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Trial registered on ANZCTR


Registration number
ACTRN12617000150347
Ethics application status
Approved
Date submitted
18/01/2017
Date registered
27/01/2017
Date last updated
20/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1/2, Open-Label Study to Assess the Safety and Efficacy of ZYN002 Administered as a Transdermal Gel to Children and Adolescents with Fragile X Syndrome
Scientific title
A Phase 1/2, Open-Label Study to Assess the Safety and Efficacy of ZYN002 Administered as a Transdermal Gel to Children and Adolescents with Fragile X Syndrome
Secondary ID [1] 290947 0
None
Universal Trial Number (UTN)
Trial acronym
ZYN2-CL-009
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fragile X Syndrome 301680 0
Condition category
Condition code
Human Genetics and Inherited Disorders 301388 301388 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A Phase 1/2, Open-Label Study to Assess the Safety and Efficacy of ZYN002 Administered as a Transdermal Gel to Children and Adolescents with Fragile X Syndrome

This is a Phase 1/2, open-label, multiple-center, multiple-dose study, including a Part 1 and Part 2, to assess the safety and efficacy of ZYN002 administered as a transdermal gel for the treatment of children and adolescent patients ages 6 to 17 years with Fragile X Syndrome.

Part 1:
This study will have a screening period of up to 28 days prior to the study start, following which will be a 12 week titration/treatment period (Clinic visits every 2 weeks until week 12 i.e. Week 2, 4, 6, 8 and 12 except Week 10 which is conducted as a phone call) . A follow up phone visit be done 4 weeks post last dose.
Following the Screening period, eligible patients will be enrolled in the titration period to receive ZYN002 50 mg daily (Treatment A) for 2 weeks. At Week 2, the patient will report to the investigative site at which time the Investigator will assess and determine if the patient should increase dose to Treatment B, ZYN002 50 mg every 12 hours (100 mg daily dose) or remain at Treatment A. At Week 4, the patient will report to the investigative site and the investigator may again choose to increase the dose of the patient from Treatment A to Treatment B or increase from Treatment B to Treatment C which is 125 mg applied every 12 hours (250 mg daily dose). The investigator may also choose to decrease the patient’s dose at this visit. Escalation of the dose will depend on the Investigator assessment of ZYN002 tolerability and patient improvement using the CGI-I, VAS for anxiety, hyperactivity and tantrum/mood lability, as well as interview with caregiver(s) and Investigator clinical judgement. Through Week 6, dosing will be flexible (Treatment A, B or C) and, based on the Investigator judgement and the relevant assessments; the dose can be adjusted upward or downward as deemed appropriate. By Week 6, all participants should be on their maintenance dose for the remainder of the treatment period.

Part 2:
This part of the study will have a treatment period of up to 64 weeks. Week 12 visit of the Part 1 of the study will be the first day of the Part 2. From then on, there will be visits at Week 16 and Week 25 and then quarterly visits (every 13 weeks) through Week 64.
The dose of ZYN002 gel prescribed in this part of the study is the same as the maintenance dose prescribed in Part 1 which was decided based on the investigator’s judgement and relevant assessments that indicated if the participant was being benefitted from that dose or not.
During Part 2 of the study also, the investigator may decide to change the dose of the study drug again, based on the participant's response.
Participants who are not on anti-epileptic drugs (AEDs) will be allowed to discontinue study medication at week 64 without a taper, and the end of Part 2 visit can be completed at week 64 visit or once the necessary assessments are achieved.


The study drug ZYN002 will be applied as a transdermal gel i.e. on the skin. The gel will be applied to clean, dry, intact skin of the shoulders and/or upper arms by the parent/caregiver using gloves.
For times where non-compliance with study gel administration occurs, a missed dose can be taken up to 6 hr after the correct time for the missed dose (up to 18 hr after the last actual dose), but the next dose should be taken at the regular time (as little as 6 hours after the missed dose was taken). If a higher dose than is prescribed is administered, the parent/caregiver should notify the study doctor as soon as possible to determine appropriate actions.
Intervention code [1] 296894 0
Treatment: Drugs
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300785 0
The primary outcome is to evaluate the safety and tolerability of ZYN002 administered as a transdermal gel formulation for 12 weeks in Phase 1 or up to a total of 64 weeks in Phase 2 (plus taper, if necessary) as therapy for the treatment of symptoms of Fragile X Syndrome (FXS) This is assessed by the change from screening in the total score for the Anxiety, Depression and Mood scale (ADAMS), a validated scale for assessing anxiety, depression and mood disorders among individuals with mental retardation,
Timepoint [1] 300785 0
Part 1 of the study:
Weeks 2, 4, 6, 8, 10, and Week 12

Part 2 of the study:
Weeks 16, 25, 38, 51 and 64
Secondary outcome [1] 330844 0
Efficacy of ZYN002 in the treatment of symptoms of FXS determined by Clinical Global Impression-Improvement (CGI-I)
Timepoint [1] 330844 0
At Baseline , Weeks 2, 4, 8 and Week 12 for Part 1 of the study
Secondary outcome [2] 330917 0
Change from screening in the PARS-R (Pediatric Anxiety Rating Scale- Revised)
Timepoint [2] 330917 0
At Baseline and at Week 12
Secondary outcome [3] 330918 0
Change from screening in Aberrant Behavior Checklist–FXS specific (ABC-FXS)
Timepoint [3] 330918 0
At Baseline, Weeks 4, 8 and Week 12
Secondary outcome [4] 330919 0
Change from screening in Visual Analog Scale (VAS) for anxiety, hyperactivity and tantrum/mood lability
This is a composite secondary outcome
Timepoint [4] 330919 0
At Baseline, Weeks 2, 4, 8 and Week 12
Secondary outcome [5] 330920 0
Change from screening in Vineland Adaptive Behavior II (VABS-II)
Timepoint [5] 330920 0
At Baseline and Week 12
Secondary outcome [6] 330921 0
Change from screening in sleep onset, total sleep, sleep onset latency and nighttime awakenings. This a composite secondary outcome
This will be assessed by Sleep diaries which will be completed at Screening and Week 12/EOS by the particpant or parent/ caregiver.
Timepoint [6] 330921 0
At Baseline and Week 12
Secondary outcome [7] 330922 0
Change from screening in Pediatric Quality of Life (PedsQLTM)
Timepoint [7] 330922 0
At Baseline and Week 12

Eligibility
Key inclusion criteria
Main Inclusion Criteria:
1. Male or female children and adolescents aged 6–17 years, inclusive, 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 acceptable by both the Investigator and Sponsor.
3. Patients must have a diagnosis of FXS through molecular documentation of Fragile X Mental Retardation 1 (FMR1) full mutation.
4. Patients have a Pediatric Anxiety Rating Scale-Revised (PARS-R) score of at least 11 at screening.
5. Patients have Clinical Global Impression Severity (CGI-S) score of at least 3 at screening.
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 3 years if not currently receiving AEDs.
7. Patients should be on a stable regimen for the 4 weeks preceding study enrollment of no more than 2 of the following AEDs: gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate, lacosamide, eslicarbazepine, carbamazepine, oxcarbazepine, perampanel and zonisamide. Patients must remain on a stable AED dose throughout the study.
8. If patients are receiving non-pharmacological educational, behavioral, and/or dietary interventions, they must be stable and have been doing so for 2 months prior to screening.
9. Patients have a body mass index between 15–30 kg/m2.
10. Females of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at all designated 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 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 (including scheduled visits and confinement periods).
Minimum age
6 Years
Maximum age
17 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Main 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 3 months after the last dose of study medication.
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, spermicide, 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 plans to take another investigational drug at any time during the study.
4. Use of cannabis or any THC or CBD-containing product within 4 weeks of Screening Visit or during the study.
5. Patient is using the following AEDs: clobazam, phenobarbital, phenytoin, ethosuximide, felbamate or vigabatrin. If a benzodiazepine (excluding clobazam) is being used as a rescue medication, it will be counted as an AED if used more than two days a week.
6. Patient is using 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 and St. John’s Wort.
7. Advanced, severe, or unstable disease that may interfere with the study outcome evaluations.
8. Plan to initiate or change pharmacologic or non-pharmacologic interventions during the course of the study.
9. Suffering from 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.
10. Use of more than one antipsychotic and one anti-anxiety medication.
11. Has suspected or confirmed cardiovascular disease.
12. Patients may not be taking minocycline for the past 30 days or throughout the study.
13. 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.
14. Any skin disease or condition, including eczema, psoriasis, melanoma, acne, contact dermatitis, scarring, or a tattoo, that may affect treatment application, application site assessments, or absorption of the study drug.
15. History of treatment for, or evidence of, drug abuse within the past year.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not 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)
NSW,QLD,VIC

Funding & Sponsors
Funding source category [1] 295370 0
Commercial sector/Industry
Name [1] 295370 0
Zynerba Pharmaceuticals Ltd.
Address [1] 295370 0
Registered office is at at:
PricewaterhouseCoopers,
Level, 2 Riverside Quay
Southbank, VIC 3006, Australia
Country [1] 295370 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Zynerba Pharmaceuticals
Address
80 West Lancaster Avenue, Suite 300,
Devon, PA 19333
Country
United States of America
Secondary sponsor category [1] 294193 0
Commercial sector/Industry
Name [1] 294193 0
Covance Pty. Ltd.
Address [1] 294193 0
Level 3, 4 Research Park Drive
North Ryde, NSW 2113
Country [1] 294193 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296705 0
Children’s Health Queensland Hospital And Health Service Human Research Ethics Committee
Ethics committee address [1] 296705 0
Level 7, Centre for Children’s Health Research
Lady Cilento Children’s Hospital Precinct
62 Graham Street, South Brisbane QLD 4101
Ethics committee country [1] 296705 0
Australia
Date submitted for ethics approval [1] 296705 0
28/11/2016
Approval date [1] 296705 0
22/12/2016
Ethics approval number [1] 296705 0
HREC/16/QRCH/384

Summary
Brief summary
This is a phase 1/2, open label, multiple center, multiple dose study to assess the safety, and efficacy of ZYN002 administered as a transdermal gel for the treatment of children and adolescent patients ages 6 to 17 years with Fragile X Syndrome (FXS). Approximately 20 participants will be enrolled in this trial to assess the safety and efficacy of ZYN002 administered as a transdermal gel.

The initial dose is 50 mg daily (QD) (Treatment A). Patients can have their dose adjusted up to 50 mg every 12 hours (Q12 H) after 2 weeks (Treatment B), and further up to 125 mg Q12 H (Treatment C) at Week 4. Through Week 6, dosing will be flexible (Treatment A, B or C) and, based on the Investigator judgement and the relevant assessments; the dose can be adjusted upward or downward as deemed appropriate.

Patient safety will be monitored during study visits using standard measures, including physical exams, examination of skin at application site, vital signs (including oral or tympanic temperature), 12lead electrocardiograms (ECGs), a Modified Suicidality Checklist for FXS patient population, safety laboratory tests, urinalysis and Adverse Event (AE) monitoring.
Each participants will be followed up 4 weeks post patient's last dose of study drug.
If the participant has completed the Part 1 of this study (12 weeks of treatment) successfully and has shown a demonstrable response to ZYN-002, he/ she will have an opportunity to continue on to the Part 2 of the study which extends up to Week 64.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71814 0
A/Prof Helen Heussler
Address 71814 0
Lady Cilento Children's Hospital
Level 12, Clinical Directorate
501 Stanley St
South Brisbane QLD 4101
Country 71814 0
Australia
Phone 71814 0
+61404469296
Fax 71814 0
Email 71814 0
H.Heussler@health.qld.gov.au
Contact person for public queries
Name 71815 0
Dr Nancy R. Tich
Address 71815 0
Zynerba Pharmaceuticals
80 West Lancaster Avenue, Suite 300, Devon, PA 19333
Country 71815 0
United States of America
Phone 71815 0
+19737274117
Fax 71815 0
Email 71815 0
Tichn@zynerba.com
Contact person for scientific queries
Name 71816 0
Dr Nancy R. Tich
Address 71816 0
Zynerba Pharmaceuticals
80 West Lancaster Avenue, Suite 300, Devon, PA 19333
Country 71816 0
United States of America
Phone 71816 0
+19089554776
Fax 71816 0
Email 71816 0
Tichn@zynerba.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary