Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000328572
Ethics application status
Approved
Date submitted
5/02/2024
Date registered
25/03/2024
Date last updated
21/05/2024
Date data sharing statement initially provided
25/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Medicinal cannabis for endometriosis: The EndoCann Trial
Scientific title
A placebo controlled, double blind, randomised controlled trial assessing the effect of medicinal cannabis on pelvic pain in adults with endometriosis: The Endocann trial
Secondary ID [1] 311296 0
None
Universal Trial Number (UTN)
Trial acronym
ENDOCANN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Endometriosis 332534 0
Condition category
Condition code
Reproductive Health and Childbirth 329227 329227 0 0
Other reproductive health and childbirth disorders
Reproductive Health and Childbirth 329813 329813 0 0
Menstruation and menopause
Alternative and Complementary Medicine 329814 329814 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Balanced THC:CBD oil
Participants will first undergo a run-in period (week 0-2) to determine their maximum dosage of interventional product. Participants will start with self-administering 0.40ml of THC:CBD oil (10mg/ml THC: 10mg/ml CBD) per day split into two doses 10-12 hours apart and ingested orally (0.20ml at breakfast and 0.20ml at dinner), providing a total starting dosage of 4mg of THC and CBD per day. This will be increased by 0.20ml per day every two to three days (based on patient preference) until participants report either (a) a 20% or greater reduction in their daily pelvic pain severity as measured on a 0-10 numeric rating scale (NRS), (b) they experience adverse psychoactive effects that are bothersome to the participant, or (c) they reach the maximum dosage of 20mg of THC per day. During the intervention period (week 3-26) participants will continue taking their maximum dosage via self-administration as determined during the run-in period.

Arm 2: Cannabidiol (CBD) full spectrum extract
Participants will first undergo a run-in period (week 0-2) to determine their maximum dosage of interventional product. Participants will start with self-administrating 0.40ml of CBD oil (100mg/ml CBD) per day split into two doses 10-12 hours apart and ingested orally (0.20ml at breakfast and 0.20ml at dinner), providing a total starting dosage of 40mg of CBD per day. This will be increased by 0.20ml per day every two to three days (based on patient preference) until participants report either (a) a 20% or greater reduction in their daily pelvic pain severity as measured on a 0-10 numeric rating scale (NRS), (b) they experience adverse psychoactive effects that are bothersome to the participant, or (c) they reach the maximum dosage of 150mg of CBD per day. During the intervention period (week 3-26) participants will continue taking their maximum dosage via self-administration as determined during the run-in period.

Both Arm 1 and 2 will have an intervention duration of 26 weeks, inclusive of the two-week run-in period.

Compliance will be measured by returning empty bottles twice during the intervention period.
Intervention code [1] 327742 0
Treatment: Drugs
Comparator / control treatment
Arm 3: Placebo oil: A flavour-matched oil identical to the Arm 1 and Arm 2 interventions. The composition is TGA approved colourant in medium chain triclyceride (MCT) oil + 1% or less terpenes to match the taste of Arm 1 and 2.

Participants will undergo a run-in period (week 0-2) to mimic the dosage schedule of intervention arms. Participants will start with self-administering 0.40ml of placebo oil per day
split into two doses 10-12 hours apart and ingested orally (0.20ml at breakfast and 0.20ml at dinner). This will be increased by 0.20ml per day every two to three days (based on patient preference) until participants report either (a) a 20% or greater reduction in their daily pelvic pain severity as measured on a 0-10 numeric rating scale (NRS), (b) they experience adverse psychoactive effects that are bothersome to the participant, or (c) they reach the maximum consumption of 1.5ml of placebo oil per day. During the intervention period (week 3-26) participants will continue taking their maximum dosage via self-administration as determined during the run-in period.

Arm 3 will have an intervention duration of 26 weeks, inclusive of the two-week run-in period.

Compliance will be measured by returning empty bottles twice during the intervention period.
Control group
Placebo

Outcomes
Primary outcome [1] 337060 0
Overall pelvic pain severity
Timepoint [1] 337060 0
During the run-in period (week 0 – week 3 after trial entry), participants will record their pelvic pain severity daily. A retrospective score of average pelvic pain severity over previous 7 days will be measured weekly during the active intervention period (weekly for 26 weeks after trial entry; the week 13 and week 26 timepoints will be primary timepoints). A retrospective score of average pelvic pain intensity over the previous month will be measured monthly during the follow-up phase (up to week 78 after trial entry; week 52 and week 78 timepoints will be primary timepoints).
Primary outcome [2] 337061 0
Safety outcome #1: Adverse events
Timepoint [2] 337061 0
Adverse events will be recorded throughout the entire trial period (78 weeks after trial entry).
Primary outcome [3] 337062 0
Safety outcome #2: Liver and kidney function
Timepoint [3] 337062 0
Safety blood tests will be taken at screening (prior to randomisation), mid-intervention (13 weeks after trial entry), end of intervention (26 weeks after trial entry), and follow-up at week 78 (18 months after trial entry). The primary timepoints are mid-intervention, end of intervention, and follow-up at week 78 after trial entry.
Secondary outcome [1] 430515 0
Most impactful symptom
Timepoint [1] 430515 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry)
Secondary outcome [2] 430516 0
Quality of life (QoL) via The Endometriosis Health Profile 30 (EHP-30).
Timepoint [2] 430516 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [3] 430517 0
Depression
Timepoint [3] 430517 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [4] 430518 0
Anxiety
Timepoint [4] 430518 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry)
Secondary outcome [5] 430519 0
Distress
Timepoint [5] 430519 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [6] 430520 0
Gastrointestinal symptoms
Timepoint [6] 430520 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [7] 430521 0
Central sensitisation
Timepoint [7] 430521 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [8] 430522 0
Analgesic medication usage
Timepoint [8] 430522 0
Analgesic medication usage will be assessed once per week (recalling the previous week) from baseline to end of intervention (week 26 after trial entry) and once per month during the follow-up phase (up to week 78 after trial entry).
Secondary outcome [9] 430523 0
Fatigue
Timepoint [9] 430523 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [10] 430524 0
Healthcare service usage
Timepoint [10] 430524 0
Participants will be followed from baseline to follow-up at week 52 (12 months after trial entry).
Secondary outcome [11] 430525 0
Endometriosis lesion progression and staging
Timepoint [11] 430525 0
All participants will have a tVUS at baseline prior to beginning the intervention. A sub-set of 45 participants (15 each arm) will have two more scans, one at end of intervention (26 weeks after trial entry) and follow-up at 78 weeks (18 months after trial entry).
Secondary outcome [12] 430527 0
Objective cognitive functioning via the Paced Auditory Serial Addition Test (PASAT).
Timepoint [12] 430527 0
Baseline, end of intervention (26 weeks after trial entry), and follow-up at week 52 (12 months after trial entry).
Secondary outcome [13] 430528 0
Inflammatory plasma markers
Timepoint [13] 430528 0
Blood samples will be taken at screening (before randomisation), mid-intervention (13 weeks after trial entry), end of intervention (26 weeks after trial entry), and follow-up at 78 weeks (18 months after trial entry).
Secondary outcome [14] 432414 0
QoL via the European Quality of Life Five Dimension (EQ-5D-5L).
Timepoint [14] 432414 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [15] 432415 0
Presence of irritable bowel syndrome (IBS)
Timepoint [15] 432415 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [16] 432416 0
IBS Severity
Timepoint [16] 432416 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [17] 432417 0
Subjective cognitive functioning via the Ecological momentary assessment.
Timepoint [17] 432417 0
Participants will log their responses daily during the run-in period (up to week 2 after trial entry), and then weekly until end of intervention (week 26 after trial entry), and thereafter monthly to end of follow up at week 78 (18 months after trial entry).
Secondary outcome [18] 432418 0
Subjective cognitive functioning via and the Functional Assessment of Cancer Therapy—Cognition (FACT-Cog) scale.
Timepoint [18] 432418 0
Baseline, end of intervention (26 weeks after trial entry), follow-up at week 52 (12 months after trial entry), and follow-up at week 78 (18 months after trial entry).
Secondary outcome [19] 432419 0
Objective cognitive functioning via the Symbol Digit Modalities Test
Timepoint [19] 432419 0
Baseline, end of intervention (26 weeks after trial entry), and follow-up at week 52 (12 months after trial entry).
Secondary outcome [20] 432420 0
Objective cognitive functioning via the Digit Span (Forward and Backward).
Timepoint [20] 432420 0
Baseline, end of intervention (26 weeks after trial entry), and follow-up at week 52 (12 months after trial entry).
Secondary outcome [21] 432421 0
Objective cognitive functioning via The Rey Auditory Verbal Learning Test (RAVLT).
Timepoint [21] 432421 0
Baseline, end of intervention (26 weeks after trial entry), and follow-up at week 52 (12 months after trial entry).
Secondary outcome [22] 432422 0
Objective cognitive functioning via The Controlled Oral Word Association Test (COWAT)
Timepoint [22] 432422 0
Baseline, end of intervention (26 weeks after trial entry), and follow-up at week 52 (12 months after trial entry).
Secondary outcome [23] 432423 0
Sleep quality
Timepoint [23] 432423 0
Baseline, end of intervention (26 weeks after trial entry), and follow-up at week 52 (12 months after trial entry).
Secondary outcome [24] 432424 0
Cannabinoid plasma markers
Timepoint [24] 432424 0
Blood samples will be taken at screening (before randomisation), mid-intervention (13 weeks after trial entry), end of intervention (26 weeks after trial entry), and follow-up at 78 weeks (18 months after trial entry).

Eligibility
Key inclusion criteria
- Aged over 18 years.
- Self-reported pelvic pain, severe enough to seek medical attention.
- Diagnosis of endometriosis via laparoscopy (with or without histological confirmation), magnetic resonance imaging (MRI), or Ultrasound imaging by a medical doctor, with input from an imaging specialist with specific endometriosis expertise.
- Have not used illicit cannabis and/or prescribed cannabinoid-based medications in the previous three months.
- Report no current, or history of, hazardous cannabis use, or dependency.
- If sexually active and pregnancy is a possibility, agree to use appropriate contraception to prevent pregnancy during the study period.
- Agree to keep all study product stored in a secure location and not to share/distribute cannabis to any other individual.
- Agree not to drive while under the effects of medicinal cannabis.
- Willing to provide informed consent and adhere to the protocol.
- Residing in New South Wales during the trial period.
- Able to travel to NICM Health Research Institute, The Royal Hospital for Women, Sydney Endometriosis, and Macquarie University for data collection.
- Able to travel to a Laverty collection centre for blood tests.
- Has internet access (either via a mobile (Apple or Android) or tablet (Apple)) for logging outcomes via the OnTracka app.
- Ability to understand and speak English.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- Have had endometriosis-related surgery in the previous six months or have any surgery planned during the study period.
- Started, stopped, or had a significant change in dosage of any endometriosis specific medication in the last three months. This includes contraceptives, GNRH-a, and neuroleptics (changes in ‘as needed’ medications such as analgesics are not reasons for exclusion).
- Have any current or past diagnoses that would be considered a risk to participation in the study, including but not limited to, schizophrenia spectrum and other psychotic disorders, bipolar-related disorders, dissociative disorders, personality disorders, cannabis use disorder, obsessive-compulsive related disorders, neurological disorders, or brain injury.
- Currently have any major haematological, endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, gastrointestinal (particularly hepatic), renal, or neurological disease (determined by the medical monitoring team).
- Current usage of anticoagulants (e.g., warfarin, heparin or any other NOAC/DOAC medications) or any other medication, including supplements (e.g., vitamin E, Gingko), that causes blood thinning.
- Currently pregnant or breastfeeding or planning on becoming pregnant during the study period.
- Abnormal liver and kidney function tests as determined during screening process.

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 will be performed by a clinical trials manager who is external to the study using REDCap's randomisation function. Allocation is concealed by this software so that none of the research team has access to this.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation will be perfomed by REDCap's randomisation function. Participants will be randomised in a 1:1:1 ratio.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Based on a minimum clinically important difference (MCID) of 20mm for pelvic pain severity, in line with both clinical expert opinion and the IMMPACT recommendations for chronic pain, and a standard deviation (SD) of 22.7 for the change in VAS, 90% power, and a two-sided alpha of 5%, each treatment group would require 29 participants. Accounting for an assumed dropout rate of 30%, 42 participants would be required per arm, with 126 total.

All analyses (excluding safety) will be by intention-to treat using the full analysis set. The primary outcome will also be analysed secondarily using the per protocol set. The safety analysis set will be used for all safety analyses. All estimates will be given as 95% confidence intervals, and so with a nominal two-sided type I error rate of 5%.

Data description will be by count and proportion expressed as percentage for categorical variables, and by mean and standard deviation (SD), inter-quartile range (IQR), and min to max as range for continuous variables.

Primary endpoint analysis (pelvic pain severity):
The primary analysis will be by general linear model (ANCOVA) with baseline pelvic pain severity score as a continuous covariate.

The pre-specified treatment comparisons (Intention to treat (ITT) and per-protocol (PP)) are:
- Arm 1 compared to placebo,
- Arm 2 compared to placebo, and
- Arm 1 compared to Arm 2.

Secondary end-point analyses:
The pre-specified treatment comparisons (Intention to treat (ITT) and per-protocol (PP)) are as specified for primary endpoint analysis.

The following methods will be used:
1) Simple t-test by time of measurement and mixed linear models for repeated measures by time:
- Change in most bothersome symptom score
- Quality of life
- Changes in analgesic medication usage
- Psychological measures (depression, anxiety, distress)
- Fatigue
- Gut measures
- Central sensitization
- Subjective cognitive functioning

2) Comparison of proportions by logistic regression:
- Adverse Events
- Serious Adverse Events
- Related Adverse Events.

Sub-group analyses:
Subgroup analyses of the primary endpoint will be made to assess the consistency of the intervention effect across the following subgroups:
- Pelvic pain severity at baseline: moderate/severe pain vs no/mild pain
- Stage of endometriosis
- Bodyweight
- Age.

If the number of participants is too small (less than 10%) within a subgroup, then the subgroup categories may be redefined prior to unblinding the study.

Other analyses:
1) Endocannabinoid and inflammatory markers
The cannabinoids and inflammatory markers will be quantified in NICMs TGA licenced analytical and PCS pharmacology laboratory. Plasma levels (in pmol/ml) of major cannabinoids (CBD, THC), related metabolites of CBD and THC (AEA, 1-AG, 2-AG, PEA, SEA and OEA), and inflammatory markers (IL-6, TNFa) will be compared to pelvic pain severity score at four time points: baseline, mid-intervention (week 13), end of intervention (week 26), and post-intervention follow-up 2 (week 78). Statistical analysis between the treatment arms in Study 1 and endocannabinoid levels will be via a linear mixed model with time and group as fixed effects. The relationship between each of the four endocannabinoids and pelvic pain intensity will be assessed using either linear or ordinal regression depending on the normality of data.

2) Endometriosis lesion progression and staging
Endometriosis lesion change will be compared in the sub-set of participants who consent to undertake undergo repeat scans over the course of the study. Disease presence by anatomical site, and stage as per #Enzian (which includes presence/absence of adenomyosis) will be used as factors in the main statistical analysis to determine if they are related to response/non-response to treatment. Although it remains unknown what metric may be the most valuable in assessing interval change (e.g. single measurement (e.g. length) versus volume), the study experts have determined a priori that a change in lesion size over time of >10% will be considered significant.

For superficial endometriosis, the size of lesions is almost negligible so assessing change will not be possible. However, we will attempt to document a change in the presence of lesions from scan to scan, but only if there is consistently sufficient fluid to assess a region. For example, if superficial endometriosis is noted on the uterosacral ligament on one scan, aided by the presence of free fluid, but no free fluid is present at the next scan, the repeat assessment will be considered incomplete for superficial endometriosis.

3) Healthcare utilisation
All data will be analysed and presented as de-identified, grouped data. Descriptive statistics such as means, standard deviations, medians, inter-quartile ranges (for the continuous variables) and frequency (for the categorical variables) will be used. Cross tabulations and relevant statistical tests (e.g., chi squared) may be performed to describe demographic characteristics associated with an endometriosis patient diagnosis, acquisition of surgical and/or medical management.

No small cell sizes will be published where they could result in the possible identification of a participant e.g., using postcode level data against key characteristics. Geographical data and related classifications will use area levels appropriate to the number of participants e.g., state, Accessibility/Remoteness Index of Australia (ARIA), Socio-Economic Indexes for Areas (SEIFA), groupings larger than postcode to prevent small cell sizes arising. No individual level data that could identify non-participants e.g., family members will be reported.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
11/04/2024
Actual
11/04/2024
Date of last participant enrolment
Anticipated
26/06/2024
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
126
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 315550 0
Charities/Societies/Foundations
Name [1] 315550 0
The Wilson Foundation
Country [1] 315550 0
Australia
Primary sponsor type
University
Name
Western Sydney University
Address
GPO Box 4658, Sydney NSW 2001
Country
Australia
Secondary sponsor category [1] 317638 0
Charities/Societies/Foundations
Name [1] 317638 0
The Wilson Foundation
Address [1] 317638 0
NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith NSW 2751
Country [1] 317638 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314449 0
Western Sydney University Human Research Ethics Committee
Ethics committee address [1] 314449 0
Western Sydney University, Werrington South Campus, Locked Bag 1797 PENRITH NSW 2751
Ethics committee country [1] 314449 0
Australia
Date submitted for ethics approval [1] 314449 0
06/11/2023
Approval date [1] 314449 0
05/03/2024
Ethics approval number [1] 314449 0
H15755

Summary
Brief summary
Endometriosis is an oestrogen-dependent, chronic inflammatory condition characterised by the presence of endometrial-like tissue outside of the uterus in the form of lesions, affecting around 1 in 7 women and those assigned female at birth in Australia. Endometriosis has a significant impact on one's physical, psychological, and social wellbeing. Unfortunately many of the pharmaceutical medications for endometriosis have bothersome side effects or should only be used for a short period of time due to concerns related to dependence and addiction. Medicinal cannabis has well described analgesic, anti-inflammatory, anxiolytic, anti-depressant, and anti-emetic actions. Cannabis use in other chronic pain conditions has resulted in “substitution” of pharmaceuticals, commonly opioid analgesics, for cannabis. Our previous research has shown that women with endometriosis in Australia are using mostly illicit sources of cannabis to manage their pain and other symptoms. We hypothesise that either a balanced THC:CBD oil or CBD alone will reduce pelvic pain and other symptoms in women with endometriosis. The primary aim of this study is to determine the efficacy and safety of two medicinal cannabis products compared to placebo in women with endometriosis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131622 0
A/Prof Mike Armour
Address 131622 0
NICM Health Research Institute, Western Sydney University, Building J, Westmead Campus, Locked Bag 1797, PENRITH NSW 2751
Country 131622 0
Australia
Phone 131622 0
+61296854720
Fax 131622 0
Email 131622 0
m.armour@westernsydney.edu.au
Contact person for public queries
Name 131623 0
A/Prof Mike Armour
Address 131623 0
NICM Health Research Institute, Western Sydney University, Building J, Westmead Campus, Locked Bag 1797, PENRITH NSW 2751
Country 131623 0
Australia
Phone 131623 0
+61296854720
Fax 131623 0
Email 131623 0
m.armour@westernsydney.edu.au
Contact person for scientific queries
Name 131624 0
A/Prof Mike Armour
Address 131624 0
NICM Health Research Institute, Western Sydney University, Building J, Westmead Campus, Locked Bag 1797, PENRITH NSW 2751
Country 131624 0
Australia
Phone 131624 0
+61296854720
Fax 131624 0
Email 131624 0
m.armour@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

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No documents have been uploaded by study researchers.

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