A study where all patients receive the test drug, in order to understand the consequences of long-term test drug use on the human body. All patients are children, adolescents and young adults who suffer from an inherited disease called Fragile X Syndrome, which affects their intellectual and behavioral development. The majority of patients in this study have previously participated in a study with the test drug, and continue taking the test drug in this study because their carers feel it had helped them.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Harmony Biosciences Management Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

26 Jul 2024 → 22 Apr 2026

Decision date (initial)

2024-05-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Harmony Biosciences Management, Inc.

External identifiers

EU CT number

2023-508165-33-00

ClinicalTrials.gov

NCT03802799

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the long-term safety and tolerability of ZYN002 administered as a transdermal gel formulation, for up to 48 months, in the treatment of symptoms of Fragile X Syndrome (FXS).

Secondary objectives 1

1. To evaluate the long-term efficacy of ZYN002 in the treatment of symptoms of FXS.

Conditions and MedDRA coding

Fragile X Syndrome (FXS)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003176-PIP02-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Must have completed protocol ZYN2-CL-033.
2. Male or female children and adolescents aged 3 to <23 years, at the time of entry into ZYN2-CL-033.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Females of childbearing potential must have a negative pregnancy test at all designated visits.

Exclusion criteria 19

1. 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.
2. Use of cannabis or any THC or CBD-containing product within 3 months of entry or during the study (aside from ZYN002).
3. 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.
4. Patient is using the following AEDs: clobazam, phenobarbital, ethosuximide, felbamate, carbamazepine, phenytoin, or vigabatrin.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. History of significant allergic condition, significant drug-related hypersensitivity, or allergic reaction to any compound or chemical class related to ZYN002 or its excipients.
11. Patient has an advanced, severe, or unstable disease that may interfere with the study outcome evaluations.
12. 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.
13. Patient has a positive result for the presence of HBsAg, HCV, or HIV antibodies.
14. 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.
15. 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.
16. 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.
17. History of treatment for, or evidence of, drug abuse within the past year.
18. Previous participation in a ZYN002 study (with the exception of patients who completed or did not enter ZYN2-CL-033).
19. Patient responds “yes” to Question ‘4’ or ‘5’ on the C-SSRS (Children) during Screening or at any time on study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Safety assessments will include collection of AEs including seizure assessment if applicable, physical and neurological examinations, 12-lead ECG, safety laboratory assessments (hematology, chemistry, reproductive hormone, prolactin tests, and urinalysis), vital signs, C-SSRS, and findings from the skin irritation checks following treatment.

Secondary endpoints 11

1. Change from Baseline (last assessment prior to the first dose of ZYN002) in the ABC-CFXS subscale scores (Social Avoidance, Irritability, Socially Unresponsive/Lethargic, Stereotypy, Inappropriate Speech, and Hyperactivity) at Months 1, 6, 12, 18, 24, 30, 36, 42, and 48/ET.
2. CGI-I at Months 1, 6, 12, 24, 36, and 48/ET.
3. Percent of patients who have ≥25% improvement from Baseline in ABC-CFXS Social Avoidance subscale score at Months 1, 6, 12, 18, 24, 30, 36, 42, and 48/ET.
4. Percent of patients who have ≥25% improvement from Baseline in ABC-CFXS Irritability subscale score at Months 1, 6, 12, 18, 24, 30, 36, 42, and 48/ET.
5. Response rate for patients having both ≥25% improvement from Baseline in ABC-CFXS Social Avoidance subscale score AND improved on CGI-I scale at Months 1, 6, 12, 18, 24, 30, 36, 42, and 48/ET.
6. Response rate for patients having both ≥25% improvement from Baseline in ABC CFXS Irritability subscale score AND improved on CGI-I scale at Months 1, 6, 12, 18, 24, 30, 36, 42, and 48/ET.
7. Percent of patients indicating improvement on the CGI-I (dichotomized) scale at Months 1, 6, 12, 24, 36, and 48/ET.
8. Change from Baseline in CGI-S at Months 1, 6, 12, 24, 36, and 48/ET.
9. Change from Baseline/Day 1 in Caregiver Global Impression of Severity at Months 6, 12, 24, 36, and 48/ET.
10. Caregiver Global Impression of Change at Months 6, 12, 24, 36, and 48/ET.
11. Change from Baseline in PedsQL at Month 6, and Month 12

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Harmony Biosciences Management Inc.

Sponsor organisation

Harmony Biosciences Management Inc.

Address

630 West Germantown Pike Suite 215

City

Plymouth Meeting

Postcode

19462-1069

Country

United States

Scientific contact point

Organisation

Harmony Biosciences Management Inc.

Contact name

Paul Kirsch

Public contact point

Organisation

Harmony Biosciences Management Inc.

Contact name

Paul Kirsch

Third parties 13

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications