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Trial registered on ANZCTR


Registration number
ACTRN12619000673145p
Ethics application status
Submitted, not yet approved
Date submitted
30/04/2019
Date registered
6/05/2019
Date last updated
6/05/2019
Date data sharing statement initially provided
6/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Clinical Study of Synthetic Cannabidiol in Children and Adolescents with 22q11.2 Deletion Syndrome
Scientific title
An Open-Label, Tolerability and Efficacy Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents with 22q11.2 Deletion Syndrome
Secondary ID [1] 298094 0
ZYN2-CL-031
Universal Trial Number (UTN)
Trial acronym
INSPIRE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pediatric 22q11.2 deletion syndrome 312606 0
Condition category
Condition code
Neurological 311114 311114 0 0
Other neurological disorders
Mental Health 311115 311115 0 0
Psychosis and personality disorders
Human Genetics and Inherited Disorders 311156 311156 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open-label single-center study, to assess the safety, tolerability and efficacy of ZYN002 (a synthetic cannabidiol) administered as a transdermal gel, for the treatment of child and adolescent patients with 22q11.2 Deletion Syndrome. Approximately 20 male and female patients ages 6 to < 18 years will be treated for 14 weeks.
The study gel will be applied to clean, dry, intact skin of the upper arms and shoulders.
All participants will undergo a screening process to assess eligibility. Eligible participants will then participate in a 14 week treatment period, where all participants will received ZYN002.
Parents/caregivers will apply the study gel twice daily for the treatment period.
Participants who weigh less than or equal to 35 kg, will receive 1 sachet of ZYN002 (125 mg of cannabidiol), applied every 12 hours (± 2 hours).
Participants who weigh more than 35 kg will receive 2 sachets of ZYN002 (250 mg of cannabidiol), applied every 12 hours (± 2 hours).
Participants who are taking anti-epileptic drugs may have an additional one or two weeks of treatment to taper off study treatment. The taper period is part of the clinical trial and will be overseen by the Principal Investigator. These patients will taper their study dose in the following manner beginning at Visit 4 or at Early Termination:
(a) For those patients weighing less than or equal to 35 kg (250 mg daily dose), the dose of study drug will be reduced to a total daily dose of 125 mg ZYN002 each day for one week (one sachet each evening), after which time the patients will discontinue from the study at Week 16.
(b) For those patients weighing greater than 35 kg (500 mg daily dose), the dose of study drug will be reduced over two weeks: during the first week of taper the dose will be reduced to 125 mg applied every 12 hours; (±2 hours); total daily dose of 250 mg, followed by a second week of taper from 250 mg total daily dose to a total daily dose of 125 mg ZYN002 each day (one sachet each evening). After the taper, patients will discontinue from the study Week 17.
Patients tapering their dose will have all Visit 4 End Of Study/Early Termination assessments completed.
At Week 14, 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 16 or 17 and have their final concomitant medication review and safety assessments completed.
Patient compliance with the intervention will be monitored by the study coordinator through drug accountability at each study visit.
Intervention code [1] 314324 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 319902 0
To evaluate the safety and tolerability of ZYN002 administered as a transdermal gel formulation, for 14 weeks, in patients ages 6 to < 18 years, in the treatment of 22q.11.2 Deletion Syndrome (22qDS).
Safety assessments will include collection of any adverse events, physical and neurological exams, the Columbia-Suicide Severity Rating Scale – Children’s version, clinical laboratory safety assessments (hematology, chemistry and urinalysis), vital signs and 12-lead ECGs. 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 (AE). An AE assessment will be made by the investigator on a routine basis throughout treatment and at each post-treatment evaluation. All AEs which occur during the course of the study must be reported in detail on the appropriate CRF page and on any other report form required by national law. All Treatment Emergent AEs must be followed to a satisfactory resolution. Examples of AEs that may occur are fatigue, headache, nausea, anxiety, throat pain, diarrhoea, urinary tract infection and poor balance.
As the study drug is delivered transdermally, tolerability to study drug application will be assessed through skin check examinations performed at each visit after treatment with study gel has been initiated.
Timepoint [1] 319902 0
Safety and tolerability will be assessed at every scheduled study visit from Day 1 to end of treatment, Scheduled visits to the study site occur on Day 1, Week 6 and Week 14. Additional site visits may include any Unscheduled Visits, including during the taper period.
Secondary outcome [1] 369824 0
Change from Day 1 to Week 14 in the Aberrant Behavior Checklist- Community (Irritability Subscale) score
Timepoint [1] 369824 0
At Day 1, Week 6, and Week 14 (End of Study or Early Termination)
Secondary outcome [2] 369825 0
Change in the Clinical Global Impression-Severity from Day 1 to Weeks 6 and 14
Timepoint [2] 369825 0
At Day 1, Week 6, and Week 14 (End of Study or Early Termination)
Secondary outcome [3] 369826 0
Change in the Clinical Global Impression-Improvement from Day 1 to Weeks 6 and 14
Timepoint [3] 369826 0
At Week 6, and Week 14 (End of Study or Early Termination)
Secondary outcome [4] 369827 0
Change in Anxiety, Depression and Mood Scale from Day 1 to Weeks 6 and 14.
Timepoint [4] 369827 0
At Day 1, Week 6, and Week 14 (End of Study or Early Termination)
Secondary outcome [5] 369828 0
Change in Qualitative Caregiver Reported Behavioral Problems from Weeks 6 to Week 14
Timepoint [5] 369828 0
At Week 6, and Week 14 (End of Study or Early Termination)
Secondary outcome [6] 369829 0
Evaluation of CBD plasma level exposure
Timepoint [6] 369829 0
At Screening (Visit 1), Week 6 (Visit 3), and Week 14 (Visit 4/End Of Study/Early Termination).
Secondary outcome [7] 369920 0
Evaluation of THC plasma level exposure
Timepoint [7] 369920 0
At Screening (Visit 1), Week 6 (Visit 3), and Week 14 (Visit 4/End Of Study/Early Termination).

Eligibility
Key inclusion criteria
1. Male or female children and adolescents aged 6 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 score on the ABC-C Irritability Subscale of 18 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 12–30 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.
Minimum age
6 Years
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 less than or equal to 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 less than or equal to 2 times the upper limit of normal (ULN) or has alkaline phosphatase levels less than or equal to 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 midazolam used at blood draws, and barbiturates used as AED medication), including ethanol.
7. Patient is using the following AEDs: phenobarbital, ethosuximide, felbamate, 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 (except single doses administered for the purposes of obtaining blood samples and ECG’s), 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, and St. John’s Wort.
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.
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.
19. Clinically unstable cardiovascular disease as indicated by history, physical examination or ECG.
20. Presence of a moderate or severe surgically uncorrected structural cardiac abnormality.
21. History of major congenital heart disease including those who had surgical repair. Congenital heart disease is defined by classification of complex (fontan circulation, hypoplastic left heart, double inlet ventricle, double outlet right ventricle, Eisenmenger’s syndrome, mitral atresia, tricuspid atresia, pulmonary atresia (with or without intact ventricular septum) , congenitally corrected transposition of great arteries, complete atrioventricular septal defect, truncus arteriosus, other single ventricle physiology, other cyanotic congenital heart disease), moderate (transposition of great vessels, tetralogy of fallot, total or partial anomalous pulmonary venous drainage, Ebstein’s anomaly, coarctation of aorta, aortic stenosis, pulmonary stenosis, ostium primum atrial septal defect, sinus of valsalva fistula/aneurysm) or simple (ventricular septal defect, atrial septal defect, persistent ductus arteriosus, mild pulmonary stenosis).
22. 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.
23. 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.
24. History of treatment for, or evidence of, drug abuse within the past year.
25. Patient responds “yes” to Question ‘4’ or ‘5’ on the C-SSRS (Children) during Screening or at any time on study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / 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.
All efficacy assessments will be summarized at Weeks 6 and 14.
Vital sign assessments (actual and change from screening) taken at study Day 1, Weeks 6 and 14 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, and Week 14 (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).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 13676 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 26359 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 302625 0
Commercial sector/Industry
Name [1] 302625 0
Zynerba Pharmaceuticals Pty Ltd
Address [1] 302625 0
2 Riverside Quay
Southbank, VIC 3006
Country [1] 302625 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Zynerba Pharmaceuticals Pty Ltd
Address
2 Riverside Quay
Southbank, VIC 3006
Country
Australia
Secondary sponsor category [1] 302536 0
None
Name [1] 302536 0
Address [1] 302536 0
Country [1] 302536 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303255 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee.
Ethics committee address [1] 303255 0
Queensland Children’s Hospital Precinct
Level 7, 62 Graham Street
South Brisbane QLD 4101
Ethics committee country [1] 303255 0
Australia
Date submitted for ethics approval [1] 303255 0
29/04/2019
Approval date [1] 303255 0
Ethics approval number [1] 303255 0

Summary
Brief summary
This is an open-label single-center study, to assess the safety, tolerability and efficacy of cannabidiol administered as ZYN002, a transdermal gel, for the treatment of child and adolescent patients with 22q11.2 Deletion Syndrome (22qDS). Male and female patients with 22qDS will be treated for 14 weeks. Patients taking Anti Epileptic Drug medications will have an additional one or two week Taper Period after the completion of doing with ZYN002. Approximately 20 male and female patients, ages 6 to < 18 years, will receive ZYN002.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93030 0
A/Prof Helen Heussler
Address 93030 0
Children’s Health Queensland Hospital and Health Services
Queensland Children’s Hospital
501 Stanley St.
South Brisbane, QLD 4101
Country 93030 0
Australia
Phone 93030 0
+61 7 3068 2920
Fax 93030 0
Email 93030 0
h.heussler@health.qld.gov.au
Contact person for public queries
Name 93031 0
Dr Nancy R Tich
Address 93031 0
Zynerba Pharmaceuticals Inc.,
80 West Lancaster Ave., Suite 300,
Devon, PA 19333
Country 93031 0
United States of America
Phone 93031 0
+1-973-727-4117
Fax 93031 0
Email 93031 0
tichn@zynerba.com
Contact person for scientific queries
Name 93032 0
Dr Donna Gutterman
Address 93032 0
Zynerba Pharmaceuticals Inc.,
80 West Lancaster Ave., Suite 300,
Devon, PA 19333
Country 93032 0
United States of America
Phone 93032 0
+1-919-522-8828
Fax 93032 0
Email 93032 0
guttermand@zynerba.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results