Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000874819
Ethics application status
Approved
Date submitted
25/05/2021
Date registered
6/07/2021
Date last updated
4/09/2023
Date data sharing statement initially provided
6/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Clinical study of cannabidiol in children, adolescents and young adults with Fragile X syndrome (RECONNECT)
Scientific title
A Randomized, Double-Blind, Placebo-Controlled Multiple-Center, Efficacy and Safety Study of ZYN002 Administered as a Transdermal Gel to Children, Adolescents and Young Adults with Fragile X Syndrome - RECONNECT
Secondary ID [1] 304014 0
ZYN2-CL-033
Universal Trial Number (UTN)
Trial acronym
RECONNECT
Linked study record
ACTRN12618001063202
ZYN2-CL-033 is a confirmatory Phase 3 trial of ZYN002 in patients with Fragile X syndrome (FXS).

Health condition
Health condition(s) or problem(s) studied:
Fragile X Syndrome 321637 0
Condition category
Condition code
Human Genetics and Inherited Disorders 319375 319375 0 0
Other human genetics and inherited disorders
Neurological 319376 319376 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomized, double-blind, placebo-controlled, multiple-center study, to assess the efficacy and safety of Cannabidiol (CBD) administered as ZYN002. ZYN002 is a pharmaceutically manufactured 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 a 18 week treatment period, and 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 30 kg, will receive 1 sachet of ZYN002, applied every 12 hours.
Participants who weigh more than 30 kg but less than or equal to 50 kg will receive 2 sachets of ZYN002, applied every 12 hours.
Participants who weigh more than 50 kg will receive 3 sachets of ZYN002, applied every 12 hours.

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

Four weeks after the final dose, patients will be followed up by a telephone call, 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] 320324 0
Treatment: Drugs
Comparator / control treatment
Treatment Group B (Placebo)
Participants randomized to Treatment Group B will receive placebo for 18 weeks.
Parents/caregivers will apply the study gel twice daily for the treatment period.
Participants who weigh less than or equal to 30 kg, will receive 1 sachet of Placebo, applied every 12 hours.
Participants who weigh more than 30 kg but less than or equal to 50 kg will receive 2 sachets of Placebo, applied every 12 hours.
Participants who weigh more than 50 kg will receive 3 sachets of Placebo, applied every 12 hours.
Control group
Placebo

Outcomes
Primary outcome [1] 327233 0
Change in the Aberrant Behavior Checklist-Community FXS specific [ABC-C(FXS)] Pre-Specified Subscale 1 score in patients with complete methylation (100%) of the FMR1 gene.
Timepoint [1] 327233 0
Change from Baseline to Week 18.
Secondary outcome [1] 394313 0
Change in ABC-C(FXS) ) Pre-Specified Subscale 2 score in patients with complete methylation of the FMR1 gene
Timepoint [1] 394313 0
Change from Baseline to Week 18
Secondary outcome [2] 394314 0
Change on the Caregiver Global Impression of Change (CaGI-C) for Pre-specified parameters among patients with complete methylation of the FMR1 gene
Timepoint [2] 394314 0
Week 18
Secondary outcome [3] 394315 0
Change on the Clinical Global Impression-Improvement (CGI-I) scale among patients with complete methylation of the FMR1 gene.
Timepoint [3] 394315 0
Week 18
Secondary outcome [4] 394316 0
Change in the ABC-C(FXS) Pre-Specified Subscale 1 score among all randomized patients (complete and partial methylation of the FMR1 gene).
Timepoint [4] 394316 0
Change from Baseline to Week 18
Secondary outcome [5] 397323 0
Ongoing evaluation of the safety and tolerability of ZYN002 Safety assessments will include collection of any adverse events, physical and neurological exams, clinical laboratory safety assessments, vital signs and 12-lead ECGs. In addition, the Penn Physician Withdrawal Checklist will be utilized to assess for any potential withdrawal characteristics of ZYN002. Skin tolerability to study drug application will be assessed through skin check assessments performed at each visit.
Timepoint [5] 397323 0
Day 1, Week 2. Week4, Week 6, Week 10, Week 14, Week 18

Eligibility
Key inclusion criteria
1. Male or female children, adolescents, and young adults aged 3 to <23 years, at the time of Screening.
2. Patient resides with caregiver who will continue to provide consistent care throughout the study.
3. 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.
4. Patients must have a diagnosis of FXS through molecular documentation of full mutation of the FMR1 gene documented through genetic testing at Screening.
5. Patients with an ABC-CFXS Pre-Specified Subscale 1 score at Screening and at Visit 2.
6. Patients with a history of seizure disorders must currently be receiving treatment with a stable regimen of no more than two AEDs for the four weeks preceding study Screening; or must be seizure-free for one year if not currently receiving AEDs.
7. Patients who are taking psychotropic medication(s) should be on a stable regimen of no more than three such medications for at least four weeks preceding study Screening and must maintain that regimen throughout the study. Psychotropic medications include (but are not limited to) antipsychotics, antidepressants, anxiolytics, attention-deficit / hyperactivity disorder (ADHD) medications, and medications for sleep.
8. 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.
9. Patients have a body mass index between 12–30 kg/m2 (inclusive).
10. 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.
11. 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. Parents/caregiver(s) must provide written consent to assist in trial drug administration.
12. Patients and parents/caregivers agree to abide by all study restrictions and comply with all study procedures, and in the Investigator’s opinion, are reliable and willing and able to comply with all protocol requirements and procedures.
Minimum age
3 Years
Maximum age
22 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.
Standard acceptable methods of contraception include abstinence (defined as refraining from heterosexual intercourse from screening to three months after the last dose of study medication) or the use of a highly effective method of contraception, including hormonal contraception, diaphragm, cervical cap, vaginal sponge, condom, spermicide, vasectomy, or intrauterine device. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception.
2. Patient has transitioned to independent living or living in a residential facility such as a university setting or congregate care.
3. History of significant allergic condition, significant drug-related hypersensitivity, or allergic reaction to any compound or chemical class related to ZYN002 or its excipients.
4. Exposure to any investigational drug or device less than or equal to 30 days prior to Screening or at any time during the study.
5. 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.
6. Use of cannabis or any THC or CBD-containing product within 3 months of Screening Visit or during the study (aside from ZYN002).
7. Patient has a positive drug screen, including ethanol, cocaine, THC, barbiturates, amphetamines (unless prescribed), benzodiazepines (except midazolam or comparable administered for blood draws and ECG collection), and opiates.
8. Patient is using the following AEDs: clobazam, phenobarbital, ethosuximide, felbamate, carbamazepine, phenytoin, or vigabatrin.
9. 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, St. John’s Wort, and grapefruit juice/products.
10. Patients may not be taking any benzodiazepines (except single doses administered for the purposes of obtaining blood samples and ECGs) 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 FXS) 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 HBsAg, HCV, or HIV antibodies.
15. Patient has known history of 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 (TdP) (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 (with the exception of patients who were screen failures in Study ZYN2-CL-016 [ACTRN12618001063202] and did not enter Study ZYN2-CL-017 [ACTRN12618001868279]).
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, and will be randomized 1:1 to either trial drug or placebo. Randomization will be stratified by gender (male, female), methylation status (complete, partial), and by weight (less than or equal to 50 kg, greater than 50 kg).
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 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Efficacy Analysis: The primary efficacy estimand is the difference between treatments (ZYN002 versus placebo) in change from Baseline to Week 18 ABC-C(FXS) Pre-specified subscale 1 score.
The primary outcome measure will be analyzed with a linear mixed model for repeated measures (MMRM). Safety Analyses will include a summary of all adverse events and quantitative measures of safety.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
24/11/2021
Actual
16/12/2021
Date of last participant enrolment
Anticipated
30/11/2023
Actual
Date of last data collection
Anticipated
26/04/2024
Actual
Sample size
Target
204
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 19164 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 19165 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 19166 0
Fragile X Alliance Inc. - Caulfield North
Recruitment hospital [4] 23715 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 33737 0
4101 - South Brisbane
Recruitment postcode(s) [2] 33738 0
2145 - Westmead
Recruitment postcode(s) [3] 33739 0
3161 - Caulfield North
Recruitment postcode(s) [4] 39151 0
5042 - Bedford Park
Recruitment outside Australia
Country [1] 23607 0
United States of America
State/province [1] 23607 0
Country [2] 23608 0
United Kingdom
State/province [2] 23608 0
Country [3] 23609 0
Ireland
State/province [3] 23609 0

Funding & Sponsors
Funding source category [1] 308395 0
Commercial sector/Industry
Name [1] 308395 0
Zynerba Pharmaceuticals Pty Ltd
Country [1] 308395 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] 309225 0
None
Name [1] 309225 0
Address [1] 309225 0
Country [1] 309225 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308358 0
Children's Health Queensland HREC
Ethics committee address [1] 308358 0
Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
62 Graham Street,
South Brisbane QLD 4101 Australia
Ethics committee country [1] 308358 0
Australia
Date submitted for ethics approval [1] 308358 0
27/04/2021
Approval date [1] 308358 0
27/05/2021
Ethics approval number [1] 308358 0
HREC/21/QCHQ/75302
Ethics committee name [2] 308359 0
BellBerry HREC
Ethics committee address [2] 308359 0
123 Glen Osmond Road Eastwood Adelaide
South Australia 5063
Ethics committee country [2] 308359 0
Australia
Date submitted for ethics approval [2] 308359 0
26/05/2021
Approval date [2] 308359 0
09/07/2021
Ethics approval number [2] 308359 0
2021-05-515
Ethics committee name [3] 308610 0
Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [3] 308610 0
The Sydney Children’s Hospitals Network (Randwick and Westmead) (incorporating The Royal Alexandra Hospital for Children), Hawkesbury Rd and Hainsworth St, Westmead, NSW, 2145
Ethics committee country [3] 308610 0
Australia
Date submitted for ethics approval [3] 308610 0
28/06/2021
Approval date [3] 308610 0
15/09/2021
Ethics approval number [3] 308610 0
2021/ETH01274

Summary
Brief summary
This study is evaluating the efficacy and safety of ZYN002, a pharmaceutically manufactured form of Cannabidiol (CBD) that is a clear gel that can be applied to the skin (called transdermal application). It is applied 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 with full mutation of FMR1 gene 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 or placebo and will undergo up to a 18-week treatment period. Participants who are taking anti-epileptic drugs may undergo an additional 1-3 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 30kg, they will receive 2 sachets of the gel through the day (1 sachet approximately every 12 hours), if they weigh more than 30kg but less than 50 kg they will receive 4 sachets of gel per day (2 sachets approximately every 12 hours) and if they weigh more than 50kg, they will receive 6 sachets of gel per day (3 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
FragileXhelp.com.au
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110438 0
A/Prof Helen Heussler
Address 110438 0
Queensland Children's Hospital
501 Stanley St, South Brisbane QLD 4101
Country 110438 0
Australia
Phone 110438 0
+61 7 3068 2920
Fax 110438 0
Email 110438 0
[email protected]
Contact person for public queries
Name 110439 0
Dr Stephen O’Quinn
Address 110439 0
Zynerba Pharmaceuticals Inc, 80 West Lancaster Ave., Suite 300, Devon, PA 19333
Country 110439 0
United States of America
Phone 110439 0
+1 919 271 1339
Fax 110439 0
Email 110439 0
[email protected]
Contact person for scientific queries
Name 110440 0
Dr Nancy R Tich
Address 110440 0
Zynerba Pharmaceuticals Inc, 80 West Lancaster Ave., Suite 300, Devon, PA 19333
Country 110440 0
United States of America
Phone 110440 0
+1 973 727 4117
Fax 110440 0
Email 110440 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
No additional documents have been identified.