Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615001025527
Ethics application status
Approved
Date submitted
17/09/2015
Date registered
1/10/2015
Date last updated
27/09/2016
Type of registration
Prospectively registered

Titles & IDs
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
Secondary ID [1] 287241 0
NIL
Universal Trial Number (UTN)
Nil
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 295848 0
Condition category
Condition code
Neurological 296103 296103 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 292529 0
Treatment: Drugs
Comparator / control treatment
Placebo– matching gel with no active ingredient
Control group
Placebo

Outcomes
Primary outcome [1] 295773 0
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.
Timepoint [1] 295773 0
Daily examination and monitoring for 5 days after treatment application
Secondary outcome [1] 316502 0
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
Timepoint [1] 316502 0
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 [2] 316503 0
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
Timepoint [2] 316503 0
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] 316504 0
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.
Timepoint [3] 316504 0
The Trail Making Test will be administered at pre-dose and 2, 4, 6, 8, and 24 hours post study drug application.

Eligibility
Key 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).
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key 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 protocol.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The trial site will receive a list of randomization numbers to be used in the study but the list of numbers will not denote which treatment the participant is receiving.

The trial site Pharmacist will be in possession of a sealed opaque envelope. The outside of each of the envelopes will be labelled with the randomization number. Inside the envelope will be the randomization sequence assigned to the specific randomization number. A sealed envelope will only be opened by the site if the blind is required to be broken.

The trial site will screen and enroll subjects that meet the study criteria. Once it is determined the subject/patient qualifies to participate in the study the site will choose from the randomization list the first randomization number for the participant. The randomization list does not denote the treatment the participant is receiving. The site will continue to use the next randomization number in the sequence provided for each subsequent subject enrolled, until they have randomized the appropriate number of subjects for the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A randomization schedule has been prepared by a statistician. The software application SAS was used to generate the randomization codes. A series unique codes have been issued on a per protocol allocation ratio of 3:1.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
Placebo-Controlled, Double-Blinded, Single
Center, Single, Ascending-Dose Study
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Pharmacokinetics: Descriptive statistics (arithmetic mean, median, standard deviation, minimum, maximum, coefficient of variation, geometric mean) for the individual PK parameters and plasma concentration over time will be presented. Actual sampling times will be used to estimate plasma PK parameters.
Neuropsychological Tests: Neuropsychological parameters will be summarized for each treatment period and time point using descriptive statistics (number of subjects, mean, standard deviation [SD], median, minimum, and maximum).
Safety Analyses: AEs will be tabulated and classified by system organ class and preferred term using the Medical Dictionary for Regulatory Affairs (MedDRA).
Vital signs collected by time point will be summarized using descriptive statistics and presented by treatment. Changes from baseline in the vital signs will also be summarized by treatment. Safety laboratory tests results and change from baseline will also be tabulated by treatment group. Pulse oximetry measured over the 24-hour treatment period will be summarized by treatment. Application site irritation will be summarized using counts and percentages for each treatment and time point.
Sample size for the study is chosen for the purpose of the study. No formal statistical assumptions are used to determine the sample size.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
20/10/2015
Actual
20/10/2015
Date of last participant enrolment
Anticipated
20/11/2015
Actual
12/04/2016
Date of last data collection
Anticipated
Actual
16/04/2016
Sample size
Target
44
Accrual to date
Final
42
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 291808 0
Commercial sector/Industry
Name [1] 291808 0
Zynerba Pharmaceuticals Inc.
Country [1] 291808 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Zynerba Pharmaceuticals Inc.
Address
80 West Lancaster Avenue
Suite 300
Devon, PA 19333
Country
United States of America
Secondary sponsor category [1] 290470 0
None
Name [1] 290470 0
Address [1] 290470 0
Country [1] 290470 0
Other collaborator category [1] 278577 0
Commercial sector/Industry
Name [1] 278577 0
Novotech (Australia) Pty Limited
Address [1] 278577 0
Level 3, 235 Pyrmont Street, Pyrmont, NSW 2009
Country [1] 278577 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293325 0
QIMR Berghofer Medical Research Institute-HREC
Ethics committee address [1] 293325 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Ethics committee country [1] 293325 0
Australia
Date submitted for ethics approval [1] 293325 0
22/06/2015
Approval date [1] 293325 0
24/07/2015
Ethics approval number [1] 293325 0

Summary
Brief summary
What is this study about? The purpose of this study is to investigate how safe and tolerable a single dose of ZYN002 transdermal gel is in healthy participants and patients with epilepsy. The study will look at how the body absorbs, distributes, breaks down and then removes the study drug from your body. This will be done by analysing the levels of ZYN002 in your blood and urine at various times following drug administration. Your skin at the application site will be checked to see if there is any irritation or reactions present after ZYN002 application. The study will also investigate the effect that ZYN002 has on your visual attention and ability to complete a simple task. The task requires you to ‘connect-the-dots’ of 25 consecutive dots as fast as possible.

Who is if for? You may be eligible to join this study if you are aged between 18 and 55 years and are either in general good health or have epilepsy with partial onset seizures that is stable.

Study details: This study will investigate various doses of ZYN002 compared to a placebo gel (a treatment with no active ingredients which looks like the real thing but it is not). This study is ‘double-blind’ which means you and your study doctor, together with the study staff administering the study treatment will not know whether you are receiving ZYN002 or placebo gel.

What does study participation involve? Your participation in the study includes a screening visit, which could be up to 28 days before your study treatment; One confinement period starting on the evening before dosing and lasting until 48 hours after the study treatment i.e. a total of about 62 hours (2.5 days). This will require three (3) nights in the clinic. There are also two out-patient clinic visits following the confinement period on Days 4 and 5. These visits will be at 72 and 96 hours after the application of the study treatment. Additional out-patient visits may be required if there is any skin irritation present at the study treatment application site.
Throughout the study you will have various medical tests (physical examinations, vital signs measured, ECG measured, neuropsychological tests) and will have several blood and urine samples collected for laboratory analysis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 59394 0
Dr ICHHYA SHRESTHA
Address 59394 0
Q-Pharm Pty Limited, Level 5, 300C Herston Road, Herston QLD 4006
Country 59394 0
Australia
Phone 59394 0
+61 73845 3636
Fax 59394 0
+61 7 3845 3637
Email 59394 0
[email protected]
Contact person for public queries
Name 59395 0
Ms Carol O’Neill
Address 59395 0
VP, Development
Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333
Country 59395 0
United States of America
Phone 59395 0
+ 1 484-581-7481
Fax 59395 0
Email 59395 0
[email protected]
Contact person for scientific queries
Name 59396 0
Ms Donna Gutterman
Address 59396 0
VP, Medical Affairs
Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333
Country 59396 0
United States of America
Phone 59396 0
+ 1 484-581-7481
Fax 59396 0
Email 59396 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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