Long-Term Safety and Tolerability of ZYN002 Transdermal Gel in Pediatric and Young Adult Patients with Fragile X Syndrome
- Trial ID
- 2023-508165-33-00
- Protocol
- ZYN2-CL-017
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the long-term **safety** and tolerability of ZYN002, a transdermal gel formulation of cannabidiol (CBD), administered for up to 48 months in the treatment of symptoms associated with **Fragile X Syndrome (FXS)**. This objective is clinically relevant as it aims to ensure that prolonged use of ZYN002 is safe and well-tolerated in children, adolescents, and young adults with FXS, a genetic condition that affects intellectual and behavioral development.
Secondary objectives include evaluating the long-term efficacy of ZYN002 in the treatment of symptoms of FXS. This assessment is crucial for understanding the sustained therapeutic benefits of ZYN002 over an extended period, thereby informing its potential role in the management of FXS symptoms.
Participants
The clinical trial involves a total of **445 participants** diagnosed with **Fragile X Syndrome (FXS)**. The study population includes both male and female children and adolescents aged 3 to less than 23 years. Participants are required to be in generally good health, as determined by medical history, physical examination, 12-lead ECG, and clinical laboratory tests. The trial population was selected based on the completion of a prior protocol, ZYN2-CL-033. Relevant lifestyle considerations include the stability of any non-pharmacological behavioral and/or dietary interventions for at least three months prior to entry. Participants with a history of seizure disorders must be on a stable regimen of no more than two antiepileptic drugs (AEDs) or be seizure-free for one year if not currently receiving AEDs. Additionally, those taking psychotropic medications should be on a stable regimen of no more than three such medications for at least four weeks preceding study entry. The study includes individuals with a body mass index between 12 and 30 kg/m², and those with a BMI greater than 30 kg/m² but less than 40 kg/m², provided they have normal liver function and no immediate family history of fatty liver disease. The trial encompasses a vulnerable population, and both participants and their caregivers must agree to comply with all study procedures and restrictions.
Plans and Procedures
The clinical trial is designed to evaluate the long-term safety and tolerability of **ZYN002 Transdermal Gel Cannabidiol (CBD)** in children, adolescents, and young adults diagnosed with **Fragile X Syndrome (FXS)**. This open-label extension study will involve participants who have previously completed protocol ZYN2-CL-033. The trial will span up to 48 months, with the primary objective of assessing the safety profile of the transdermal gel formulation. The study will not employ a randomized, double-blind, or controlled design, as all participants will receive the investigational product.
Participants will be required to attend a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, health status, and previous participation in the ZYN2-CL-033 protocol. Follow-up visits will occur at regular intervals, specifically at Months 1, 6, 12, 18, 24, 30, 36, 42, and 48, or at the end of treatment (ET). These visits will include comprehensive safety assessments, such as adverse event monitoring, physical and neurological examinations, 12-lead ECGs, and laboratory tests. The end-of-study visit will conclude the participant's involvement, ensuring all safety and efficacy data are collected.
The expected duration of participant involvement is up to 48 months, contingent upon continued compliance with study procedures and absence of any conditions warranting early termination. Conditions that may lead to early withdrawal include significant adverse events, non-compliance with study protocols, or withdrawal of consent by the participant or their caregiver. The study aims to provide valuable insights into the long-term effects of **cannabidiol** treatment in managing symptoms associated with **Fragile X Syndrome**.
Treatment
The clinical trial involves the administration of **ZYN002 Transdermal Gel Cannabidiol (CBD)**, an experimental medication designed to evaluate its long-term safety and tolerability in individuals with Fragile X Syndrome. The active substance in this formulation is **cannabidiol**, a chemical compound derived from cannabis. The pharmaceutical form of the medication is a transdermal gel, which is applied directly to the skin, allowing for the active ingredient to be absorbed into the bloodstream through the dermal layers. The maximum daily dose of the gel is 750 mg, with a total maximum dose of 1.1 kg over the course of the treatment period. The treatment is administered via transdermal use, and the maximum treatment period is 49 days. The formulation is not specifically designed for pediatric use, although the study includes children, adolescents, and young adults.
In this study, **ZYN002** is the sole investigational product, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The study is an open-label extension, meaning that all participants and investigators are aware of the treatment being administered. The trial aims to assess the long-term safety and tolerability of the transdermal gel over a period of up to 48 months. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. The study is conducted under the sponsorship of Zynerba Pharmaceuticals Inc, and the product has been designated as an orphan drug, indicating its use in treating a rare condition.
Efficacy
Efficacy in this clinical trial will be assessed through a series of secondary endpoints designed to evaluate the impact of ZYN002 Transdermal Gel on symptoms of **Fragile X Syndrome**. The primary efficacy parameters include changes from baseline in the Aberrant Behavior Checklist-Community Fragile X Syndrome (ABC-CFXS) subscale scores, which cover Social Avoidance, Irritability, Socially Unresponsive/Lethargic, Stereotypy, Inappropriate Speech, and Hyperactivity. These assessments will be conducted at multiple timepoints: Months 1, 6, 12, 18, 24, 30, 36, 42, and 48 or at the end of treatment (ET).
Additional efficacy measures include the Clinical Global Impression-Improvement (CGI-I) scale, evaluated at Months 1, 6, 12, 24, 36, and 48/ET, and the percentage of patients achieving a ≥25% improvement from baseline in specific ABC-CFXS subscale scores. The response rate for patients showing both a ≥25% improvement in ABC-CFXS subscale scores and improvement on the CGI-I scale will also be calculated at the same intervals. Furthermore, changes from baseline in the Clinical Global Impression-Severity (CGI-S) and Caregiver Global Impression of Severity and Change will be assessed at specified months. The Pediatric Quality of Life Inventory (PedsQL) will be evaluated at Month 6 and Month 12 to further support efficacy outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Must have completed protocol ZYN2-CL-033.
- Male or female children and adolescents aged 3 to <23 years, at the time of entry into ZYN2-CL-033.
- Judged by the Investigator to be in generally good health at entry 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.
- 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 entry; or must be seizure-free for one year if not currently receiving AEDs.
- 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 entry. Psychotropic medications include (but are not limited to) antipsychotics, antidepressants, anxiolytics, attention-deficit / hyperactivity disorder (ADHD) medications, and medications for sleep.
- 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 entry.
- Patients have a body mass index between 12–30 kg/m2 (inclusive) and patients with a body mass index >30 kg/m2 and <40 kg/m2 with normal liver function laboratory values and with no immediate family history of fatty liver disease.
- 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.
- Patients and parents/caregivers must be adequately informed of the nature, risks of the study, and give written informed consent prior to enrollment in ZYN2-CL-017.
- Females of childbearing potential must have a negative pregnancy test at all designated visits.
Exclusion Criteria
- Patient is receiving or has received an investigational drug or device less than or equal to 30 days prior to screening, with the exception of ZYN002 or placebo in the previous Zynerba FXS trial, ZYN2-CL-033.
- Use of cannabis or any THC or CBD-containing product within 3 months of entry or during the study (aside from ZYN002).
- 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.
- Patient is using the following AEDs: clobazam, phenobarbital, ethosuximide, felbamate, carbamazepine, phenytoin, or vigabatrin.
- 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.
- Patients may not be taking any benzodiazepines (except single doses administered for the purposes of obtaining blood samples and ECGs) at entry or throughout the study.
- Patient has an ongoing serious adverse event (SAE) or has experienced an SAE in study ZYN2-CL-033 which, in the opinion of the Investigator, should exclude them from participation.
- Females who are pregnant, nursing, or planning a pregnancy; females of childbearing potential (fertile, following menarche and until becoming post-menopausal unless permanently sterile) 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 trial drug. 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 (acceptable only if associated with inhibition of ovulation), 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.
- Patients who have alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels ≥ 2 times the upper limit of normal (ULN) or has alkaline phosphatase levels ≥3 times the ULN as determined from patient safety laboratories.
- History of significant allergic condition, significant drug-related hypersensitivity, or allergic reaction to any compound or chemical class related to ZYN002 or its excipients.
- Patient has an advanced, severe, or unstable disease that may interfere with the study outcome evaluations.
- 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.
- Patient has a positive result for the presence of HBsAg, HCV, or HIV antibodies.
- 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.
- Any clinically significant condition or abnormal findings at entry that would, in the opinion of the Investigator, preclude study participation or interfere with the evaluation of the study medication.
- 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.
- History of treatment for, or evidence of, drug abuse within the past year.
- Previous participation in a ZYN002 study (with the exception of patients who completed or did not enter ZYN2-CL-033).
- Patient responds “yes” to Question ‘4’ or ‘5’ on the C-SSRS (Children) during Screening or at any time on study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Ireland | Not Recruiting | 26 Feb 2024 | 5 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ZYN002 Transdermal Gel CannabidiolCBD | Test | TRANSDERMAL GEL | TRANSDERMAL USE | 750 | 49 | PRD11007565 |