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Trial registered on ANZCTR


Registration number
ACTRN12616000674437
Ethics application status
Approved
Date submitted
19/05/2016
Date registered
24/05/2016
Date last updated
26/09/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Study of ZYN002 (transdermal gel) in 42 Healthy Volunteers
Scientific title
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Single-Center, Multiple-Dose Study to Assess the Safety and Pharmacokinetics of ZYN002 Administered as a Transdermal Gel to Healthy Subjects
Secondary ID [1] 289256 0
ZYN2-CL-08
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 298832 0
Condition category
Condition code
Neurological 298893 298893 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A total of 42 eligible subjects will be randomized in 1:1:1:1:1:1:1 ratio to one of the seven treatment cohorts. Then within a cohort, a subject will be further randomized in 2:1 ratio to receive either ZYN002 or placebo. Therefore, six eligible unique subjects will be randomized to a treatment cohort. Within a treatment cohort, four subjects will be randomized to receive ZYN002 and two subjects will be randomized to receive placebo. Participants will be randomised to one of seven treatment groups as indicated below.
Treatment A – 10 g of 2.5% ZYN002 or placebo applied twice daily (AM and PM) to right and left upper arms/shoulders (Total active daily dose 500mg)
Treatment B – 10 g of 2.5% ZYN002 or placebo applied twice daily (AM and PM) to right and left upper thighs (Total active daily dose 500mg)
Treatment C – 10 g of 2.5% ZYN002 or placebo applied twice daily on right and left upper arms/shoulders AM and right and left upper thighs (PM) (Total active daily dose 500mg)
Treatment D – 6 g of 4.2% ZYN002 or placebo applied twice daily (AM and PM) to right and left upper arms/shoulders (Total active daily dose 504mg)

Treatment E – 6 g of 4.2% ZYN002 or placebo applied twice daily on right and left upper arms/shoulders AM and right and left upper thighs (PM) (Total active daily dose 504mg)
Treatment F – 4.7 g of 4.2% ZYN002 or placebo applied twice daily (AM and PM) to right and left upper arms/shoulders (Total active daily dose 394.8mg)
Treatment G – 4.7 g of 4.2% ZYN002 or placebo applied twice daily on right and left upper arms/shoulders AM and right and left upper thighs (PM) (Total active daily dose 394.8mg)
Participants will receive the same number of treatments of placebo gel as the number of active study drug in order to keep the study blinded.
The gel will be thoroughly massaged into right and left upper arms/shoulders or right and left upper thighs by the participant. Once the participant has completed their treatment application they will be instructed to wash their hands thoroughly with soap and water to remove any residual gel. Participants will be instructed to not lay or lean on either shoulder/arm, for at least 30 minutes post dosing/ Subjects will be permitted to shower more than 90 minutes prior to each morning’s dosing.. Dosing period will be 13 days plus one morning dose on day 14. Adherence to treatment will be monitored by empty gel syringe return and collection and review of participant dosing diary.
Intervention code [1] 294800 0
Treatment: Drugs
Comparator / control treatment
Placebo - matching gel with no active ingredient
Control group
Placebo

Outcomes
Primary outcome [1] 298363 0
Primary Outcome 1: To evaluate the safety and tolerability of ZYN002 administered as a transdermal gel formulation twice daily for 13 consecutive days with a morning dose on day 14 to healthy subjects.
Assessed by: monitoring physical examinations, examination of skin application site, vital signs, 12-lead ECG, laboratory tests, the Columbia Suicide Severity Rating Scale (C-SSRS) testing and adverse events throughout the study. Possible adverse events could include- appetite change, diarrhoea, sleepiness.application site skin dryness.
Timepoint [1] 298363 0
Timepoint: Daily examination and monitoring for up to and including 20 days after final treatment dose
Secondary outcome [1] 323944 0
Secondary Outcome 1: To evaluate the pharmacokinetics (PK) of ZYN002 (CBD) and Delta 9-tetrahydrocannabinol (THC) assessed in plasma.

Assessed by: collecting blood samples for analysis. PK parameters include-Cmax, Tmax, AUC.

Timepoint [1] 323944 0
Timepoint: Blood samples collected daily through days 1-15, 17, 19, 21, 23, 27, 31 and 35 days.

Eligibility
Key inclusion criteria
Main Inclusion Criteria:
1. Healthy male or female adults, 18-55 years of age, inclusive, 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, 12-lead ECG, and clinical laboratory test results. Laboratory results outside of the reference range, but acceptable, must be documented as not clinically significant (NCS) at the discretion of the investigator.
3. Subjects have a body mass index between 18-34 kg/m2.
4. Females of childbearing potential must have a negative pregnancy test at the Screening Visit and pre-dose on Day 1, Day 7 and Day 14.
5. Subject agrees to abide by all study restrictions and comply with all study procedures.
6. Subject must be adequately informed of the nature and risks of the study and give written informed consent prior to screening.
7. In the investigator’s opinion, the subject is reliable and is willing and able to comply with all protocol requirements and procedures.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Main Exclusion Criteria:
Any of the following is considered criterion for exclusion:
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. Use of tobacco/nicotine-containing products within one month of Screening Visit or during study.
3. Subjects using any prescription drugs except hormonal contraception or herbal supplements within four weeks prior to the Screening Visit or any OTC drugs/vitamins within 72 hours prior to first dose of study medication.
4. Use of cannabis or any CBD-containing product within 4 weeks of Screening Visit or during the study.
5. Positive result for the presence of Hepatitis B surface antigen (HBsAg), Hepatitis C virus antibodies (HCV-Ab), or human immunodeficiency virus (HIV) antibodies.
6. Positive drug screen for ethanol, cocaine, Delta 9-tetrahydrocannabinol (THC), barbiturates, amphetamines, benzodiazepines, and opiates.
7. 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.
8. 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.
9. Use of cosmetics on the shoulder/upper arms or thighs, during the study period.
10. 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.
11. Has taken grapefruit products within the last four weeks or during the study.
12. 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 until the End of Study Visit.
13. 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.
14. Has suspected or confirmed cardiovascular disease.
15. Participation in any investigational product or device study within 30 days prior to Screening Visit (except clinical study ZYN2-CL-01 or ZYN2-CL-02), or is scheduled to participate in an investigational device or another investigational drug study during the course of this study.
16. Patient has a history of actual suicide attempt in the last 5 years or more than one lifetime suicide attempt.
17. Patient responded “yes” to Question 4 or 5 of C-SSRS during Screening.
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 will be blinded to which treatment the participant is receiving. 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 the first randomization number for the participant. 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 will be prepared by a statistician. The software application SAS will be used to generate the randomization codes. A series unique codes will be issued on a per protocol treatment cohort allocation. On Day 1 eligible healthy subjects will be randomized to one of the seven treatment cohorts receiving randomized treatment twice daily. Subjects in each treatment cohort will be randomized to receive either active treatment or placebo in a 2:1 ratio.
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
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Pharmacokinetics: PK parameters listed above for ZYN002 (CBD) and THC will be calculated/derived from the data using non-compartmental analysis with WinNonlin. Actual sampling times and actual dose will be used to estimate plasma PK parameters. 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 by treatment group and time point. Differences in dose-dependent PK parameters (Cmax,ss, Cmin,ss, Cav,ss, AUC) between Treatments (A-G) will be compared via an Analysis of Variance (ANOVA) model or an appropriate non-parametric approach.
The pre-dose Ctrough plasma levels over the days of dosing will be compared statistically for assessment of steady-state for each ZYN002 dose level. Attainment of steady-state will be concluded if the 90% CI for the geometric mean ratio between two consecutive time points (i.e. Day 10 vs. Day 8) is completed within the acceptance range of (0.80 – 1.25).
Safety Analyses: All subjects who receive at least one dose of study drug will be included in the safety analysis.
AEs will be classified by system organ class and preferred term using the MedDRA version 19.0 or higher. AEs and SAEs will be tabulated by treatment group. Additionally, the total number of AEs and the total number of subjects with AEs will be identified for each treatment.
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. ECGs, safety laboratory test results and change from baseline will also be tabulated by treatment group. 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
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 5822 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 13273 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 293633 0
Commercial sector/Industry
Name [1] 293633 0
Zynerba Pharmaceuticals Inc.
Address [1] 293633 0
80 West Lancaster Avenue
Suite 300
Devon, PA 19333
Country [1] 293633 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] 292468 0
None
Name [1] 292468 0
Address [1] 292468 0
Country [1] 292468 0
Other collaborator category [1] 278998 0
Commercial sector/Industry
Name [1] 278998 0
Novotech (Australia) Pty Limited
Address [1] 278998 0
Level 3, 235 Pyrmont St
Pyrmont NSW 2009
Australia
Country [1] 278998 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295070 0
Bellberry
Ethics committee address [1] 295070 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 295070 0
Australia
Date submitted for ethics approval [1] 295070 0
27/04/2016
Approval date [1] 295070 0
26/05/2016
Ethics approval number [1] 295070 0
2016-04-314

Summary
Brief summary
What is this study about The purpose of this study is to investigate how safe and tolerable repeat doses (applied twice daily for 13 days and once on the 14th day) of ZYN002 transdermal gel is in healthy volunteers. The study will look at how the body absorbs the study drug. This will be done by analysing the levels of ZYN002 in your blood at various times following drug administration.
Your skin at the application sites and your hands will be checked to see if there is any irritation or reactions present after ZYN002 application. In the study you will be provided with moisturizer to apply to assist with potential dryness of the skin caused by the study treatment.
Who is if for? You may be eligible to join this study if you are aged between 18 and 55 years and are in general good health.

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..Throughout the study you will have various medical tests (physical examinations, vital signs measured, ECG measured, C-SSRS assessment and will have several blood and urine samples collected for laboratory analysis.

You will report to the clinic your first day of treatment (Day 1). The study treatment will be applied twice daily for 13 days with one treatment on day 14. Days 1-13, each morning while at the research facility, you will apply your AM treatment of ZYN002 or placebo gel. You will apply the study treatment to the treatment site assigned to you (either your left and right shoulder and/or upper arms, or your left and right upper thighs). You will apply your AM dose of all the study drug to clean, dry, intact skin, thoroughly massaging it into the application sites assigned. You will continue to massage study drug into the application site until the application site feels dry to the touch. This will take approximately 2-4 minutes but everyone’s skin is different so it could take less or more time for you. You will repeat this procedure at your home for the afternoon application on Days 1 to 13. You will return to the research facility every morning on Days 1-13 for the AM dose. On Day 14 you will stay at the research facility until the evening of Day 15, 36 hours after the last study treatment. You will return to the research facility on Days 17, 19, 21, 23, 27, 31 and Day 35 for study assessments.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65998 0
Dr Jessica Bunker
Address 65998 0
Q-Pharm Pty Limited, Level 5, 300C Herston Road, Herston QLD 4006
Country 65998 0
Australia
Phone 65998 0
+61 7 3845 3636
Fax 65998 0
+61 7 3845 3637
Email 65998 0
J.Bunker@qpharm.com.au
Contact person for public queries
Name 65999 0
Ms Carol O’Neill
Address 65999 0
VP, Development
Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333
Country 65999 0
United States of America
Phone 65999 0
+1-484-581-7481
Fax 65999 0
Email 65999 0
oneillc@zynerba.com
Contact person for scientific queries
Name 66000 0
Dr Donna Gutterman
Address 66000 0
VP, Medical Affairs
Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333
Country 66000 0
United States of America
Phone 66000 0
+1-484-581-7481
Fax 66000 0
Email 66000 0
guttermand@zynerba.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary