Study of ZYN002 (transdermal gel) in Healthy Volunteers and Patients with Epilepsy

• Register: ANZCTR
• Last refreshed on: 13 January 2020
• Main ID: ACTRN12615001025527
• Date of registration: 01/10/2015
• Prospective Registration: Yes
• Primary sponsor: Zynerba Pharmaceuticals Inc.
• Public title: Study of ZYN002 (transdermal gel) in Healthy Volunteers and Patients with Epilepsy
• Scientific title: A Phase 1, Five-Period, Randomized, Placebo-Controlled, Double- Blinded, Single Center, Single, Ascending-Dose Study to Assess the Safety and Pharmacokinetics of ZYN002 Administered as a Transdermal Gel to Healthy Subjects and Patients with Epilepsy
• Date of first enrolment: 20/10/2015
• Target sample size: 44
• Recruitment status: Stopped early
• URL: https://anzctr.org.au/ACTRN12615001025527.aspx
• Study type: Interventional
• Study design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Other;Type of endpoint: Safety;
• Phase: Phase 1

Countries of recruitment

Australia

Contacts

• Name: Ms Carol O’Neill

• Name: Ms Donna Gutterman

Key inclusion & exclusion criteria

Inclusion criteria: 1. Healthy male or female adults, 18-55 years of age,
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.
3. Patients enrolled in Part 2 must have a diagnosis of epilepsy with partial onset seizures that is stable. Currently seizure-free or controlled on one or two antiepileptic drugs [AEDs] with a monthly seizure frequency of less than 5 seizures per month. The patient should have had the diagnosis for at least one year which has been documented by review of the most informative electroencephalogram (EEG), scan (either computed tomography [CT] or magnetic resonance imaging [MRI]), and narrative, including detailed descriptions of each seizure type from the physician who manages the patient’s epilepsy. The historical baseline of seizures over the previous 8 weeks should show a reasonably stable pattern of seizure occurrence without clustering of seizures.
4. Patients enrolled in Part 2 must be on a stable dose (no changes in AED regimen for the 4 weeks preceding study enrollment) of no more than two approved AEDs limited to: gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate, lacosamide, and zonisamide. Patients must remain on a stable AED dose regimen throughout the study.
5. Subject/patient has a body mass index between 18-30 kg/m2.
6. Females of childbearing potential, must have a negative urine pregnancy test at the Screening Visit and a negative urine pregnancy prior to study treatment.
7. Subject/patient agrees to abide by all study restrictions and comply with all study procedures.
8. Subject/patient must be adequately informed of the nature and risks of the study and give written informed consent prior to screening.
9. In the investigator’s opinion, the subject/patient is reliable and is willing and able to comply with all protocol requirements and procedures (including keeping an accurate diary of seizures, scheduled visits and confinement periods).

Exclusion criteria: 1. Females who are pregnant, nursing or planning a pregnancy; females of childbearing potential who are unwilling or unable to use an acceptable method of contraception as outlined in this protocol from at least 21 days prior to the first dose of study medication and for 28 days after the last dose of study medication.
a. Standard acceptable methods include abstinence or the use of a highly effective method of contraception, including; hormonal contraception, diaphragm, cervical cap, vaginal sponge, condom, vasectomy, intrauterine device.
2. Patients with epilepsy enrolled in Part 2 cannot have a history of status epilepticus or the occurrence of seizure clusters (bouts of seizures so close together that an accurate seizure counts are not possible).
3. Use of tobacco/nicotine-containing products within one month of Screening Visit or during study.
4. Use of the following AEDs: phenytoin, carbamazepine, phenobarbital, oxcarbazepine and valproate, valproic acid, tiagabine, ethosuximide, clobazam, clonazepam, or vigabatrin.
5. Use of any prescription drugs except hormonal contraception and AEDs (for patients in Part 2), or herbal supplements within four weeks prior to Screening or any over-the-counter (OTC) drugs/vitamins within 72 hours prior to first dose of study medication through the End of Study Visit.
6. Use of cannabis or any cannabidiol (CBD)-containing product within four weeks of the Screening Visit or during the study.
7. Positive result for the presence of Hepatitis B surface antigen (HBsAg), Hepatitis C virus antibodies (HCVAb), or human immunodeficiency virus (HIV) antibodies.
8. Positive drug screen, for ethanol, cocaine, delta-9-tetrahydrocannabinol (THC), barbiturates, amphetamines, benzodiazepines (except clonazepam when prescribed as an AED medication), and opiates.
9. 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.
10. Any skin disease or condition, including eczema, psoriasis, melanoma, acne or contact dermatitis, scarring, imperfections, lesions, tattoos or discoloration that may affect treatment application, application site assessments, or affect absorption of the study drug.
11. Use of cosmetics or lotions on the shoulder/upper arms during the study.
12. History of significant allergic condition, significant drug-related hypersensitivity, or allergic reaction to any adhesives, compound, or chemical class related to ZYN002 or its excipients.
13. Has taken caffeine or xanthine products within 24 hours of dosing. Has taken grapefruit products within the last four weeks or during the study.
14. History of treatment for, or evidence of alcohol or drug abuse within the past year or regular alcohol consumption exceeding an average of two units of alcohol per day.
15. History or current diagnosis of a significant psychiatric disorder that would, in the opinion of the investigator, affect the subject’s ability to comply with the study requirements.
16. Has suspected or confirmed cardiovascular disease.
17. Participation in any investigational product or device study within 30 days prior to Screening Visit, or is scheduled to participate in an investigational device or another investigational drug study during the course of this study.
18. Demonstrates behavior indicating unreliability or inability to comply with the requirements of the proto

Age minimum: 18 Years
Age maximum: 55 Years
Gender: Both males and females

Health Condition(s) or Problem(s) studied

Epilepsy;
Epilepsy

Neurological - Epilepsy

Intervention(s)

During the first part of the study with 32 healthy volunteers, participants will be randomised to one of five treatment groups as indicated below.
- Treatment A: 5 g of 1% ZYN002
- Treatment B: 10 g of 1% ZYN002
- Treatment C: 5 g of 2.5% ZYN002
- Treatment D: 10 g of 2.5% ZYN002
- Treatment E: 5 g or 10g of placebo
During the second part of the study with 12 patients diagnosed with epilepsy, will receive the highest tolerated dose (Treatment A, B, C or D) from the first part of study or placebo.
ZYN002 or placebo gel will be applied to the skin on the right or left shoulder and/or upper arm as a single application.
The gel will be thoroughly massaged into the shoulders and/or upper arms by a member of the research facility. Participants will not be permitted to wash their shoulder and/or upper arm (application site) for at least 12 hours after application.

Primary Outcome(s)

To evaluate the safety and tolerability of two concentrations and two doses of ZYN002 in healthy volunteers to determine the appropriate dose for administration to patients with epilepsy.
Assessed by: monitoring physical examinations, examination of skin application site, vital signs, 12-lead ECG, laboratory tests, neuropsychological tests and adverse events throughout the study. Possible adverse events could include- appetite change, diarrhoea, sleepiness.
[Daily examination and monitoring for 5 days after treatment application
]

Secondary Outcome(s)

Secondary Outcome 2: evaluate the pharmacokinetics (PK) of tetrahydrocannabinol assessed in plasma and urine
Assessed by: collecting blood and urine samples for analysis.
PK parameters include-Cmax, Tmax, AUC
[Blood samples collected at pre-treatment, 15, 30 minutes, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours after treatment. Urine collection will be completed at the following time intervals: 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours and 36 to 48 hours]

Secondary Outcome 1: evaluate the pharmacokinetics (PK) of ZYN002 assessed in plasma and urine
Assessed by: collecting blood and urine samples for analysis.
PK parameters include-Cmax, Tmax, AUC
[Blood samples collected at pre-treatment, 15, 30 minutes, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours after treatment. Urine collection will be completed at the following time intervals: 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours and 36 to 48 hours]

Secondary Outcome 3: To administer neuropsychological tests to determine the effect of ZYN002 on visual attention, task switching, capacity and rate of information processing
Assessed by: neuropsychological tests known as the Trail Making Test. The Trail Making Test is a neuropsychological test of visual attention and task switching. It consists of Part A and Part B in which the subject is instructed to connect a set of dots as fast as possible while maintaining accuracy.
[The Trail Making Test will be administered at pre-dose and 2, 4, 6, 8, and 24 hours post study drug application.]

Secondary ID(s)

NIL

Source(s) of Monetary Support

Zynerba Pharmaceuticals Inc.

Ethics review

Status: Approved
Approval date:
Contact:

QIMR Berghofer Medical Research Institute-HREC