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

Study Overview

• Status: Completed
• Conditions: 22Q11.2 Deletion Syndrome
• Intervention / Treatment: Drug: ZYN002

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Lady Cilento Children's Hospital - South Brisbane
  • Victoria
    • Melbourne, Victoria, Australia, 3161
      • Genetics Clinics Australia
• United States
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenwood Genetic Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Open-label

Drug: ZYN002; Synthetic CBD (sCBD) Transdermal Gel pharmaceutically manufactured. sCBD formulated as a clear gel (transdermal delivery). Dose received is based on weight. 1. Participants who weigh ≤ 35 kilogram (kg) will receive 125 mg CBD Q12H (every 12 hours ± 2 hours); for a total daily dose of 250 mg CBD. 2. Participants who weigh > 35 kg will receive 250 mg CBD Q12H (±2 hours) for a total daily dose of 500 mg CBD. Patients in both weight ranges ≤ 35 kg or > 35 kg may receive an increased daily dose of 500 mg sCBDor 750 mg sCBD, respectively.; Other Names: Cannabidiol Transdermal Gel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (SAEs)	An adverse event (AE) is an undesirable medical occurrence or worsening of a pre-existing medical condition that occurs at any time after signing of the informed consent form whether or not it is considered to be related to treatment. Any AE that results in one or more of the following is considered a SAE: death, life threatening, in-patient hospitalization, persistent or significant disability/incapacity, congenital abnormality or birth defect, and other medically important events. TEAEs are defined as AEs with onset dates on or after the start of study drug. Adverse event data were collected as a single arm because, based on pharmacokinetics modeling, exposure is consistent between doses.	From first dose of study drug administration (Day 1) up to end of the study, approximately 306 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Aberrant Behavior Checklist - Community (ABC-C) at Week 14 (Period 1) and Week 38 (Period 2)	The Aberrant Behavior Checklist - Community (ABC-C) instrument is a scale for rating inappropriate and maladaptive behavior of participants with developmental disabilities, including intellectual disability and autism spectrum disorder. The ABC-C was completed by the parent/caregiver with support from the site staff. The ABC-C asks responders to rate behaviors from "0= not at all a problem" to "3= the problem is severe in degree" across 58 questions. The ABC-C consists of 5 subscales: hyperactivity noncompliance subscale (scale range from 0 to 48), irritability subscale (scale range from 0 to 45), inappropriate speech subscale (scale range from 0 to 12), stereotypic behavior subscale (scale range from 0 to 21) and social withdrawal subscale (scale range from 0 to 48). Total scores range from 0 (not at all a problem) to 174 (the problem is severe in degree). Higher scores indicate higher severity. Baseline was defined as the last assessment prior to the first dose of ZYN002.	Period 1: Baseline (Day 1) and Week 14 (Day 98 ± 3 days); Period 2: Week 14 (Day 98 ± 3 days) and Week 38 (Day 266 ± 3 days).
Change From Baseline in Anxiety, Depression and Mood Scale (ADAMS) at Week 14 (Period 1) and Week 38 (Period 2)	The Anxiety, Depression and Mood Scale (ADAMS) was completed by the parent/caregiver with support from the site staff. The ADAMS is comprised of 28 items (question 3 is counted in two subscales), which are rated on a scale of "0=not a problem" to "3=severe problem". The ADAMS consists of 5 subscales: depressed mood subscale (scale range from 0 to 21), general anxiety subscale (scale range from 0 to 21), manic/hyperactive behavior subscale (scale range from 0 to 15), obsessive/compulsive behavior subscale (scale range from 0 to 9) and social avoidance subscale (scale range from 0 to 21). Total score range is 0 to 84. Higher scores indicate higher severity/worse outcome. Baseline was defined as the last assessment prior to the first dose of ZYN002.	Period 1: Baseline (Day 1) and Week 14 (Day 98 ± 3 days); Period 2: Week 14 (Day 98 ± 3 days) and Week 38 (Day 266 ± 3 days).Period 2: Baseline (Day 1 of
Change From Baseline in Clinical Global Impression-Severity (CGI-S) at Week 14 (Period 1) and Week 38 (Period 2)	The Clinical Global Impression-Severity (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment relative to the clinician's past experience with participants who have the same diagnosis. Considering total clinical experience, a participant was assessed on severity of mental illness at the time of rating as follows: 1= normal, not at all ill; 2= borderline mentally ill; 3= mildly ill; 4= moderately ill; 5= markedly ill; 6= severely ill; or 7= extremely ill. The CGI-S score range from 0 (not a problem) to 7 (severe problem). Higher scores indicate higher severity. Baseline was defined as the last assessment prior to the first dose of ZYN002.	Period 1: Baseline (Day 1) and Week 14 (Day 98 ± 3 days); Period 2: Week 14 (Day 98 ± 3 days) and Week 38 (Day 266 ± 3 days).
Number of Participants With Clinical Global Impression-Improvement (CGI-I) at Week 14 (Period 1) and Week 38 (Period 2)	The CGI-I is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1= very much improved; 2= much improved; 3= minimally improved; 4= no change; 5= minimally worse; 6= much worse; or 7= very much worse. Baseline was defined as the last assessment prior to the first dose of ZYN002. Higher scores indicate worse outcome.	Period 1: Week 14 (Day 98 ± 3 days); Period 2: Week 38 (Day 266 ± 3 days).
Number of Participants With Changes in Caregiver Reported Behavioral Problems at Week 14 (Period 1) and Week 38 (Period 2)	The parent/caregiver was asked the following question "What are the three behavioral, emotional, or social problems that most impacted your son/daughter and his/her family in approximately the past year?". At each study visit the parent/caregiver was reminded of their responses from the screening visit in order to rate the 3 questions for improvement or worsening.	Period 1: Week 14 (Day 98 ± 3 days); Period 2: Week 38 (Day 266 ± 3 days).
Change From Baseline in Pediatric Anxiety Rating Scale-Revised (PARS-R) Total Severity Score at Week 14 (Period 1) and Week 38 (Period 2)	The Pediatric Anxiety Rating Scale-Revised (PARS-R) is a clinician-rated caregiver interview that covers 61 behaviors related to anxiety. The interviewer assesses 7 items: overall severity of anxiety feelings; overall number, frequency, and severity of anxiety symptoms; overall severity of anxiety (physical symptoms); overall avoidance of anxiety-provoking situations; and anxiety interference with family and peer relationships and/or performance at home or outside of the home. Each of the 7 severity items was scored on a scale of 1 to 5, with 5 being the most severe and frequent. The total score for the PARS-R is the sum of the 7 items; range from 0 (not a problem) to 35 (severe problem). Higher scores indicate higher severity. Baseline was defined as the last assessment prior to the first dose.	Period 1: Baseline (Day 1) and Week 14 (Day 98 ± 3 days); Period 2: Week 14 (Day 98 ± 3 days) and Week 38 (Day 266 ± 3 days).
Plasma Concentrations of Cannabidiol and Δ9-tetrahydrocannabinol	Blood samples were collected to determine the plasma concentrations of cannabidiol and Δ9-tetrahydrocannabinol.	Week 14 (Day 98 ± 3 days) and Week 38 (Day 266 ± 3 days).

Collaborators and Investigators

• Sponsor: Harmony Biosciences Management, Inc.
• Collaborators: Zynerba Pharmaceuticals, Inc.
• Investigators: Study Director: Kristen Bzdek, MD, Harmony Biosciences Management, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2020
• Primary Completion (Actual): November 9, 2022
• Study Completion (Actual): November 9, 2022

Study Registration Dates

• First Submitted: October 5, 2021
• First Submitted That Met QC Criteria: December 7, 2021
• First Posted (Actual): December 8, 2021

Study Record Updates

• Last Update Posted (Actual): March 9, 2026
• Last Update Submitted That Met QC Criteria: February 16, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Velocardiofacial syndrome; DiGeorge syndrome; Shprintzen syndrome; 22qDS; Chromosome 22q11.2 deletion syndrome; Autosomal dominant Opitz G/BBB syndrome; Conotruncal anomaly face syndrome (CTAF); Velo-cardio-facial syndrome (VCFS); CATCH22 syndrome; Cayler cardio facial syndrome
• Additional Relevant MeSH Terms: Endocrine System Diseases; Musculoskeletal Diseases; Cardiovascular Diseases; Heart Diseases; Genetic Diseases, Inborn; Lymphatic Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Parathyroid Diseases; Cardiovascular Abnormalities; Heart Defects, Congenital; Abnormalities, Multiple; Chromosome Disorders; Lymphatic Abnormalities; Hypoparathyroidism; 22q11 Deletion Syndrome; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; DiGeorge Syndrome; Anticonvulsants; Cannabidiol
• Other Study ID Numbers: ZYN2-CL-031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to make individual participant data available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No