ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12616001104448

Ethics application status

Approved

Date submitted

3/08/2016

Date registered

16/08/2016

Date last updated

10/10/2017

Type of registration

Prospectively registered

Titles & IDs

Public title

Study of ZYN002 (transdermal gel) in Patients with Knee Pain due to Osteoarthritis

Scientific title

A Phase 2A, Randomized, Double-Blind, Placebo-Controlled, Multiple Center, Multiple-Dose Study to Assess the Efficacy and Safety of ZYN002 Administered as a Transdermal Gel to Patients with Knee Pain due to Osteoarthritis

Secondary ID [1]

ZYN2-CL-005

Universal Trial Number (UTN)

Nil

Trial acronym

STOP 1

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Osteoarthritis

Condition category

Condition code

Musculoskeletal

Osteoarthritis

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Participants will undergo a 1-week Washout Period to discontinue current anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs)) and other analgesics (except acetaminophen) followed by a 1-week Baseline Period capturing daily pain ratings using a 0 to 10 numeric rating scale (NRS). After the washout and baseline periods, participants will receive one of three treatments as indicated below:
- Treatment A: ZYN002 – CBD 250 mg every 12 hours, or
- Treatment B: ZYN002 – CBD 125 mg every 12 hours, or
- Treatment C: placebo every 12 hours
for 12 weeks.

ZYN002 or placebo gel will be applied to the skin of both the right and left shoulder and/or upper arms.

Participants will bring used and unused sachets to each visit for site to check treatment compliance.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo - matching gel with no active ingredient

Control group

Placebo

Outcomes

Primary outcome [1]

To evaluate the efficacy of ZYN002 administered as a transdermal gel for 12 weeks as treatment for knee pain due to osteoarthritis (OA) of the knee.
Assessed by: change in weekly mean of the 24-hour average worst pain score, change in Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) score, rescue pain medication usage,

Timepoint [1]

Assessed at every study visit from Screening visit to End of study visit (baseline, Day 1, Weeks 4, 8 and 12).

Secondary outcome [1]

To evaluate the safety of ZYN002 in osteoarthritis (OA) patients.
Assessed by: monitoring side effects, physical examinations, electrocardiogram and neurological exams.
Studies to date have demonstrated that ZYN002 is generally well tolerated with most common side effect is site application dryness. There have also been some reports of headache. Most side effects have been mild in nature and similar between placebo patients and those receiving ZYN002.

Timepoint [1]

Safety will be assessed at every study visit from Screening visit to End of study visit (baseline, Day 1, Weeks 4, 8 and 12).

Secondary outcome [2]

To evaluate the tolerability of ZYN002 in osteoarthritis (OA) patients.
Assessed by: skin assessment, blood and urine tests, measuring vital signs, completion of Columbia Suicidality Severity Rating Scale (C-SSRS) and presence of effusion in the knee.

Timepoint [2]

Tolerability will be assessed at every study visit from Screening visit to End of study visit (baseline, Day 1, Weeks 4, 8 and 12).

Eligibility

Key inclusion criteria

- Eligible participants are those who are aged 40 to 75 years
- moderate to severe knee pain due to OA, are in general good health
- body mass index between 18-40 kg /m2
- able and willing to maintain daily pain and skin diaries, able to read, speak and understand English.
- Females of childbearing potential must have a negative serum pregnancy test and must agree to use an acceptable method of contraception. Males with a partner of childbearing potential must use an acceptable method of contraception.

Minimum age

40 Years

Maximum age

75 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- participants who are allergic/hypersensitive to ZYN002 type products
- exposed to any investigational drug/device in the last 30 days
- used cannabis or any CBD or THC-containing products in last 4 weeks
- change in tobacco products in last 30 days
- used opioids more than half the days in the last month
- using any concomitant OA therapies, who have any diseases or conditions that are likely to require changes in drug therapy during the study or interfere with the objectives of the study; who are breastfeeding, who are at risk of suicide; who have Hepatitis or HIV; or who have a history of alcohol or drug abuse.
- Prohibited medications include: midazolam, oral ketoconazole, fluconazole, nefazadone, rifampin, alfentanil, alfuzosin, amiodarone, cyclosporine, dasatinib, docetaxol, eplerenone, ergotamine, everolimus, fentanyl, halofantrine, irinotecan, lapatinib, levomethadyl, lumefantrine, nilotinib, pimozide, quinidine, ranolazine, sirolimus, tacrolimus, temsirolimus, toremifene, tretinioin, vincristine, vinorelbine, St. John’s Wort, benzodiazepines, and any supplements with anti-inflammatory and/or analgesic properties.

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)

On Day 1, participants with knee pain due to OA of the knee will be randomized in a 1:1:1 ratio to receive either Treatment A ZYN002 – CBD 250 mg Q12 H, Treatment B ZYN002 - CBD 125 mg Q12 H or Treatment C placebo Q12 H for 12 weeks.
Once a participant qualifies to participate in the study, the respective site will receive the randomization number for the participant.
The un-blinded randomization schedule will be maintained within the interactive web response system (IWRS).

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 code has been issued on a per protocol allocation ratio of 1:1:1.

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 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

Primary Efficacy Analysis
The primary efficacy analysis will be a mixed-model repeated measures (MMRM) model on the change from baseline (ChgPAIN). The model will include terms for treatment group, site, week and treatment-by-week interaction, and Baseline Period pain score a) PAIN(Baseline) and b) baseline-by-week interaction. The contrast at Week 12 comparing each active dose against placebo will be used to test the significance of treatment effect.
To assess the impact of missing data, an analysis of covariance (ANCOVA) will be conducted at Week 12 with PAIN(Baseline) as the covariate using last observation carried forward (LOCF), baseline observation carried forward (BOCF) and a modified BOCF (mBOCF) imputation strategies. In the mBOCF approach, a BOCF strategy will be used to impute missing data from dropouts due to lack of efficacy (LOE) or AE and an LOCF strategy will be used to impute missing data from dropouts due to other reasons.

Secondary Efficacy Analysis
The secondary analyses will include:
a) 30% and 50% responder rate: Logistic regression with factors for treatment and center will be used to compare the active treatment group to placebo at Weeks 4, 8, and 12.
b) Percent change from Baseline in weekly mean pain: %ChgPAIN. Descriptive statistics including number (N), mean, median, standard deviation (SD), minimum, and maximum will be presented by treatment group. Graphs of cumulative distribution functions for %ChgPAIN will be presented by treatment group.
c) Change from Baseline (ChgPAIN) in the weekly mean of the 24-hour average worst pain score at Weeks 4 and 8. Descriptive statistics including N, mean, median, SD, minimum, and maximum will be presented by treatment group.
d) Change from Baseline in the WOMAC Pain, Stiffness and Physical Function Subscales at Weeks 4, 8, and 12. ANCOVA will be used to compare each active treatment group to placebo at each time point (Week 4, Week 8, and Week 12) with factors for treatment and Baseline PAIN scores.
e) Percentage of patients using rescue pain medication weekly during the 12-week treatment period. Descriptive statistics will be presented by treatment group.
f) Physician assessment of presence of joint effusion. Descriptive statistics will be presented by treatment group

The sample size of 100 patients per treatment group is sufficient to have a power of 80% to detect a difference of 1.0 between the change from Baseline for active and placebo with a standard deviation (SD) of 2.5. To account for a possible screening failure rate of approximately 8%, a total of 320 patients should be enrolled to ensure there will be 300 patients to randomize.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

22/08/2016

Actual

30/08/2016

Date of last participant enrolment

Anticipated

27/01/2017

Actual

24/03/2017

Date of last data collection

Anticipated

19/07/2017

Actual

28/07/2017

Sample size

Target

320

Accrual to date

Final

320

Recruitment in Australia

Recruitment state(s)

NSW,QLD,VIC

Recruitment hospital [1]

Royal North Shore Hospital - St Leonards

Recruitment hospital [2]

Holdsworth House Medical Practice - Sydney

Recruitment hospital [3]

University of Sunshine Coast Health Clinics - Sippy Downs

Recruitment postcode(s) [1]

2065 - St Leonards

Recruitment postcode(s) [2]

4556 - Sippy Downs

Recruitment postcode(s) [3]

4075 - Oxley

Recruitment postcode(s) [4]

2292 - Broadmeadow

Recruitment postcode(s) [5]

3145 - Malvern East

Recruitment postcode(s) [6]

2289 - Kotara

Recruitment postcode(s) [7]

2010 - Darlinghurst

Recruitment postcode(s) [8]

4215 - Australia Fair

Recruitment postcode(s) [9]

3121 - Richmond

Recruitment postcode(s) [10]

4558 - Cotton Tree

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Zynerba Pharmaceuticals Inc.

Address [1]

80 West Lancaster Avenue
Suite 300
Devon, PA 19333

Country [1]

United States of America

Primary sponsor type

Commercial sector/Industry

Name

Zynerba Pharmaceuticals Pty Ltd

Address

At the office of PricewaterhouseCoopers, Level 27
Freshwater Place, 2 Southbank Boulevard,
Southbank, VIC 3006

Country

Australia

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

Novotech (Australia) Pty Limited

Address [1]

Level 3, 235 Pyrmont St
Pyrmont NSW 2009

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Limited

Ethics committee address [1]

129 Glen Osmond Rd, Eastwood, SA 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

25/07/2016

Ethics approval number [1]

2016-06-471

Summary

Brief summary

This study aims to investigate the effectiveness and safety of twice daily ZYN002, for 12 weeks in 320 (300 randomized) adults with knee pain due to osteoarthritis of the knee. This will be done by analysing a daily pain score and skin check, knee pain and rescue medication diary, and side effects. Safety will be monitored during the treatment visits using standard measures, including physical and neurological exams, vital signs (including oral temperature), 12-lead ECGs, clinical laboratory tests and side effect monitoring. Skin at the application sites will be checked to see if there is any irritation or reactions present after applications. 

Who is if for? You may be eligible to join this study if you are aged between 40 and 75 years, have knee pain due to osteoarthritis of the knee and are in otherwise general good health. 

Study details: This study will investigate two 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 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; a 1 week washout period, a 1 week baseline period; a 12 week study treatment period; and an end of study (EOS) visit at Week 12. 

During the washout period, participants will be asked to discontinue their anti-inflammatory agents (e.g., NSAIDs) and other analgesics prior to the Baseline Period. Only paracetemol (not more than 3 grams per day) will be allowed as rescue medication.
During the Baseline Period, participants will use a 0 to 10 point numeric rating scale to capture their worst pain severity every day. Only paracetemol (not more than 3 grams per day) will be allowed as rescue medication. Participants will record rescue pain medication in a daily diary (Skin Check, Knee Pain, Rescue Medication Diary.

During the treatment period four clinic visits are required for: blood sampling; review of daily diary, medications, AEs and skin irritation; measurement of blood pressure, heart rate, breathing rate and temperature ; suicide risk; and possibly, a brief physical and neurological exam, pregnancy tests (females only, if applicable) and an ECG. Participants will record rescue pain medication in a daily diary (Skin Check, Knee Pain, Rescue Medication Diary.
Participants will apply all study drug to clean, dry, intact skin, thoroughly massaging it into both the right and left shoulders and/or upper arms until the area is dry.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof David Hunter

Address

Royal North Shore Hospital
Rheumatology Department,
Pacific Highway, St Leonards NSW 2065

Country

Australia

Phone

+61 2 9463 1887

Fax

david.hunter@sydney.edu.au

Contact person for public queries

Name

Nancy Tich

Address

Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333

Country

United States of America

Phone

+1 973-727-4117

Fax

tichn@zynerba.com

Contact person for scientific queries

Name

Donna Gutterman

Address

Zynerba Pharmaceuticals, Inc.
80 West Lancaster Avenue
Devon, PA 19333

Country

United States of America

Phone

+1 919-522-8828

Fax

guttermand@zynerba.com

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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No additional documents have been identified.

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