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Trial registered on ANZCTR


Registration number
ACTRN12624000828527p
Ethics application status
Submitted, not yet approved
Date submitted
21/06/2024
Date registered
4/07/2024
Date last updated
4/07/2024
Date data sharing statement initially provided
4/07/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Medicinal Cannabis for Endometriosis: The Gut Microbiome
Scientific title
Exploring Medicinal Cannabis Effects on Endometriosis via Gut Microbiome Modulation: A Double-Blind Placebo-Controlled Clinical Trial
Secondary ID [1] 312381 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
endometriosis 334175 0
Condition category
Condition code
Reproductive Health and Childbirth 330841 330841 0 0
Menstruation and menopause
Alternative and Complementary Medicine 330896 330896 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial will be testing two medicinal cannabis oil products (a CBD full spectrum oil and a THC:CBD balanced oil) that are potentially effective for the treatment of endometriosis- associated symptoms. The medication (in oil form) will be manufactured and supplied in the same high-quality form, composition and dosage as currently permissible under this category. A dose-finding period will be performed during the first 10 days of the intervention phase to determine the lowest dosage for market, if clinical benefit is observed.
All randomized arms will undergo the same dosage finding process to maintain blinding. This occurs during the first 10 days – dose-finding phase – of the intervention phase.

1. Begin with 2 x 0.20mL of oral oil per day (one dose in the morning and one dose at night).
a. Arm 1 total starting dosage: 4mg of THC and 4mg of CBD per day
b. Arm 2 total starting dosage: 40mg of CBD per day
c. Arm 3 total starting dosage: no active ingredients

2. Increase total consumption by 0.2ml (an additional 0.1ml per dose) every two days until participants report any of the following:
a. Adverse psychoactive effects are reported that are bothersome to the participant, or
b. The maximum dosage of 10mg of THC per day (Arm 1) or 100mg of CBD per day (Arm 2) is reached. In Arm 2 the maximum amount of THC per day at the maximum dose is no more than 10mg in total.
c. Maximum amount of Arm 3 is 1ml per day.

If adverse psychoactive effects are reported during dosage finding, participants will be asked to reduce their dosage until these effects are either no longer bothersome or no longer occur. Participants will be offered to undergo a ‘challenge’ test where they can increase their dosage again to see if the adverse effects no longer occur. This is optional and designed to allow participants time to adjust to any psychoactive effects.

Once the daily dosage has been determined participants will use this as their maximum dosage per day. This means that depending on the presenting symptom severity and other personal factors, participants are able to take a dosage each day that is equal to or less than the daily dosage, but not to exceed this.

To measure symptom improvement during the dose-finding phase, the following question will be asked each day:
“Thinking of the last 24 hours, do you think that your endometriosis symptoms (pelvic pain, fatigue, gastrointestinal symptoms, nausea) have improved compared to before you started on the trial?
Y/N”

Intervention drugs and doses:
Elan oil (100mg/mL CBD): up to 1mL per day
Luna oil (10mg/mL CBD + 10mg/mL THC): up to 1mL per day

Mode and duration of administration: Oral oil for 3 months

Strategies to monitor compliance:
Participants will self-administer the study intervention at home and compliance with study intervention will be actively monitored. Compliance will be assessed by asking participants to return the empty bottle(s) in all treatment arms via paid postage. Final study drug reconciliation will be performed at the End of Treatment or after Early Termination. Any discrepancies will be thoroughly explained on the accountability form. Intervention start and stop dates, including dates for intervention delays and/or dose reductions will also be recorded. Participants will only be supplied with enough IMP to complete their treatment course. Returned study drug may not be administered to another subject.

Each subject must be counselled on the importance of compliance with the dosing schedule. Compliance is defined as taking 75% of the maximum daily dosage per day on average for each dispensing period and will be determined by:

a) confirmation of dosage the dosage taken each day via reminders from REDCap, and
b) weighing returned study treatment bottles at the two reconciliation timepoints to determine the average daily dosage.
Intervention code [1] 328879 0
Treatment: Drugs
Comparator / control treatment
Vehicle control matched to Luna oil for taste, appearance and smell.
Control group
Placebo

Outcomes
Primary outcome [1] 338612 0
Composite primary outcome: Severity of endometriosis symptoms (pelvic pain, fatigue, gastrointestinal symptoms and nausea) and changes in gut microbiota, endocannabinoids and vaginal microbiota.
Timepoint [1] 338612 0
Baseline (1st menstrual cycle; trial entry), end of treatment (3rd menstrual cycle; approx 3 months after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention
Secondary outcome [1] 436618 0
1. To assess the effect of two MC products on pelvic pain severity .
Timepoint [1] 436618 0
Baseline (1st menstrual cycle; trial entry), midpoint (2nd menstrual cycle after trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [2] 436619 0
2. To assess the effect of two MC products on endometriosis-specific quality of life.
Timepoint [2] 436619 0
Baseline (1st menstrual cycle; trial entry), midpoint (2nd menstrual cycle after trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [3] 436620 0
3. To assess the effect of two MC products on general quality of life.
Timepoint [3] 436620 0
Baseline (1st menstrual cycle; trial entry), midpoint (2nd menstrual cycle after trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [4] 436621 0
4. To assess changes associated with MC use in gut microbiota.
Timepoint [4] 436621 0
Baseline (1st menstrual cycle; trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [5] 436622 0
5. To assess changes associated with MC use in vaginal microbiota.
Timepoint [5] 436622 0
Baseline (1st menstrual cycle; trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [6] 436623 0
6. To assess changes associated with MC use in prostaglandin PGF2a.
Timepoint [6] 436623 0
Baseline (1st menstrual cycle; trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [7] 436624 0
7. To assess changes associated with MC use in endocannabinoids and cannabinoid metabolites (composite secondary outcome) - major cannabinoids (CBD, THC, AEA, 1-AG, 2-AG, PEA, SEA and OEA).
Timepoint [7] 436624 0
Baseline (1st menstrual cycle; trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [8] 436625 0
8. To assess changes associated with MC use in inflammatory markers TNF-a and IL-6.
Timepoint [8] 436625 0
Baseline (1st menstrual cycle; trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [9] 436626 0
9. To assess whether MC use is associated with changes in nausea.
Timepoint [9] 436626 0
Baseline (1st menstrual cycle; trial entry), midpoint (2nd menstrual cycle after trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [10] 436627 0
10. To investigate whether MC use is associated with changes in fatigue.
Timepoint [10] 436627 0
Baseline (1st menstrual cycle; trial entry), midpoint (2nd menstrual cycle after trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [11] 436872 0
11. To assess whether MC use is associated with changes in gastrointestinal symptoms.
Timepoint [11] 436872 0
Baseline (1st menstrual cycle; trial entry), midpoint (2nd menstrual cycle after trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [12] 436873 0
12. To assess the safety and tolerability of MC (composite secondary outcome).
Timepoint [12] 436873 0
Baseline (1st menstrual cycle; trial entry) and end of treament (3rd menstrual cycle after trial entry)
Secondary outcome [13] 436874 0
13. To assess whether MC use is associated with development of cannabis use disorder (CUD)
Timepoint [13] 436874 0
Baseline (1st menstrual cycle; trial entry), midpoint (2nd menstrual cycle after trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry; 2 months post-intervention)
Secondary outcome [14] 436875 0
14. To investigate if MC use is associated with change globally
Timepoint [14] 436875 0
End of treatment (3rd menstrual cycle after trial entry; 2 months post-intervention)

Eligibility
Key inclusion criteria
• Aged 18-50 years.
• Self-reported pelvic pain, severe enough to seek medical attention.
• Diagnosis of endometriosis via laparscopy, MRI or ultrasound imaging by a medical doctor.
• Residing in Sydney.
• Regular menstruation (i.e. 21-35 day cycle)
• Cannabis naïve or have not used illicit cannabis or prescribed cannabinoid-based medications in the previous three months.
• Report no current, or history of, hazardous cannabis use or dependency.
• Agree to keep all study products in a secure location and not to share/distribute cannabis to any other individual.
• If sexually active and pregnancy is a possibility, agree to use appropriate contraception to prevent pregnancy during the study period.
• Able to travel to a Laverty Pathology (or sister site) collection centre for two blood tests
• Safety markers in full blood exam, liver and kidney function (as per blood tests) found within normal ranges.
• Able to complete study questionnaires via invitations sent to email.
• Willing to give informed consent to participate in the study.
Minimum age
18 Years
Maximum age
50 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
• Not residing in Sydney.
• Endometriosis-related surgery in the previous six months
• Not experiencing regular menstruation (i.e. 21-35 day cycle)
• Must not have started, stopped or had a significant dosage of any endometriosis-specific in the last three months including contraceptives, GNRH-a and neuroleptics (changes in ‘as needed’ medications such as analgesics are not reasons for exclusions).
• Must not have any current or past diagnoses that would be considered a risk to participation in the study, including schizophrenia spectrum and other psychotic disorders, bipolar-related disorders, dissociative disorders, personality disorders, cannabis use disorder and obsessive-compulsive related disorders.
• Currently have any major haematological, endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, gastrointestinal (particularly hepatic), renal or neurological disease (determined by the medical monitoring team).
• Has used cannabis in the past 3 months
• Pregnant or planning to become pregnant during the study duration
• Unwilling to use contraception for the duration of the study
• Unable to travel to a Laverty Pathology (or sister site) collection centre for three blood tests
• Full blood exam, liver and kidney function (including urea and electrolytes) safety markers not within normal ranges.
• Current medical condition which in the opinion of the Principal Investigator or medical monitor is a contraindication for medicinal cannabis
• Family history or personal history of drug dependence
• Unwilling to complete study assessments via email.
• Unwilling or unable to provide informed consent to participate in the study

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
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
Safety/efficacy
Statistical methods / analysis
The study will generate data at four time-points (baseline, midpoint (2nd menstrual cycle after trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry, 2nd menstrual cycle post-intervention)) which will be compared with baseline measurements over 5 months. The dataset analysis will utilise a number of statistical methods in order to gain insight into the impact that ingested medicinal cannabis has had on participant reported outcome variables.

The primary outcome variable (endpoint) is the mean severity of endometriosis symptoms (pelvic pain, fatigue, nausea and gastrointestinal symptoms) and explore any association between symptoms changes and changes in gut microbiota, endocannabinoids and vaginal microbiota.

Descriptive statistics will be provided for demographic data (age, height, weight, etc.).
Data will be aggregated in order to conduct within-groups analyses to assess changes in outcome variables, comparing mean outcomes of rating scales or questionnaire scores with baseline, at midpoint (2nd menstrual cycle after trial entry), end of treatment (3rd menstrual cycle after trial entry) and follow-up (5th menstrual cycle after trial entry, 2nd menstrual cycle post-intervention). The data will be checked for normality. Where data is normal, a paired t-test between baseline and end of treatment will be used. Where data is non-normal, the non-parametric equivalent of this test, the Wilcoxon Signed Ranks Test will be used. Side effect data and results of blood pathology tests will be reported as frequency data.

Other statistical methods will include analyses of the repeated measures data to examine changes in symptomatology over time, regression-based methods and trajectory-based methods, such as latent trajectory analyses. Such methods allow for the identification of specific symptom trajectories (e.g., gradual reduction in symptoms vs. rapid reduction) and examination of whether individuals following these different trajectories vary on personal characteristics (e.g., gender, symptom intensity at start of treatment) or treatment characteristics (e.g., product type, dose).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/09/2024
Actual
Date of last participant enrolment
Anticipated
2/06/2025
Actual
Date of last data collection
Anticipated
30/11/2025
Actual
Sample size
Target
42
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 316789 0
University
Name [1] 316789 0
Western Sydney University
Country [1] 316789 0
Australia
Primary sponsor type
University
Name
Western Sydney University
Address
Country
Australia
Secondary sponsor category [1] 319011 0
None
Name [1] 319011 0
Address [1] 319011 0
Country [1] 319011 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 315558 0
University of Western Sydney Human Research Ethics Committee
Ethics committee address [1] 315558 0
Ethics committee country [1] 315558 0
Australia
Date submitted for ethics approval [1] 315558 0
31/05/2024
Approval date [1] 315558 0
Ethics approval number [1] 315558 0
H16068

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

Contacts
Principal investigator
Name 135070 0
A/Prof Mike Armour
Address 135070 0
Western Sydney University Locked Bag 1797 Penrith NSW 2751
Country 135070 0
Australia
Phone 135070 0
+61 2 9685 4720
Fax 135070 0
Email 135070 0
m.armour@westernsydney.edu.au
Contact person for public queries
Name 135071 0
Mike Armour
Address 135071 0
Western Sydney University Locked Bag 1797 Penrith NSW 2751
Country 135071 0
Australia
Phone 135071 0
+61 2 9685 4720
Fax 135071 0
Email 135071 0
m.armour@westernsydney.edu.au
Contact person for scientific queries
Name 135072 0
Toobah Farooqi
Address 135072 0
Western Sydney University Locked Bag 1797 Penrith NSW 2751
Country 135072 0
Australia
Phone 135072 0
+61 2 9685 4720
Fax 135072 0
Email 135072 0
toobah.farooqi@westernsydney.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.