Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000516280
Ethics application status
Approved
Date submitted
3/04/2018
Date registered
9/04/2018
Date last updated
11/12/2018
Date data sharing statement initially provided
11/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Clinical study of Cannabidiol in children and adolescents with Developmental and Epileptic Encephalopathy
Scientific title
Open Label Study to Assess the Safety and Efficacy of ZYN002 Administered as a Transdermal Gel to Children and Adolescents (3 to <18 years) with Developmental and Epileptic Encephalopathy (BELIEVE 1)
Secondary ID [1] 294461 0
ZYN2-CL-025
Universal Trial Number (UTN)
Trial acronym
BELIEVE 1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 307217 0
Developmental disability 307288 0
Condition category
Condition code
Neurological 306329 306329 0 0
Epilepsy
Neurological 306405 306405 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A sequential, multi-stage, open-label, multi-national, multiple-center, multiple-dose study to assess the long-term safety and tolerability of ZYN002 in child and adolescent epilepsy patients 3 to <18 years of age having seizures associated with developmental and epileptic encephalopathies (DEE)
ZYN002 is a synthetically manufactured Cannabidiol (CBD), which is developed as a clear gel that can be applied to the skin (called transdermal delivery) to provide consistent, controlled levels of CBD in the blood.
The gel will be applied to clean, dry, intact skin of the upper arm from the top of the shoulder to the elbow, or upper thigh until area is dry.
In Period A, all participants will undergo screening process. Eligible participants will then participate in a baseline period of 4 weeks. Subjects who meet baseline seizure requirements will initiate a 2-week titration period, followed by a 24-week maintenance period. Patients will be treated for a total of 26 weeks. For patients not progressing to Period B, following Week 26 or Early Termination, study drug will be tapered over a 1 to 3-week period depending on the patient’s dose at the time of taper). After the final dose, patients will be followed weekly for 4 weeks by telephone, prior to discharge from the study.
Patients progressing to Period B will receive a further 24-weeks of open-label treatment. Upon treatment termination, there will be a taper period ranging from one to three weeks, depending on the patient’s dose at the time of the taper. Patients will complete an End of Study Visit (EOS) after completing their taper period. Patients who discontinue before Week 50 will be asked to attend the ET visit and then taper off the study medication.
Patients weighing <25 kg will receive 125 mg CBD Q12H (+2 hours), for a total daily dose of 250 mg CBD (2 sachets) for the two-week titration period. Additional dose titration (up or down) during the maintenance period may be allowed based upon safety and efficacy parameters. Patients weighing >25 kg will receive 250 mg CBD Q12H (+2 hours), for a total daily dose of 500 mg CBD (4 sachets) for the two-week titration period. Additional dose titration (during the maintenance period) may be allowed based upon safety and efficacy parameters. At the end of the 26-week or 50-week treatment period, there will be a taper period ranging from one to three weeks, depending on a patient’s dose at the time of the taper.
Patient compliance with the intervention will be monitored by the study coordinator through drug accountability at each study visit.
Intervention code [1] 300754 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 305341 0
The primary outcome of the study is to evaluate the safety and tolerability of ZYN002, over a 26-week period in Period A, or up to a total of 50 weeks in Period B in child and adolescent epilepsy patients with developmental and epileptic encephalopathies. Safety will be assessed by: physical examination, neurological examination, examination of skin, vital signs, ECGs, clinical laboratory tests e.g. haematology, chemistry, urinalysis, pregnancy test (when applicable), assessing suicide risk and adverse event (AE) monitoring.
Timepoint [1] 305341 0
For Period A of the Study:
At Screening Visit, Baseline Visit, Day 1, Weeks 2, 4, 6, 14, and 26 visits, at all unscheduled visits until subject is discharged from the Study.
For Period B of the Study:
At Weeks 38 and 50, at all unscheduled visits until subject is discharged from the Study.
Secondary outcome [1] 344907 0
To evaluate, over a 26-week treatment period in Period A, or up to a total of 50 weeks in Period B, the efficacy of ZYN002 in terms of patient seizure frequency by use of Daily seizure diaries
Timepoint [1] 344907 0
For Period A of the Study:
At baseline, Day 1 and Weeks 2, 4, 6, 14 and 26

Secondary outcome [2] 344908 0
To evaluate, over a 26-week treatment period in Period A, or up to a total of 50 weeks in Period B, the efficacy of ZYN002 in terms of change in patient's DEE symptoms as reflected in measurements of caregiver stress by use of the University of Washington Caregiver Stress Scale
Timepoint [2] 344908 0
For Period A of the Study:
At Day 1, Week 4 and Week 26

Secondary outcome [3] 344909 0
To evaluate, over a 26-week treatment period in Period A, or up to a total of 50 weeks in Period B, the efficacy of ZYN002 in terms of change in patient quality of life by use of the ELDQOL Quality of Life (Modified) assessment.
Timepoint [3] 344909 0
For Period A of the Study:
At Day 1, Week14 and Week26

Secondary outcome [4] 344910 0
To evaluate, over a 26-week treatment period in Period A, or up to a total of 50 weeks in Period B, the efficacy of ZYN002 in terms of assessment of patient sleep disturbances by use of the SDSC Sleep Questionnaire
Timepoint [4] 344910 0
For Period A of the Study:
At Day 1, Week14 and Week 26

Secondary outcome [5] 344911 0
To evaluate, over a 26-week treatment period in Period A, or up to a total of 50 weeks in Period B, the efficacy of ZYN002 in terms of assessment of patient adaptive behavior by use of the Vineland Adaptive Behavior Scale™-3
Timepoint [5] 344911 0
For Period A of the Study:
At Day 1 and Week 26
For Period B of the Study
At Week 50
Secondary outcome [6] 344912 0
To evaluate, over a 26-week treatment period in Period A, or up to a total of 50 weeks in Period B, the efficacy of ZYN002 in terms of assessment of the patient’s day (“good day / bad day”) by Administration of Daily Questionnaire (“Good Day, Bad Day”)
Timepoint [6] 344912 0
For Period A of the Study:
At Baseline, Day 1, Weeks 2, 4, 6, 14 and 26
For Period B of the Study
At Weeks 38 and 50
Secondary outcome [7] 344913 0
To evaluate the pharmacokinetics of CBD and CBD metabolite(s) following administration of ZYN002 in child and adolescent epilepsy patients with DEE b measurement of plasma levels of CBD and CBD metabolite(s)
Timepoint [7] 344913 0
For Period A of the Study
At Day 1 and Weeks 4, 6, 14 and 26.
For Period B of the Study
At Weeks 38 and 50

Eligibility
Key inclusion criteria
1. Male or female, 3 to less than 18 years of age, inclusive, at the time of screening.
2. Judged by the Investigator to be in generally good health at the Screening Visit based upon the results of a medical history, physical examination, 12-lead ECG, and clinical laboratory test results.
3. Patients must have a diagnosis of developmental and epileptic encephalopathy (DEE) as defined by the International League Against Epilepsy Classification (Scheffer 2017) with generalized motor, focal motor and focal impaired awareness or focal bilateral to tonic-clonic seizures. Examples of DEE that may be included, but not limited to: Lennox-Gastaut Syndrome, Dravet Syndrome, West Syndrome/ Infantile Spasms and Doose Syndrome. The diagnosis must be established for 1 years and documented by review of electroencephalogram (EEG), , and or genetic testing if available, and narrative from the physician who manages the patient’s epilepsy. The patient/legally authorized representation may elect to have the patient participate in genetic seizure panel testing to characterize a genetic diagnosis.
4. Patient must experience a threshold number of generalized motor seizures (i.e. tonic, clonic, atonic, tonic-clonic seizures, and generalized tonic-clonic), focal motor, focal impaired awareness or focal to bilateral tonic-clonic seizures during the Baseline period.
5. Patient is currently being treated and maintained with a stable regimen of between one (1) and four (4) AEDs for at least 4 weeks before screening, and willing to maintain a stable regimen during the treatment period. If a benzodiazepine is used as a rescue medication greater than 2 times per week, it will be counted as an AED. Patient taking ethosuximide, felbamate and vigabatrin must be on stable therapy for at least 6 months. Patient taking felbamate must have had no clinically relevant changes in hematology or liver function.
6. Patient has history of developmental delay with regression, slowing or plateau in at least one developmental domain.
7. All interventions for epilepsy must be stable for at least one month prior to screening.
8. Patient/caregiver is able and willing to maintain daily diaries for seizures, daily skin assessments and good day/bad day assessment.
9. Patient has a body mass index between 13 and 35 kg/m2 and weighs no less than 12 kg.
10. Sexually active females of childbearing potential must use an acceptable method of contraception. Acceptable methods of contraception include: hormonal contraception, diaphragm, cervical cap, vaginal sponge, condom, vasectomy, and intrauterine device.
11. Females of childbearing potential must have a negative pregnancy test at the Screening Visit, as well as at Day 1.
12. Patient is reasonably stable medically and is unlikely to require changes in drug therapy during the Treatment Period of the study, or interfere with the objectives of the study, or the ability to adhere to protocol requirements.
13. Patient/caregiver/legally authorized representative must be adequately informed of the nature and risks of the study and give written informed consent prior to screening.
14. In the Investigator’s opinion, the patient and/or caregiver is reliable and is willing and able to comply with all protocol requirements and procedures.
Minimum age
3 Years
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient has a history of significant allergic condition, significant drug-related hypersensitivity, or allergic reaction to any adhesives, compound, or chemical class related to ZYN002 or its excipients.
2. Patient has been exposed to any investigational drug or device less than 30 days prior to screening or plans to take another investigational drug at any time during the study.
3. Patient has used cannabis or any CBD- or THC-containing product within 12 weeks of the Screening Visit or during the study.
4. Patient on the following AEDs for less than 6 months: ethosuximide, felbamate and vigabatrin.
5. Patient has had a change in AED regimen in the 4 weeks prior to screening.
6. Patient has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels equal to 3x the upper limit of normal (ULN) as determined from Screening safety laboratories.
7. Patient/caregiver demonstrates behavior indicating unreliability or inability to comply with the requirements of the protocol.
8. Patient has had a change in epilepsy dietary therapy in the 4 weeks prior to screening.
9. Patient has seizures secondary to illicit drug or alcohol use.
10. Patient is using any strong inhibitor/inducer of CYP3A4 or sensitive substrate for CYP3A4 including the following medications: midazolam, oral ketoconazole, fluconazole, nefazodone, rifampin, alfentanil, alfuzosin, amiodarone, cyclosporine, dasatinib, docetaxel, eplerenone, ergotamine, everolimus, fentanyl, halofantrine, irinotecan, lapatinib, levomethadyl, lumefantrine, nilotinib, pimozide, quinidine, ranolazine, sirolimus, tacrolimus, temsirolimus, toremifene, tretinoin, vincristine, vinorelbine and St. John’s Wort.
11. Patient has a history of suicide attempt in the last 5 years or more than one lifetime suicide attempt.
12. Patient responds “yes” to Question 4 or 5 of C-SSRS (Children) during Screening and at any time during the study.
13. Patient has a positive result for the presence of Hepatitis B surface antigen (HBsAg), Hepatitis C virus antibodies (HCV-Ab), or human immunodeficiency virus (HIV) antibodies.
14. Patient has 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 treatment.
15. Patient has known history of cardiac disease.
16. Patient has any skin disease or condition, including eczema (on shoulders/arms, back or thighs), psoriasis, melanoma, acne (on shoulders/arms/back or thighs), contact dermatitis, scarring, imperfections, lesions, tattoos, or discoloration that may affect treatment application, application site assessments, or absorption of the study drug.

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)
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
The primary endpoint is the safety profile of ZYN002. Safety variables including adverse events, physical examinations, ECG, clinical laboratory assessments, Marijuana withdrawal checklist (short form), C-SSRS (children) reporting and results of skin check examinations will be summarized by dose with descriptive statistics. AEs will be tabulated by the actual treatment dose of 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).
Efficacy variables including seizure frequency, Washington Caregiver Stress Scale, ELDQOL quality of life, SDSC Sleep Questionnaire, Vineland Adaptive Behavior Scale and “Good Day, Bad Day” questionnaire will be summarized with descriptive statistics by dose.
Seizure frequency captured via the daily diary will be analyzed per 28-day period (SF28). The reduction from Baseline in seizure frequency (RedSF) is defined for each period as:
RedSF=SF28(Period X)-SF28(Baseline)
The percent reduction from Baseline in seizure frequency is defined as:
%RedSF=100*[SF28(Period X)-SF28 (Baseline)/SF28(Baseline)]
The change in frequency of generalized motor, focal motor, focal impaired awareness and focal to bilateral tonic-clonic seizures and the frequency of generalized non-motor seizures (e.g. absence) that occur with consistent, countable frequency will be analyzed separately.
The plasma concentrations for AEDs, CBD and CBD metabolites (if analyzed) will be summarized descriptively for all patients.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
9/04/2018
Actual
10/04/2018
Date of last participant enrolment
Anticipated
14/12/2018
Actual
Date of last data collection
Anticipated
2/12/2019
Actual
Sample size
Target
55
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10512 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 22226 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 10244 0
New Zealand
State/province [1] 10244 0
Wellington

Funding & Sponsors
Funding source category [1] 299085 0
Commercial sector/Industry
Name [1] 299085 0
Zynerba Pharmaceuticals Pty Ltd
Country [1] 299085 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Zynerba Pharmaceuticals Pty Ltd
Address
Zynerba Pharmaceuticals Pty Ltd
Offices of Pricewaterhouse Coopers
2 Riverside Quay
Southbank VIC 3006
Country
Australia
Secondary sponsor category [1] 298333 0
None
Name [1] 298333 0
Address [1] 298333 0
Country [1] 298333 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300021 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 300021 0
Research Ethics
Office for Research
Level 8, Harold Stokes Building
Austin Health
PO Box 5555
Heidelberg
Victoria
Australia 3084
Ethics committee country [1] 300021 0
Australia
Date submitted for ethics approval [1] 300021 0
28/02/2018
Approval date [1] 300021 0
05/04/2018
Ethics approval number [1] 300021 0

Summary
Brief summary
A sequential, multi-stage, open-label, multi-national, multiple-center, multiple-dose study to assess the long-term safety and tolerability of ZYN002 (transdermal CBD gel) in child and adolescent epilepsy patients 3 to <18 years of age with seizures associated with developmental and epileptic encephalopathies (DEE) according to the International League Against Epilepsy (ILEA) classification.
In Period A patients will undergo a baseline period of 4-weeks, followed by a 2-week titration period, and a 24-week maintenance period. Patients will be treated for a total of 26 weeks. For Patients not continuing to Period B, following Week 26 or Early Termination, study drug will be tapered over a 1 to 3-week period (depending on dose). After the final dose, patients will be followed weekly for 4 weeks by telephone. After the 4 weeks, the patient will be discharged from the study.
Patients progressing to Period B will continue to receive ZYN002 for a further 24 weeks at the same maintenance dose received at Week 26 (e.g. end of Period A). Upon treatment termination, the patient will be required to complete the taper and follow-up period. After the final tapered dose, patients will be followed weekly for 4 weeks by telephone. After the 4 weeks of follow-up, the patient will be discharged from the study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82286 0
Prof Ingrid Scheffer
Address 82286 0
Epilepsy Research Centre
Melbourne Brain Centre
245 Burgundy Street, Heidelberg
Victoria, Australia, 3084
Country 82286 0
Australia
Phone 82286 0
+61 3 9035 7344
Fax 82286 0
+61 3 9496 2291
Email 82286 0
[email protected]
Contact person for public queries
Name 82287 0
Dr Nancy R. Tich, Ph.D.
Address 82287 0
Zynerba Pharmaceuticals Pty, Ltd.
80 West Lancaster Ave., Suite 300, Devon, Pennsylvania
Country 82287 0
United States of America
Phone 82287 0
+1-973-727-4117
Fax 82287 0
Email 82287 0
[email protected]
Contact person for scientific queries
Name 82288 0
Dr Donna Gutterman, Pharm. D.
Address 82288 0
Zynerba Pharmaceuticals Pty, Ltd.,
80 West Lancaster Ave., Suite 300, Devon, Pennsylvania
Country 82288 0
United States of America
Phone 82288 0
+1-919-522-8828
Fax 82288 0
Email 82288 0
[email protected]

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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseSafety and Tolerability of Transdermal Cannabidiol Gel in Children with Developmental and Epileptic Encephalopathies: A Nonrandomized Controlled Trial.2021https://dx.doi.org/10.1001/jamanetworkopen.2021.23930
N.B. These documents automatically identified may not have been verified by the study sponsor.