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Trial registered on ANZCTR


Registration number
ACTRN12622000723785
Ethics application status
Approved
Date submitted
29/03/2022
Date registered
20/05/2022
Date last updated
20/05/2022
Date data sharing statement initially provided
20/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Topical application of Cannabis oils and substitutes for the relief of osteoarthritic pain
Scientific title
Phase IIa randomized, placebo-controlled, double-blind crossover pilot study of tolerability and efficacy of cannabidiol (CBD) and palmitoylethanolamide (PEA) applied to the skin for the relief of osteoarthritic joint pain.
Secondary ID [1] 306628 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
osteoarthritis 325548 0
Condition category
Condition code
Musculoskeletal 322919 322919 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stage1: Dose finding study involving 2 visits. The patient with osteoarthritis will be given cannabidiol (CBD) or palmitoylethanolamide (PEA) in cream form over an affected painful joint, similar to Voltaren gel. Bloods will be taken to find the optimal dose using pharmakokinetics HPLC studies. The patient will have bloods taken 5 times over the course of Day 1 (including baseline) and return for 1 blood sample on Day 2, all up providing 6 blood samples for HPLC studies. The starting doses are 62.5mg of CBD (3 subjects) or PEA (3 subjects). Doses are escalated as follows. If after the first dose 0/3 patients reach the target plasma concentration, then the dose of CBD and PEA will be doubled to 125mg. If 1/3 patients reach the target plasma concentration, then the dose of CBD and PEA will be increased by 50% to 94mg. If 2/3 patients reach the target plasma concentration, the dose of CBD and PEA will be increased by 25% to 78mg. After the second dose escalation, the same escalation strategy will be used.

This will be repeated on newly recruited patients (unique cohorts of participants) for each dose escalation until the target plasma concentration of CBD and PEA is reached; 33.3ng/mL and 23pmol/mL, respectively. Dose escalations will be capped at a total of 5 escalations, to a maximum of 1000mg CBD or PEA applied to the skin. As cohorts for each dose are unique, no washout periods are required and the next dose can be given as soon as the next consenting subjects are recruited. Adherence monitoring is not required as staff will apply the cream on the patients in stage 1.

Stage 2: Safety, efficacy and tolerability study for 26 weeks (once daily application). This stage is a three arm crossover, with each arm being 8 weeks followed by washout periods of 7days. Doses will be determined by Stage 1 for PEA and CBD arms. The third arm is placebo. Patients will also be given quality of life questionnaires to assess pain. Bloods will be taken to assess for safety measures such as liver function. A dosing diary will be supplied to patients and they will be asked to return empty cream bottles at study visits.
Intervention code [1] 323067 0
Treatment: Drugs
Comparator / control treatment
The placebo has no active ingredients. The composition is as follows: Deionized Water, Glycerin, Emulsifying Wax NF, Fractioned Coconut Oil, Olive Oil, Cetyl Alcohol,
Safflower Oil, Fragrance, Shea Butter, Dimethicone, Ethylhexylglycerin & Phenoxyethanol
(Preservatives), Vitamin E, CBD Isolate, Xanthan Gum
Control group
Placebo

Outcomes
Primary outcome [1] 330921 0
Stage 1: Profile of CBD levels post-application assessed using liquid chromatography mass spectrometry (LCMS) analysis of blood samples.
Timepoint [1] 330921 0
1hr, 2hr, 4hr, 8hr (primary endpoint) post-intervention commencement per dose of CBD application - single topical dose to affected joint.
Primary outcome [2] 330922 0
Stage 2: To determine any efficacy of CBD and PEA for analgesia. Any change in joint pain will be using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and visual analogue scale (VAS) pain questionnaires as composite outcomes. Drug dosing will be the optimal dose found in Stage 1.
Timepoint [2] 330922 0
Week 8, 18, and 28 in the study timeline are endpoints of the patient on each study arm. This corresponds to 8 weeks post-commencement of each study arm. Each of those dates are the endpoint of being trialed on the placebo, PEA, or CBD arm just prior to the seven day washout before the next arm. The beginning of each arm is at week 1, 10, and 20. The cream will be applied once daily.
Primary outcome [3] 331124 0
Stage 1: Profile of PEA levels post-application assessed using liquid chromatography mass spectrometry (LCMS) analysis of blood samples.
Timepoint [3] 331124 0
1hr, 2hr, 4hr, 8hr (primary endpoint) post-intervention commencement per dose of CBD application - single topical dose to affected joint.
Secondary outcome [1] 408088 0
Stage 1: Drug clearance, final blood sample for pharmacokinetics taken on Day 2.
Timepoint [1] 408088 0
24hours post-intervention commencement
Secondary outcome [2] 408089 0
Stage 2: Assessing the impact of CBD and PEA on quality of life outcomes in patients with osteoarthritis. EQ-5D-5L, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Visual analogue scale (VAS) will be the questionnaires administered as composite outcomes. Additionally, adverse events and changes in concomitant medications will be recorded.
Timepoint [2] 408089 0
Week 8, 18, and 28 in the study timeline are endpoints of the patient on each study arm. This corresponds to 8 weeks post-commencement of each study arm. Each of those dates are the endpoint of being trialed on the placebo, PEA, or CBD arm just prior to the seven day washout before the next arm. The beginning of each arm is at week 1, 10, and 20. The cream will be applied once daily.
Secondary outcome [3] 408090 0
Stage 2: Assessing for treatment emergent adverse events through patient self report and blood tests to assess liver function and blood composition. e.g. dry mouth, reduced appetite.
Timepoint [3] 408090 0
Week 8, 18, and 28 in the study timeline are endpoints of the patient on each study arm. This corresponds to 8 weeks post-commencement of each study arm. Each of those dates are the endpoint of being trialed on the placebo, PEA, or CBD arm just prior to the seven day washout before the next arm. The beginning of each arm is at week 1, 10, and 20. The cream will be applied once daily.

Eligibility
Key inclusion criteria
1. Diagnosis of OA defined by X-ray evidence of joint damage;
2. Age 30–90;
3. Disease duration of 2 years or more;
4. Continued pain in any of the knee, hip, hands or lower lumbar spine joints despite oral
medications;
5. No previous use of oral or smoked cannabinoids for pain management; able to complete
questionnaire;
6. Able to attend outpatient clinic at monitoring and follow-up time points.
Minimum age
30 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of psychiatric disorder;
2. History of drug dependency;
3. Known sensitivity to cannabinoid agents;
4. History of epilepsy; patient pain explained by fibromyalgia;
5. Recurrent or recent malignancy;
6. Pregnancy or breastfeeding;
7. Change of pain medication in the preceding 4 weeks;
8. Severe renal or liver dysfunction (patient excluded if there is an elevation of baseline liver enzymes);
9. Concomitant medications: Prior or current cannabis use; current use of valproate, clobazam, topiramate, and/or rufinamide.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
For stage 1, see other design features.

For stage 2:
1:1:1 randomisation using software Sealed Envelope
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
Stage 1 allocation: The procedure of patient allocation in dose escalation to find the target plasma concentration for PEA and CBD will be the same and recruitment will happen in tangent by research staff. Patients will be allocated to either group as per need to make up patient numbers, without blinding. The nature of the dose escalation study is to cease further recruitment should the target plasma concentration be reached. Three patients will receive the same dose at all dose levels. Baseline begins with 3 patients for PEA and 3 patients for CBD. If 1/3 patients reach the target plasma concentration, then the dose will increase by 50% for the next three patients. If 2/3 patients reach the target plasma concentration, the dose increases by 25% to 78mg for the next three patients. If 3/3 patients reach the target plasma concentration, the endpoint is reached. The respective dose starting points for CBD and PEA are 62.5mg cream once off each. For safety, if the target plasma concentration is not reached, the maximum dose escalations allowed are 5, and the maximum dose of CBD or PEA will be 1000mg.

Stage 2: 1:1:1 randomisation using software Sealed Envelope. The three groups are for order of treatment and will experience all three arms. The arms are PEA to CBD to Placebo, CBD to placebo to PEA, and placebo to PEA to CBD.
Phase
Phase 2
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Statistical analysis will be performed using SPSS (version 24.0). Pre- and post-treatment
outcome data will be summarised in both graphical and tabular form. Patients will be assigned a pain response status. This will be either poor (0–29 percent reduction), moderate (30–49 percent reduction) or good (50 percent or greater reduction), in accordance with clinical practice and based on their pain questionnaire scores.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
8/06/2022
Actual
Date of last participant enrolment
Anticipated
31/08/2022
Actual
Date of last data collection
Anticipated
15/03/2023
Actual
Sample size
Target
72
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 22063 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 37185 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 310959 0
Charities/Societies/Foundations
Name [1] 310959 0
Westmead Research Foundation
Country [1] 310959 0
Australia
Primary sponsor type
Hospital
Name
Westmead Hospital
Address
Westmead Hospital - Hawkesbury Rd. Westmead NSW 2145
Country
Australia
Secondary sponsor category [1] 312475 0
None
Name [1] 312475 0
none
Address [1] 312475 0
none
Country [1] 312475 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310518 0
Western Sydney Local Health District HREC
Ethics committee address [1] 310518 0
Ethics committee country [1] 310518 0
Australia
Date submitted for ethics approval [1] 310518 0
23/02/2022
Approval date [1] 310518 0
02/03/2022
Ethics approval number [1] 310518 0

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

Contacts
Principal investigator
Name 117930 0
Prof Nicholas Manolios
Address 117930 0
Department of Rheumatology, Westmead Hospital, Cnr Darcy and Hawkesbury Roads WESTMEAD NSW 2145
Country 117930 0
Australia
Phone 117930 0
+61 288908099
Fax 117930 0
Email 117930 0
nicholas.manolios@sydney.edu.au
Contact person for public queries
Name 117931 0
Nicholas Manolios
Address 117931 0
Department of Rheumatology, Westmead Hospital, Cnr Darcy and Hawkesbury Roads WESTMEAD NSW 2145
Country 117931 0
Australia
Phone 117931 0
+61 2 8890 8099
Fax 117931 0
Email 117931 0
nicholas.manolios@sydney.edu.au
Contact person for scientific queries
Name 117932 0
Nicholas Manolios
Address 117932 0
Department of Rheumatology, Westmead Hospital, Cnr Darcy and Hawkesbury Roads WESTMEAD NSW 2145
Country 117932 0
Australia
Phone 117932 0
+61 2 88908099
Fax 117932 0
Email 117932 0
nicholas.manolios@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.