Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000104459
Ethics application status
Approved
Date submitted
22/12/2015
Date registered
1/02/2016
Date last updated
7/09/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A multiple dose study of ZYN002 (transdermal gel) in Healthy Volunteers and Patients with Epilepsy
Scientific title
A Phase 1, Three-Period, Randomized, Double-Blind, Placebo-Controlled, Multiple- Center, Multiple-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] 288214 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 297123 0
Condition category
Condition code
Neurological 297359 297359 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
During the first part of the study with 24 participants ,periods 1 and 2, participants will be randomised to one of four treatment groups as indicated below.
Treatment A – (2 tubes of 5 g = 10 g) of 2.5% ZYN002 applied once daily for 7 days (Period 1 – Healthy Volunteers)
Treatment B – (2 tubes of 5 g = 10 g) of 2.5% ZYN002 applied twice daily for 7 days (Period 2 – Healthy Volunteers)
Treatment C – (2 tubes of 5 g = 10 g) of Placebo gel applied once (Period 1) or twice daily (Period 2) for 7 days. 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.
Treatment D – (2 tubes of 5 g = 10 g) of 1.0% ZYN002 applied twice daily for 7 days (Period 2 – Healthy Volunteers)
During the second part of the study (Period 3 – Patients with Epilepsy) with 12 participants, participants will receive the highest tolerated dose (Treatment A or B or D) from the first part of the study or placebo (Treatment C).
ZYN002 or placebo will be applied to the skin on the left and right shoulder and/or upper arm as a single application.
The gel will be thoroughly massaged into the left and right shoulders and/or upper arms 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. Once the application sites are dry each participant will wear a long sleeved t-shirt. Participants will be provided a clean t-shirt on a daily basis. Subjects will be permitted to shower more than 1 hour prior to each morning’s dosing. All doses supervised by study staff at study site. Subjects are confined during the dosing period.
Intervention code [1] 293509 0
Treatment: Drugs
Comparator / control treatment
Placebo - matching gel with no active ingredient
Control group
Placebo

Outcomes
Primary outcome [1] 296912 0
Primary Outcome 1: To evaluate the safety and tolerability of ZYN002 administered as a transdermal gel formulation either once daily or twice daily for seven consecutive days to healthy subjects 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] 296912 0
Timepoint: Daily examination and monitoring for up to and including 6 days after treatment application
Secondary outcome [1] 319682 0
Secondary Outcome 1: To evaluate the pharmacokinetics (PK) of ZYN002 (CBD) and delta-9-tetrahydrocannabinol (THC) assessed in plasma and urine.

Assessed by: collecting blood and urine samples for analysis. PK parameters include-Cmax, Tmax, AUC.
Timepoint [1] 319682 0
Blood samples collected at pre-treatment, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 and 144 hours after treatment. A baseline urine sample (=15 mL) will be collected prior to the first dosing. Complete urine samples will be collected for the following time intervals on Day 7: 0 to 12 hours, and 12 to 24 hours.
Secondary outcome [2] 319683 0
To compare the PK of ZYN002 between healthy subjects and epilepsy patients and once daily and twice daily application of either a 1% or 2.5% concentration.
Timepoint [2] 319683 0
Blood samples collected at pre-treatment, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 and 144 hours after treatment. A baseline urine sample (=15 mL) will be collected prior to the first dosing. Complete urine samples will be collected for the following time intervals on Day 7: 0 to 12 hours, and 12 to 24 hours.
Secondary outcome [3] 319684 0
To administer neuropsychological assessments to determine the neuropsychological effects of ZYN002
Assessed by: Trail Making Tests A and B, Paced Auditory Serial Addition Test [PASAT], Divided Attention Test [DAT], Addiction Research Center Inventory Measurement of Euphoria [ARCI], Positive and Negative Affect Schedule [PANAS], Inventory of Depression and Anxiety Symptoms [IDAS], and Columbia Suicide Severity Rating Scale [CSSRS]
Timepoint [3] 319684 0
The neuropsychological assessments will be administered at pre-dose and 2, 4, 8, and 11 hours post study drug application.

Eligibility
Key inclusion criteria
1. Healthy male or female adults, 18-55 years of age, inclusive, at the time of screening for subjects enrolling in Periods 1 and 2; and male or female patients having a diagnosis of epilepsy with partial onset seizures, 18 – 55 years of age, inclusive, at the time of screening for patients enrolling in Period 3.
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. Patients enrolled for Period 3 must have a diagnosis of epilepsy with partial onset seizures with or without associated generalized tonic-clonic seizures (so called secondarily generalized seizures). Patients having ONLY generalized tonic-clonic seizures may be included ONLY if these seizures are considered to be a manifestation of partial onset seizures. The Patient’s epilepsy should be stable, i.e., currently seizure-free OR controlled by one or two antiepileptic drugs [AEDs] with an average monthly seizure frequency of less than 5 seizures per month.
4. The patient should have a confirmed epilepsy diagnosis for at least one year, with a history of assessments, such as 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.
5. Patients enrolled in Period 3 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: carbamazepine, clonazepam, gabapentin, lacosamide, lamotrigine, levetiracetam, pregabalin, topiramate, valproate, valproic acid, or zonisamide. Patients must remain on a stable AED dose regimen throughout the study.
6. Subjects in Periods 1-2 have a body mass index between 18-30 kg/m2. Patients in Period 3 have a body mass index between 18-32 kg/m2.
7. Females of childbearing potential must have a negative pregnancy test at the Screening Visit and on Day -1.
8. Subject/patient agrees to abide by all study restrictions and comply with all study procedures.
9. Subject/patient must be adequately informed of the nature and risks of the study and give written informed consent prior to screening.
10. 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 seizure diary, 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 Period 3 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: clobazam, ethosuximide, oxcarbazepine, phenytoin, phenobarbital, tiagabine, or vigabatrin.
5. For subjects in Period 1 and 2 use of 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.
6. For patients in Period 3 use of any prescription drugs except hormonal contraception, AEDs, antidepressants (except citalopram, vilazodone, and trazodone) or herbal supplements within four weeks prior to the Screening Visitor any OTC drugs/vitamins within 72 hours prior to first dose of study medication.
7. Use of cannabis or any CBD-containing product within 4 weeks of Screening Visit or during the study.
8. Positive result for the presence of HBsAg, HCAb, or HIV antibodies.
9. Positive drug screen for ethanol, cocaine, delta-9-tetrahydrocannabinol (THC), barbiturates, amphetamines, benzodiazepines (except clonazepam when prescribed as an AED medication), and opiates.
10. 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.
11. 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.
12. Use of cosmetics or lotions on the shoulder/upper arms during the study.
13. 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.
14. Has taken grapefruit products within the last four weeks or during the study.
15. 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.
16. 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.
17. Has suspected or confirmed cardiovascular disease.
18. Participation in any investigational product or device study within 30 days prior to Screening Visit (except ZYN2-CL-01 study), or is scheduled to participate in an investigational device or another investigational drug study during the course of this study.
19. 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 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
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Sample size for the study is chosen for the purpose of the study. No formal statistical assumptions are used to determine the sample size.
Pharmacokinetics: PK parameters listed above for ZYN002 (CBD) and THC will be calculated/derived from the data using non-compartmental analysis with WinNonlin. Plasma PK will be calculated on Days 1 and 7, urine PK will be calculated on Day 7 only. Actual sampling times 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 period.
Differences in dose-dependent PK parameters (Cmax,ss, Cmin,ss, Cav,ss, AUC) between Treatment A and Treatment B in healthy subjects will be compared via an Analysis of Variance (ANOVA) model or an appropriate non-parametric approach. Similarly, differences between the healthy subjects and the patients will be compared using the same approach. The predose Ctrough plasma levels over all the days of dosing will be compared statistically for assessment of steady-state at each dose regimen using mixed effect ANOVA model. Attainment of steady-state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7 and 6/7 are completely within the acceptance range of (0.80 – 1.25).
Neuropsychological Tests: The neuropsychological assessment 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). The maximum change from pretreatment values, time to maximum change, and area under the change curve, will be calculated and summarized by treatment. In addition, the maximum change and area under the change curve will be
analyzed using t-tests comparing each treatment. The time to maximum change will be analysed using a Wilcoxon rank-sum test.
Safety Analyses: All subjects who receive at least one dose of study drug will be included in the safety analysis.
AEs will be tabulated and classified by system organ class and preferred term using the Medical Dictionary for Regulatory Affairs (MedDRA) 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. Safety laboratory test results and change from baseline will also be tabulated by treatment group. Pulse oximetry measured on Day 1 through Day 7 will be summarized by treatment. Application site irritation will be summarized using counts and percentages for each treatment and time point.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
23/12/2015
Date of last participant enrolment
Anticipated
12/05/2016
Actual
6/05/2016
Date of last data collection
Anticipated
Actual
24/05/2016
Sample size
Target
36
Accrual to date
Final
36
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 4991 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment hospital [2] 6021 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 12479 0
4006 - Herston
Recruitment postcode(s) [2] 13452 0
3050 - Royal Melbourne Hospital

Funding & Sponsors
Funding source category [1] 292602 0
Commercial sector/Industry
Name [1] 292602 0
Zynerba Pharmaceuticals Inc.
Country [1] 292602 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] 291319 0
None
Name [1] 291319 0
Address [1] 291319 0
Country [1] 291319 0
Other collaborator category [1] 278748 0
Commercial sector/Industry
Name [1] 278748 0
Novotech (Australia) Pty Limited
Address [1] 278748 0
Level 3, 235 Pyrmont St
Pyrmont NSW 2009
Australia
Country [1] 278748 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294083 0
QIMR Berghofer Medical Research Institute-HREC
Ethics committee address [1] 294083 0
Ethics committee country [1] 294083 0
Australia
Date submitted for ethics approval [1] 294083 0
02/11/2015
Approval date [1] 294083 0
18/12/2015
Ethics approval number [1] 294083 0
p2156
Ethics committee name [2] 295331 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [2] 295331 0
Ethics committee country [2] 295331 0
Australia
Date submitted for ethics approval [2] 295331 0
23/02/2016
Approval date [2] 295331 0
24/03/2016
Ethics approval number [2] 295331 0
HREC/16/MH/50

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62382 0
Dr Paul Griffin
Address 62382 0
Q-Pharm Pty Limited, Level 5, 300C Herston Road, Herston QLD 4006
Country 62382 0
Australia
Phone 62382 0
+61 73845 3636
Fax 62382 0
+61 7 3845 3637
Email 62382 0
[email protected]
Contact person for public queries
Name 62383 0
Carol O’Neill
Address 62383 0
Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333
Country 62383 0
United States of America
Phone 62383 0
+1-484-581-7481
Fax 62383 0
Email 62383 0
[email protected]
Contact person for scientific queries
Name 62384 0
Donna Gutterman
Address 62384 0
VP, Medical Affairs
Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333
Country 62384 0
United States of America
Phone 62384 0
+1-484-581-7481
Fax 62384 0
Email 62384 0
[email protected]

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