Open-Label Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With 22q11.2 Deletion Syndrome (INSPIRE)

An Open-Label Tolerability and Efficacy Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With 22q11.2 Deletion Syndrome

To evaluate the safety and tolerability of ZYN002 administered as a transdermal gel formulation, for up to 38 weeks, in participants ages 4 to <18 years, in the treatment of 22q.11.2 Deletion syndrome (22qDS).

This was an open-label study that assessed the safety, tolerability and efficacy of cannabidiol (CBD) administered as ZYN002, a transdermal gel, for the treatment of child and adolescent participants with 22qDS. Male and female participants with 22qDS were treated in Period 1 for 14 weeks. Participants that met study criteria were allowed to continue to Period 2 for an additional 24 weeks of treatment. At the end of the study, participants taking antiepileptic drug (AED) medication(s) had an additional one- or two-week Taper Period. Approximately 20 male and female participants, ages 4 to < 18 years, received ZYN002.

Inclusion Criteria:

1. Male or female children and adolescents aged 4 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, and clinical laboratory test results.
3. Participants must have a diagnosis of 22qDS confirmed by genetic testing.
4. Participants have a Clinical Global Impression-Severity (CGI-S) score of 4 or higher at Screening and Visit 2.
5. Participants must have a Pediatric Anxiety Rating Scale-Revised (PARS-R) severity score of 10 or higher at Screening and Visit 2.
6. Participants 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.
7. If participants are receiving non-pharmacological behavioral and/or dietary interventions, they must be stable for three months prior to Screening.
8. The participant has demonstrated stable calcium levels for one year prior to Screening.
9. Participants have a body mass index between 12-35 kg / m² (inclusive).
10. Females of childbearing potential must have a negative pregnancy test at the Screening Visit and a negative pregnancy test at all designated study visits.
11. Participants and parents/caregivers agree to abide by all study restrictions and comply with all study procedures.
12. Participants 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.
13. Parents/caregiver(s) must provide written consent to assist in study drug administration.
14. In the Investigator's opinion, participants and parents/caregivers are reliable and willing and able to comply with all protocol requirements and procedures.

Exclusion Criteria:

1. Females who are pregnant, nursing, or planning a pregnancy; females of childbearing potential and male participants 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. Participant has Alanine transaminase (ALT), Aspartate transaminase (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 Screening safety laboratories.
5. Use of cannabis or any Δ9-tetrahydrocannabinol (THC) or CBD-containing product within three months of Screening Visit or during the study.
6. The participant has a positive drug screen.
7. The participant is using the following AEDs: clobazam, phenobarbital, ethosuximide, felbamate, carbamazepine, phenytoin or vigabatrin.
8. Participant is using any strong inhibitor/inducer of CYP3A4 or sensitive substrate for CYP3A4 including but not limited to 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, St. John's Wort, and grapefruit juice/products.
9. Participant with diagnosis of known genetic disorder, other than 22qDS.
10. Participant has diagnosis of DiGeorge or Velocardiofacial syndrome without the presence of 22qDS.
11. Participant has a primary psychiatric diagnosis other than 22qDS or anxiety, including bipolar disorder, psychosis, schizophrenia, Post traumatic stress disorder (PTSD) or major depressive disorder.
12. Participant is on stable treatment of >6 months of not more than two psychoactive medications at screening or throughout the study (with the exception of one psychoactive medication prescribed for sleep).
13. Participant has an advanced, severe, or unstable disease that may interfere with the study outcome evaluations.
14. Participant is expected to initiate or change pharmacologic or non-pharmacologic interventions during the course of the study.
15. Participant has an acute or progressive neurological disease, or any psychiatric disorder or severe mental abnormalities that are likely to require changes in drug therapy or interfere with the objectives of the study or ability to adhere to protocol requirements.
16. Participant has a positive result for the presence of Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV), or Human immunodeficiency virus (HIV) antibodies.
17. Participants at risk of needing cardiovascular surgical repair within the upcoming 12 months.
18. Participant has unstable cardiovascular disease, such as advanced arteriosclerosis, 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), other serious or other clinically unstable cardiac problems as indicated by history, physical examination, or ECG.
19. 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.
20. Any skin disease or condition that may affect treatment application, application site assessments, or absorption of the study drug.
21. History of treatment for, or evidence of, drug abuse within the past year.
22. Participant responds "yes" to Question '4' or '5' on the Columbia Suicide Severity Rating Scale Children (C-SSRS) during Screening or at any time on study.