2-CL-031 Gel 
Application Instructio 

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20.2. 
Skin Irritation Diary 
The Skin Irritation Diary is attached. 
 
 
ZYN2-CL-031 Daily 
skin check diary_V1_