Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000183280
Ethics application status
Approved
Date submitted
30/01/2018
Date registered
5/02/2018
Date last updated
26/04/2019
Date data sharing statement initially provided
26/04/2019
Date results information initially provided
26/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Study of ZYN002 (cannabidiol gel) in 40 Healthy Volunteers
Scientific title
A Phase 1, Randomized, Placebo-Controlled, Double-Blind, Multiple-Dose, Parallel-Group, Relative Bioavailability Study to Evaluate the Pharmacokinetics of ZYN002 (CBD) Following Application to the Skin of the Upper Arms/Shoulders Compared to Upper Arms/Shoulders and Upper Thighs
Secondary ID [1] 293915 0
ZYN2-CL-014
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fragile X Syndrome 306398 0
Epilepsy 306399 0
Osteoarthritis 306400 0
Condition category
Condition code
Mental Health 305484 305484 0 0
Other mental health disorders
Neurological 305485 305485 0 0
Epilepsy
Musculoskeletal 305486 305486 0 0
Osteoarthritis
Human Genetics and Inherited Disorders 305538 305538 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A total of 40 eligible subjects will be enrolled with 10 unique subjects per Cohort. Within each Cohort, subjects will be randomised in a 4:1 ratio to receive either ZYN002 gel (n=8) or placebo gel (n=2).
Subjects will be randomised to one of four Cohorts as indicated below:
Cohort A – 9.28 g of 4.2% ZYN002 or placebo applied twice daily (AM and PM) to upper arms/shoulders (Total active daily dose 780 mg).
Cohort B – 9.28 g of 4.2% ZYN002 or placebo applied twice daily AM to upper arms/shoulders and PM to upper thighs (Total active daily dose 780 mg).
Cohort C – 5.0 g of 7.5% ZYN002 or placebo applied twice daily (AM and PM) to upper arms/shoulders (Total active daily dose 780 mg).
Cohort D – 5.0 g of 7.5% ZYN002 or placebo applied twice daily AM to upper arms/shoulders and PM to upper thighs (Total active daily dose is 780 mg).
Subjects 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 subject will apply the gel to clean, dry, intact skin thoroughly massaging it into both the right and left shoulders and/or upper arms and/or right and left upper thighs, dependent on the treatment randomization. Dosing will be twice per day (every 12 hours).
On Day 1 after dose application, subjects will remove any residual gel from their hands with alcohol wipes after ZYN002 has been applied to each of the dose sites, prior to washing their hands with soap and water. After subsequent dose applications, the subject will wash their hands with soap and water.
The application site will remain dry for 6 hours post dosing. Subjects will not be permitted to wash their upper thighs, upper arms and/or shoulders (application sites) for at least 6 hours after application. Subjects are not allowed to swim, bathe, take saunas, or perform strenuous exercise that would cause sweating during the treatment period. Subjects may not shower within 60 minutes prior to each dose application.
The dosing period will be 13 days plus one morning dose on Day 14.
Treatment compliance will be monitored by study site staff supervising the application procedure.
Intervention code [1] 300185 0
Treatment: Drugs
Comparator / control treatment
Placebo - matching gel with no active ingredient
Control group
Placebo

Outcomes
Primary outcome [1] 304621 0
Primary Outcome 1: The primary objective of this study is to evaluate the relative bioavailability of ZYN002 (CBD) gel applied to the skin of the upper arms/shoulders (test) compared to the upper arms/shoulders and upper thighs (reference) following single and multiple dosing. The same amount of CBD will be applied although the amount of gel applied and the surface area of application will vary as well as the site of application.
Assessed by: collecting blood samples for analysis. PK parameters include: Cmax, Tmax, AUC.
Timepoint [1] 304621 0
Timepoint: Blood samples collected on Day 1 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose; on Days 8, 10 and 12 pre-dose; on Day 14 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose; Day 20 at follow-up.
Secondary outcome [1] 342594 0
Secondary Outcome 1: The secondary objective of this study is to evaluate the safety and tolerability of a ZYN002 7.5% CBD concentration (first in man) vs the 4.2% concentration of CBD following repeated application to healthy adult male and female 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, fatigue, tiredness, drowsiness, application site skin reactions (e.g. dryness, itching, inflammation, tingling or pain).
Timepoint [1] 342594 0
Timepoint: Daily examination and monitoring for up to and including 20 days after initial treatment dose.

Eligibility
Key inclusion criteria
1. Healthy male or female adults, 18-70 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 must have a body mass index between 18-30.4 kg/m2, inclusive.
4. Females of childbearing potential must have a negative pregnancy test at Screening and a negative pregnancy test on Day -1 at admission to the CRU. If females are of non-child bearing potential, they must be post-menopausal defined as: age > 55 with no menses within the past 12 months and with a follicle stimulating hormone (FSH) level > 40 IU/L or history of hysterectomy, or history of bilateral oophorectomy, or bilateral tubal ligation.
5. Males must consent to use a condom throughout the entire study period and for 90 days after their last study drug application. They must agree to not donate sperm for 90 days after their last study drug application.
6. Subject must agree to abide by all study restrictions and comply with all protocol requirements and study procedures.
Minimum age
18 Years
Maximum age
70 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, and male subjects with a partner 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 30 days after the last dose of study medication.
a. Standard acceptable methods include: males to use a condom, female participants and female partners of male participants who are women of child bearing potential to use an actual highly effective method of contraception (i.e. hormonal method with a <1% annual failure rate or an IUD), abstinence, and vasectomy.
2. Has eaten any food or drink/beverage containing alcohol, grapefruit or grapefruit juice, apple or orange juice, vegetables from the mustard family (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussel sprouts, or mustard), and charbroiled meats within one week prior to study start through the end of the study.
3. Use of tobacco/nicotine-containing products within one month of Screening Visit or during the study.
4. Use of any prescription drugs, except hormonal contraception, 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.
5. Use of cannabis or any CBD-containing product within four weeks of the Screening Visit or during the study.
6. Positive result for the presence of Hepatitis B surface antigen (HBsAg), Hepatitis C virus antibodies (HCV-Ab), or human immunodeficiency virus (HIV) antibodies.
7. Positive drug screen for ethanol, cocaine, delta-9-tetrahydrocannabinol (THC), barbiturates, amphetamines, benzodiazepines, and opiates at Screening and Day -1.
8. 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.
9. 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.
10. Use of cosmetics (excluding study moisturizer) on the shoulder/upper arms or upper thighs, during the study period.
11. 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.
12. History of treatment for, or evidence of alcohol or drug abuse within the past year or current alcohol consumption exceeding an average of two units of alcohol per day.
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, or is scheduled to participate in an investigational device or another investigational drug study during the course of this study.
16. Subject responded “yes” to Question 4 or 5 of C-SSRS during Screening and Day-1.
17. Demonstrates behaviour indicating unreliability or inability to comply with the requirements of the protocol.
18. Subject has a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds).
19. A history of additional risk factors for Torsades de pointes, (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
20. The use of concomitant medications that prolong the QT/QTc interval.
21. Subjects with ALT/AST >3 times the upper limit of normal.

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 enrol subjects that meet the study criteria. Once it is determined the subject 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 each study drug concentration and application site location.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated randomization schedule will be prepared by a statistician prior to study initiation. The site will receive a password protected file with only the randomization numbers to be used for each study treatment but will be blinded to which treatment the subject is receiving.
Subjects in each treatment cohort will be randomized to receive either active treatment or placebo in a 4:1 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
Pharmacokinetics
Statistical methods / analysis
Pharmacokinetics: PK parameters (Cmax, Tmax, AUC0-12) will be derived from the plasma concentration 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 Cohort and time point. Differences in dose-dependent PK parameters (Cmax, AUC0-12) between Cohort (A-D) will be compared via an Analysis of Variance (ANOVA) model or an appropriate non-parametric approach. Effect of application sites (Upper Arms/Shoulders only vs Upper Arms/Shoulders plus Upper thighs) on PK parameters will be assessed.
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 Medical Dictionary for Regulatory Affairs (MedDRA, version 20.1 or higher). The frequency of each AE term will be tabulated by treatment groups. Additionally, the total number of AEs and the total number of subjects with AEs will be identified for each treatment group.
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 and 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.
Concentration QTc analyses for time matched CBD concentrations and QTc intervals will be reported in a separate report.
Sample size for the study is chosen for the purpose of the study. The sample size is not based on a power calculation but is based on feasibility and the ability to determine the PK parameters for each site of application.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
5/02/2018
Actual
5/02/2018
Date of last participant enrolment
Anticipated
28/02/2018
Actual
28/02/2018
Date of last data collection
Anticipated
21/03/2018
Actual
9/05/2018
Sample size
Target
40
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 9944 0
Nucleus Network - Melbourne
Recruitment hospital [2] 9945 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 18757 0
3004 - Melbourne
Recruitment postcode(s) [2] 18758 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 298541 0
Commercial sector/Industry
Name [1] 298541 0
Zynerba Pharmaceuticals Pty. Ltd.
Country [1] 298541 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Zynerba Pharmaceuticals Pty. Ltd.
Address
Level 27, Freshwater Place
2 Riverside Quay
Southbank, VIC 3006
Country
Australia
Secondary sponsor category [1] 297687 0
Commercial sector/Industry
Name [1] 297687 0
CPR Pharma Services Pty Ltd
Address [1] 297687 0
28 Dalgleish Street
Thebarton
SA 5031
Country [1] 297687 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299513 0
Bellberry
Ethics committee address [1] 299513 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 299513 0
Australia
Date submitted for ethics approval [1] 299513 0
03/01/2018
Approval date [1] 299513 0
24/01/2018
Ethics approval number [1] 299513 0
2018-01-002

Summary
Brief summary
What is this study about? The purpose of this study is to investigate if ZYN002 applied by massaging it into the upper thighs provides the same amount of drug as when it is applied by massaging it into the arms/shoulders after repeat doses (applied twice daily for 13 days and on the morning of Day 14). Two concentrations of ZYN002 will be tested; one concentration containing 4.2% cannabadiol (CBD) and one containing 7.5% CBD. The study will look at blood levels of the drug in the body after it is administered in these three body locations in different people. How safe and well tolerated ZYN002 is will also be investigated.

Who is it for? You may be eligible to join this study if you are aged between 18 and 70 years and are in general good health.

Study details: This study will enrol a maximum of 40 participants across 4 treatment groups with 10 participants in each group, and will investigate the amount of ZYN002 detected in blood samples after administration of the treatment. In each group, 8 participants will receive the active drug (ZYN002) and 2 will receive the placebo. A placebo is a gel that looks like ZYN002 but does not contain any active ingredients. You will not have a choice as to whether you receive ZYN002 or the placebo (you will be assigned randomly, like flipping a coin). Neither you nor the study staff will know if you are assigned to receive ZYN002 or the placebo as the allocation will be masked, although in an emergency, the study staff can find out.

What does study participation involve? Participation in the study includes a screening visit during the 28 days before the first study treatment. Throughout the study participants 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.

Participants will report to the study centre on the day prior to the first day of treatment (Day 1) and will be required to remain in the study centre overnight for 15 nights, until Day 15. The study treatment will be applied twice daily for 13 days with one treatment on Day 14. Days 1-13, while at the study centre, you will apply your AM and PM treatment of ZYN002 or placebo gel. You will apply the study treatment to the treatment site assigned to you (either your upper arms/shoulders and/or your upper thighs). You will apply your dose of 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. On Day 14 there will be only an AM dose. You will be discharged on Day 15 and return to the study centre on Day 20 for a follow-up assessment visit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80674 0
Dr Jason Lickliter
Address 80674 0
Nucleus Network Limited, Level 5, Burnet Institute, AMREP Precinct, 89 Commercial Road, Melbourne, Victoria, 3004
Country 80674 0
Australia
Phone 80674 0
+61 3 9076 8960
Fax 80674 0
+61 3 9076 8911
Email 80674 0
[email protected]
Contact person for public queries
Name 80675 0
Ms Carol O’Neill
Address 80675 0
VP, Development
Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333
Country 80675 0
United States of America
Phone 80675 0
+1-484-581-7481
Fax 80675 0
Email 80675 0
[email protected]
Contact person for scientific queries
Name 80676 0
Ms Carol O’Neill
Address 80676 0
VP, Development
Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333
Country 80676 0
United States of America
Phone 80676 0
+1-484-581-7481
Fax 80676 0
Email 80676 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No data sharing plan was required at the time of participant enrollment for this trial.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.