Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001063202
Ethics application status
Approved
Date submitted
12/06/2018
Date registered
26/06/2018
Date last updated
9/06/2021
Date data sharing statement initially provided
27/02/2020
Date results information initially provided
27/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Clinical study Of caNNabidiol in childrEn and adolesCenTs with Fragile X
(CONNECT-FX)
Scientific title
A Randomized, Double-Blind, Placebo-Controlled Multiple-Center, Efficacy and
Safety Study of ZYN002 Administered as a Transdermal Gel to Children and
Adolescents with Fragile X Syndrome – CONNECT-FX
Secondary ID [1] 294339 0
ZYN2-CL-016
Universal Trial Number (UTN)
Trial acronym
CONNECT-FX
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fragile X Syndrome 307060 0
Condition category
Condition code
Human Genetics and Inherited Disorders 306171 306171 0 0
Other human genetics and inherited disorders
Neurological 307226 307226 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ZYN002 is a pharmaceutically manufactured Cannabidiol (CBD) that is developed as a clear gel that can be applied to the skin (called transdermal delivery).

The gel will be applied to clean, dry, intact skin of the shoulders and/or upper arms.

All participants will undergo a screening process. Eligible participants will then participate in up to a 14 week treatment period, where all participants may receive placebo or active study drug

Treatment group A (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, applied every 12 hours (± 2 hours).
• Participants who weigh more than 35 kg will receive 2 sachets of ZYN002, applied every 12 hours (± 2 hours).

Participants who are taking Anti-epileptic drugs may have an additional one or two weeks of blinded treatment to taper off study treatment.

After the final dose, patients will be followed weekly for 4 weeks by telephone, prior to discharge from the study.

Patient compliance with the intervention will be monitored by the study coordinator through drug accountability at each study visit.
Intervention code [1] 300696 0
Treatment: Drugs
Comparator / control treatment
Treatment group B (Placebo):
• Participants who weigh less than or equal to 35 kg, will be given 1 sachet of the placebo gel that will have to be applied every 12 hours (± 2 hours). That would mean 2 sachets in total per day, each sachet containing 2.98 g of placebo gel.
• Participants who weigh more than 35 kg will be given 2 sachets of the placebo to be applied every 12 hours (± 2 hours). That would mean 4 sachets in total per day, each sachet containing 2.98 g of placebo gel.
Control group
Placebo

Outcomes
Primary outcome [1] 305267 0
The change in the Aberrant Behavior Checklist-Community Fragile X factor (ABC-C) Pre-specified Subscale 1
Timepoint [1] 305267 0
Change from Baseline to End of Treatment. Subscale 1 to be assessed at all study visits: Screening, Day 1, Week 2, Week 6, Week 10 and Week 14 (primary endpoint)
Secondary outcome [1] 344659 0
Change in the ABC-C Fragile X factor Pre-specified Subscale 2
Timepoint [1] 344659 0
Change from Baseline to End of Treatment. Subscale 2 to be assessed at all study visits: Screening, Day 1, Week 2, Week 6, Week 10 and Week 14.
Secondary outcome [2] 344661 0
Change in the ABC-C Fragile X factor Pre-specified Subscale 3
Timepoint [2] 344661 0
Change from Baseline to End of Treatment. Subscale 3 to be assessed at all study visits: Screening, Day 1, Week 2, Week 6, Week 10 and Week 14.
Secondary outcome [3] 344662 0
Change in CGI-I
Timepoint [3] 344662 0
Change in CGI-I at End of Treatment. To be assessed at Week 2, Week 6, Week 10 and Week 14.
Secondary outcome [4] 348219 0
To evaluate the safety and tolerability of ZYN002
Safety assessments will include regular collection of any adverse events, physical and neurological exams (including Tanner staging), clinical laboratory safety assessments (hematology, chemistry and urinalysis), vital signs and 12-lead ECGs. In addition, the Behavior Checklist and Penn Physician Withdrawal Checklist will be utilized to assess for any potential withdrawal characteristics of ZYN002. Finally, 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 [4] 348219 0
Safety and tolerability will be assessed at every study visit from Day 1 to End of Study, including Day 1, Week 2, Week 6, Week 10 and Week 14, any Unscheduled Visits and telephone follow up visit through End of Study.

Eligibility
Key inclusion criteria
1. Male or female children and adolescents aged 3 to less than 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, 12-lead ECG, and clinical laboratory test results. Laboratory results outside of the reference range must be documented as not clinically significant by both the Investigator and Sponsor.
3. Patients must have a diagnosis of FXS through molecular documentation of FMR1 full mutation.
4. Patients must be assessed by the Investigator as being moderately to severely impacted due to FXS.
5. 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.
6. Patients who are taking psychotropic medication(s) should be on a stable regimen of no more than two such medications for at least four weeks preceding study Screening and must maintain that regimen throughout the study.
7. If patients are receiving non-pharmacological, behavioral, and/or dietary interventions, they must be stable and have been doing so for three months prior to Screening.
8. Patients have a body mass index between 12–30 kg /m2 (inclusive).
9. Females of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative serum or urine pregnancy test at all designated visits.
10. 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.
11. Parents/caregiver(s) must provide written consent to assist in trial drug administration.
12. 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
3 Years
Maximum age
17 Years
Sex
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 for the duration of therapy and for three months after the last dose of study medication.
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 greater than or equal to 2 times the upper limit of normal (ULN) or has alkaline phosphatase levels greater 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 (aside from ZYN002) within three months of Screening Visit or during the study.
6. Patient has a positive drug screen, including ethanol, cocaine, THC, barbiturates, amphetamines (unless prescribed), benzodiazepines, and opiates.
7. Patient is using the following AEDs: clobazam, phenobarbital, ethosuximide, felbamate, or vigabatrin.
8. Patient is using any strong inhibitor/inducer of CYP3A4 or sensitive substrate for CYP3A4
9. Patients may not be taking minocycline for 30 days prior to Screening or throughout the study.
10. Patients may not be taking any benzodiazepines at screening or throughout the study.
11. Patient has an advanced, severe, or unstable disease that may interfere with the study outcome evaluations.
12. Patient is expected to initiate or change pharmacologic or non-pharmacologic interventions during the course of the study.
13. Patient has an acute or progressive neurological disease, psychosis, schizophrenia, or any psychiatric disorder or severe mental abnormalities (other than Fragile X Syndrome) that are likely to require changes in drug therapy or interfere with the objectives of the study or the ability to adhere to protocol requirements.
14. Patient has a positive result for the presence of Hepatitis B Surface antigen (HBsAg), Hepatitis C virus antibodies (HCV), or human immunodeficiency virus (HIV) antibodies.
15. Has suspected or confirmed cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, 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 (e.g. heart failure, hypokalemia, family history of Long QT Syndrome), or other serious cardiac problems .
16. 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.
17. 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 trial drug.
18. History of treatment for, or evidence of, drug abuse within the past year.
19. Previous participation in a ZYN002 study.
20. 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
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Concealed allocation. (double-blind treatment group assignment); central randomization by IXRS
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to treatment according to a computer generated randomization scheme. Randomisation allocation to active or placebo treatment groups will use 1:1 allocation ratio. Randomisation will be stratified by gender (Male vs. Female), weight category (less than or equal to 35 kg vs. greater than 35 kg) and region.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The sample size was estimated for the primary efficacy endpoint using Power Analysis and Sample Size Software (PASS 15). A sample size of 102 patients per treatment group (204 patients total) will be enrolled.

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 by randomized treatment group.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
27/06/2018
Actual
28/06/2018
Date of last participant enrolment
Anticipated
29/04/2019
Actual
26/02/2020
Date of last data collection
Anticipated
15/05/2020
Actual
15/06/2020
Sample size
Target
204
Accrual to date
Final
212
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 10425 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [2] 11082 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 22893 0
2145 - Westmead
Recruitment postcode(s) [2] 22131 0
4101 - South Brisbane
Recruitment outside Australia
Country [1] 10232 0
New Zealand
State/province [1] 10232 0
Wellington
Country [2] 10233 0
United States of America
State/province [2] 10233 0

Funding & Sponsors
Funding source category [1] 298983 0
Commercial sector/Industry
Name [1] 298983 0
Zynerba Pharmaceuticals Pty. Ltd.
Country [1] 298983 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] 299053 0
None
Name [1] 299053 0
Address [1] 299053 0
Country [1] 299053 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299912 0
Bellberry Human Research Ethics Committee E
Ethics committee address [1] 299912 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 299912 0
Australia
Date submitted for ethics approval [1] 299912 0
28/03/2018
Approval date [1] 299912 0
22/05/2018
Ethics approval number [1] 299912 0
EC00450
Ethics committee name [2] 299979 0
Children's Health Queensland HREC
Ethics committee address [2] 299979 0
Lady Cilento Children’s Hospital Precinct
Level 7, 62 Graham Street
South Brisbane QLD 4101
Ethics committee country [2] 299979 0
Australia
Date submitted for ethics approval [2] 299979 0
11/06/2018
Approval date [2] 299979 0
Ethics approval number [2] 299979 0

Summary
Brief summary
This study is evaluating the efficacy and safety of ZYN002, a clear gel that can be applied to the skin (called transdermal application) twice a
day for treatment of symptoms of Fragile X Syndrome (FXS)

Who is it for?
Patients who have been diagnosed with Fragile X Syndrome and are aged between 3 and less than 18 years old.

Study details
All participants will undergo a screening process. Eligible participants will be randomized 1:1 to drug and placebo and will undergo up to a 14-week treatment period. Participants who are taking anti-epileptic drugs may undergo an additional 1-2 weeks of blinded treatment to taper off study drug treatment. During the treatment period, all participants may be either assigned to ZYN002 or placebo. All participants may receive placebo during the trial. The assignment will be done by a computer generated system and neither the study doctor or the participant or their caregivers will know which treatment is being given to them. The dose of the treatment will depend on the weight of the participants. If the participants weigh less than or equal to 35kg, they will receive 2 sachets of the gel through the day (1 sachet approximately every 12 hours) and if they weigh more than 35kg, they will receive 4 sachets of gel per day (2 sachets approximately every 12 hours). Parents/ caregivers will be instructed on proper application of the gel. The gel will be applied to clean, dry, intact skin of the upper arms/ shoulders.

Blood samples will be collected for safety analysis of ZYN002. An independent analytical laboratory will also perform CGG repeat and methylation status analyses. Additionally, the parents/caregivers will be asked to complete some questionnaires. There will be other questionnaires and scales that will be completed at the site by the study doctor and/or with the participant and their parents/caregivers.

Participation in this study may help the child’s/ adolescent’s FXS symptoms; however, we cannot guarantee that he/ she will get any benefits from this study. The results of this study may benefit future patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81966 0
Dr Helen Heussler
Address 81966 0
Lady Cilento Children's Hospital
501 Stanley St, South Brisbane QLD 4101
Country 81966 0
Australia
Phone 81966 0
+617 3068 2920
Fax 81966 0
Email 81966 0
h.heussler@health.qld.gov.au
Contact person for public queries
Name 81967 0
Dr Nancy R. Tich
Address 81967 0
Zynerba Pharmaceuticals Inc, 80 West Lancaster Ave., Suite 300, Devon, PA 19333
Country 81967 0
United States of America
Phone 81967 0
+1-973-727-4117
Fax 81967 0
Email 81967 0
Tichn@zynerba.com
Contact person for scientific queries
Name 81968 0
Dr Donna Gutterman
Address 81968 0
Zynerba Pharmaceuticals Inc., 80 West Lancaster Ave., Suite 300, Devon, PA 19333
Country 81968 0
United States of America
Phone 81968 0
+1-919-522-8828
Fax 81968 0
Email 81968 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
We are not releasing IPD (Individual patient data) into the public domain


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
No additional documents have been identified.