Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000037707
Ethics application status
Approved
Date submitted
31/05/2021
Date registered
17/01/2022
Date last updated
1/03/2023
Date data sharing statement initially provided
17/01/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Medicinal Cannabis for symptom burden in children with advanced cancer
Scientific title
A prospective, multicentre, randomised, blinded, two-arm parallel trial of Medicinal Cannabis Products for symptom burden in children with advanced cancer
Secondary ID [1] 304258 0
Nil known
Universal Trial Number (UTN)
UTN 1111-1270-1838
Trial acronym
MINI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced cancer 321981 0
Condition category
Condition code
Cancer 319702 319702 0 0
Children's - Brain
Cancer 319703 319703 0 0
Children's - Leukaemia & Lymphoma
Cancer 319704 319704 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The trial will commence with a two-week baseline observation period, where measurements relating to symptom burden will be measured. Participants will then be randomised to one of two-arms to receive combinations of Tetrahydrocannabinol (THC) and Cannabidiol (CBD) oral cannabis oil. Doses will be titrated upwards over two weeks, to a dose where symptom relief with tolerable side effects is achieved (as measured by clinical assessment and the 32 item Memorial Symptom Assessment Scale (MSAS) Global Distress Index). This will be followed by a four week maintenance phase on a stable dose as determined by the 2-week titration period. Blood will be drawn for pharmacokinetic and biomarker analysis at week -1 (week prior to commencement of intervention), week 2 of dose titration, and week 6 of intervention (end of 4-week maintenance phase). Symptom burden will be measured at weekly clinic appointments through the trial using the Memorial Symptom Assessment Scale. Confirmed documented disease will be assessed at days 14 and 28, 42 and 56 (where applicable). Participants wishing to access medicinal cannabis beyond the clinical trial period will be able to do so via the Special Access Scheme B. Patients not wishing to continue use of medicinal cannabis will have the product slowly titrated down over a one week period at the end of the clinical trial. Participants will be contacted at day 86 (+ 4 weeks post last dose) for the purposes of safety follow up and recording of post-study medicinal cannabis use.

Arm 1: THC: CBD Equivalent Investigational Product, with a 1:1 ratio of 10 mg THC and 10 mg CBD per mL in an oral MCT oil vehicle (Little Green Pharma).
This Investigational Product will be upwardly titrated during a two-week Dose Titration Phase from 0.1mg/0.1mg/kg/day to a maximum of 1 mg/1 mg/kg/day, with a maximum possible dose of 20 mg of THC and 20 mg CBD per day (0.1mL/kg/day to a maximum of 2mL per day). This dose will be given in two divided doses.

The two-week Dose Titration Phase will be followed by a four-week maintenance phase with the maintenance dose being determined by the two-week titration phase.

Arm 2: CBD-Dominant Investigational Product with with a ratio of THC to CBD of 1:100. This Investigational Product contains CBD and THC at 100 mg/mL and 1 mg/mL respectively in an oral solution (Little Green Pharma). This will be upwardly titrated in the two-week Dose Titration Phase, with a dose range of CBD 1 mg/kg/day and THC 0.01mg/kg/day, up to a maximum of 200 mg/kg/day of CBD and 2 mg/kg/day of THC. The maximum possible dose is 200 mg of CBD and 2 mg of THC per day (0.1 mL/kg/day to a maximum dose of 2ml). This dose will be given in two divided doses.

The two-week Dose Titration Phase will be followed by a four-week maintenance phase with the maintenance dose being determined by the two-week titration phase.

Dose/day (mL/kg) Titration Sechedule for Arm 1 and Arm 2 Investigational Products
Day 1 0.005 mL/kg, to a max of 0.1 mL
Day 2 0.01 mL/kg, to a max of 0.2 mL
Day 3 0.02 mL/kg, to a max of 0.4 mL
Day 4 0.025 mL/kg, to a max of 0.5 mL
Day 5 0.03 mL/kg, to a max of 0.6 mL
Day 6 0.04 mL/kg, to a max of 0.8 mL
Day 7 0.045 mL/kg, to a max of 0.9 mL
Day 8 0.05 mL/kg, to a max of 1.0 mL
Day 9 0.06 mL/kg, to a max of 1.2 mL
Day 10 0.065 mL/kg, to a max of 1.3 mL
Day 11 0.07 mL/kg, to a max of 1.4 mL
Day 12 0.08 mL/kg, to a max of 1.6 mL
Day 13 0.085 mL/kg, to a max of 1.7 mL
Day 14 0.09 mL/kg, to a max of 1.8 mL
Day 15 0.1 mL/kg, to a max of 2 mL

Dose/day (mL/kg) Weaning Schedule for Arm 1 and Arm 2 Investigational Products
Day 1 0.09 mL/kg, to a max of 1.8 mL
Day 2 0.085 mL/kg, to a max of 1.7 mL
Day 3 0.08 mL/kg, to a max of 1.6 mL
Day 4 0.07 mL/kg, to a max of 1.4 mL
Day 5 0.065 mL/kg, to a max of 1.3 mL
Day 6 0.06 mL/kg, to a max of 1.2 mL
Day 7 0.05 mL/kg, to a max of 1.0 mL
Day 8 0.045 mL/kg, to a max of 0.9 mL
Day 9 0.04 mL/kg, to a max of 0.8 mL
Day 10 0.03 mL/kg, to a max of 0.6 mL
Day 11 0.025 mL/kg, to a max of 0.5 mL
Day 12 0.02 mL/kg, to a max of 0.4 mL
Day 13 0.01 mL/kg, to a max of 0.2 mL
Day 14 0.005 mL/kg, to a max of 0.1 mL
Day 15 0 mL/kg - No dose given

Adherence to the trial drug will be monitored weekly by checking the volume of Investigational Product used/remaining each week, documentation of spillage of Investigational Product, completion of participant study diary and analysis of participant blood and saliva samples. Participants will be required to return and unused or spoilt Investigational Products and empty bottles to their respective clinical trial pharmacy.
Intervention code [1] 320598 0
Treatment: Drugs
Comparator / control treatment
Arm 2 Control
THC:CBD Dominant (THC 1 mg and CBD 100 mg/mL) oral cannabis oil.
Control group
Dose comparison

Outcomes
Primary outcome [1] 327587 0
The change in total symptom burden from baseline to maintenance phase as measured by the 32 item Memorial Symptom Assessment Scale (MSAS) Global Distress Index.
Timepoint [1] 327587 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [1] 395784 0
Individual MSAS Symptom Subscales (lack of appetite, weight loss, lack of energy, pain, dry mouth, drowsiness, constipation, nausea, vomiting, change in taste, feeling bloated and dizziness), as measured by the 32 item MSAS.
Timepoint [1] 395784 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [2] 395785 0
Individual MSAS Psychological Symptom Subscales (Worrying, feeling sad, feeling nervous, difficulty sleeping, feeling irritable and difficulty concentrating), as measure by the 32 item MSAS.
Timepoint [2] 395785 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [3] 395786 0
Ratio of THC:CBD maintenance dose needed to achieve optimal symptom relief with acceptable side effects as measured by clinical assessment and MSAS.
Timepoint [3] 395786 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [4] 395787 0
Oral Morphine Equivalent (OME) as measured by medication and or medical records and converted using the conversion table in the Children’s Health Queensland Hospital and Health services practical guide to palliative care in paediatrics
Timepoint [4] 395787 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [5] 395788 0
Other medication use as measured by a diary of concurrent medication(s).
Timepoint [5] 395788 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [6] 395789 0
Functional status as measured by the Lansky Performance Scale for children equal to or less than 16 years of age, and as measured by the Karnofsky Performance Scale for individuals more than 16 years of age.
Timepoint [6] 395789 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [7] 395790 0
Nursing dependency as measured by the RUG-ADL.
Timepoint [7] 395790 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [8] 395791 0
Change in symptoms as measured by the Patient Global Impression of Change (PGIC).
Timepoint [8] 395791 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [9] 395793 0
Patient quality of life as measured by the PedsQL (TM).
Timepoint [9] 395793 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [10] 395795 0
Participant's emotional distress as measured by the Paediatric Index of Emotional Distress (PI-ED) for participants aged 7 to 17 years.
Timepoint [10] 395795 0
Weeks -2 and -1 (baseline), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [11] 395800 0
Composite level of mood and anxiety as measured by the 21 item Depression Anxiety Stress Scales12 (DASS 21) (for participants aged 18 to 21).
Timepoint [11] 395800 0
Weeks -2 and -1 (baseline phase), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [12] 395801 0
Participant’s weight as measured by the assessing clinician, using digital scales.
Timepoint [12] 395801 0
Weeks -2 (commencement of baseline phase) and week 6 (end of maintenance phase).
Secondary outcome [13] 395803 0
Composite anorexia and cachexia related quality of life, as measured by the 10-utem Paediatric Functional Assessment of Anorexia and Cachexia Therapy (peds FAACT-10).
Timepoint [13] 395803 0
Weeks -2 (commencement of baseline phase) and week 6 (end of maintenance phase).
Secondary outcome [14] 395804 0
Participant actigraphy - daytime physical activity (total steps and category of activity – asleep, sedentary, light, moderate vigorous), as measured by an accelerometer on their non-dominant arm.
Timepoint [14] 395804 0
Week -2 (commencement of baseline phase), week 3 and week 6 (maintenance phase).
Secondary outcome [15] 395805 0
Participant Actigraphy - sleep patterns at night (total sleep and total wake time), as measured by an accelerometer on their non-dominant arm.
Timepoint [15] 395805 0
Week -2 (commencement of baseline phase), week 3 and week 6 (maintenance phase).
Secondary outcome [16] 395806 0
Quantification of blood cannabinoid (THC & CBD) and metabolites, as measure by mass spectrometry.
Timepoint [16] 395806 0
Week -1 (baseline phase), week 2 (titration phase) and week 6 (maintenance phase).
Secondary outcome [17] 395807 0
Blood parameters as measured by routine haematology (Full Blood Count (FBC) with differential),
Timepoint [17] 395807 0
Week -1 (baseline phase), week 2 (titration phase) and week 6 (maintenance phase).
Secondary outcome [18] 404285 0
Exploratory biochemistry measures as measured by routing chemistry screening (Sodium; Potassium; Chloride, Bicarbonate, Anion Gap; Calcium; Ca Alb Corr; Phosphate; Magnesium; Urea; Uric Acid; Creatine; eGFR), Liver function tests (Total Protein; Albumin; Estimated Globulins; Bilirubin Total, AST, ALT, GGT; ALF), Urinalysis.
Timepoint [18] 404285 0
Week -1 (baseline phase), week 2 (titration phase) and week 6 (maintenance phase).
Secondary outcome [19] 404286 0
Measurement of blood Endocannabinoids (Anandamide and 2-AG) as measured by mass spectrometry.
Timepoint [19] 404286 0
Week -1 (baseline phase), week 2 (titration phase) and week 6 (maintenance phase).
Secondary outcome [20] 404287 0
Measurement of blood lipidome as measured by mass spectrometry.
Timepoint [20] 404287 0
Week -1 (baseline phase), week 2 (titration phase) and week 6 (maintenance phase).
Secondary outcome [21] 404288 0
Measurement of blood inflammatory markers (prostaglandins & eicosanoids), as measured by mass spectrometry.
Timepoint [21] 404288 0
Week -1 (baseline phase), week 2 (titration phase) and week 6 (maintenance phase).
Secondary outcome [22] 404289 0
Measurement of saliva Endocannabinoids (Anandamide and 2-AG) as measured by mass spectrometry.
Timepoint [22] 404289 0
Week -1 (baseline phase), week 2 (titration phase) and week 6 (maintenance phase).
Secondary outcome [23] 404290 0
Measurement of saliva lipidome as measured by mass spectrometry.
Timepoint [23] 404290 0
Timepoint 24: Week -1 (baseline phase), week 2 (titration phase) and week 6 (maintenance phase).
Secondary outcome [24] 404291 0
Measurement of saliva inflammatory markers (prostaglandins & eicosanoids), as measured by mass spectrometry.
Timepoint [24] 404291 0
Week -1 (baseline phase), week 2 (titration phase) and week 6 (maintenance phase).
Secondary outcome [25] 404292 0
Disease progression, as measured by clinical evaluation and patient records (including results of investigations).
Timepoint [25] 404292 0
Weeks -2 and -1 (baseline phase), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).
Secondary outcome [26] 404293 0
Survival, as measured by clinical evaluation and patient records (including results of investigations).
Timepoint [26] 404293 0
Weeks -2 and -1 (baseline phase), weeks 1 and 2 (titration phase) and weeks 3, 4, 5 and 6 (maintenance phase).

Eligibility
Key inclusion criteria
1. Aged 6 months to 21 years
2. Have advanced cancer (metastatic or locally advanced solid tumours, brain tumours or advanced hematological malignancies)
3. Have been referred to, or are known to the paediatric palliative care service
4. Are symptomatic according to the MSAS Scale
5. Have a performance status of =>30
Minimum age
6 Months
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of unstable, untreated cardiovascular disease
2. Severe hepatic or renal impairment
3. History of psychiatric disorder
4. Known substance use disorder
5. History suggesting drug diversion may occur
6. Participation in a trial of an investigational agent within the last 28 days
7. Pregnancy
8. Breastfeeding

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)
Permuted block randomisation schedule held by the central registry.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment for each participant will be allocated according to a permuted block randomisation schedule. Block randomisation within each centre will ensure even allocation to each arm at each site.
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
Not applicable
Phase
Phase 2 / Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Descriptive analysis and frequency distributions will be generated from the participant's demographic and clinical characteristics. Linear Mixed Models will be used to assess changes in MSAS Global Disease Index, MSAS Total Score, MSAS physical symptom subscale and MSAS psychological symptom sub-scale over time and across treatment groups.
Results from pharmacokinetic analysis of CBD and THC will be correlated with patients' clinical status (age, weight, diagnosis) and dose.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
13/03/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 19532 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 19533 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 19534 0
Monash Children’s Hospital - Clayton
Recruitment hospital [4] 19535 0
John Hunter Children's Hospital - New Lambton
Recruitment postcode(s) [1] 34141 0
4101 - South Brisbane
Recruitment postcode(s) [2] 34142 0
3052 - Parkville
Recruitment postcode(s) [3] 34143 0
3168 - Clayton
Recruitment postcode(s) [4] 34144 0
2305 - New Lambton

Funding & Sponsors
Funding source category [1] 308638 0
Government body
Name [1] 308638 0
Australian Government Medical Research Future Fund
Country [1] 308638 0
Australia
Primary sponsor type
University
Name
Queensland University of Technology
Address
2 George Street
Brisbane
Queensland 4001
Australia
Country
Australia
Secondary sponsor category [1] 309509 0
None
Name [1] 309509 0
Address [1] 309509 0
Country [1] 309509 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308564 0
Children's Health Queensland Human Research Ethics Committee
Ethics committee address [1] 308564 0
Level 7, Centre for Children's Health Research
62 Graham Street
South Brisbane
Queensland 4101
Ethics committee country [1] 308564 0
Australia
Date submitted for ethics approval [1] 308564 0
19/07/2021
Approval date [1] 308564 0
16/12/2021
Ethics approval number [1] 308564 0
HREC/21/QCHQ/76288

Summary
Brief summary
This study is aimed at establishing tolerable and potentially effective doses of two medicinal cannabis products in paediatric palliative care.

Who is it for?
Participants may be eligible for this study if they are aged 6 months to 21 years, have advanced cancer (metastatic or locally advanced solid tumours, brain tumours or advanced hematological malignancies) and have been referred to or are known by the paediatric palliative service.

Study details
Participants will undergo baseline measurements, before being randomly allocated to either of two cannabis oil treatments which will be delivered daily for a total of 6 weeks. Participants will visit the clinic weekly to have their symptom burden assessed.

Results from this study will help determine clinical dosing of medicinal cannabis for relief of symptom burden in children with advanced cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111154 0
A/Prof Anthony Herbert
Address 111154 0
Queensland University of Technology
L5, Centre for Children's Health Research
62 Graham Street,
South Brisbane
Queensland 4101
Country 111154 0
Australia
Phone 111154 0
+61 7 3068 3775
Fax 111154 0
Email 111154 0
[email protected]
Contact person for public queries
Name 111155 0
Dr Alison Bowers
Address 111155 0
Queensland University of Technology
L5, Centre for Children's Health Research
62 Graham Street,
South Brisbane
Queensland 4101
Country 111155 0
Australia
Phone 111155 0
+61 7 3069 7291
Fax 111155 0
Email 111155 0
[email protected]
Contact person for scientific queries
Name 111156 0
A/Prof Anthony Herbert
Address 111156 0
Queensland University of Technology
L5, Centre for Children's Health Research
62 Graham Street,
South Brisbane
Queensland 4101
Country 111156 0
Australia
Phone 111156 0
+61 7 3068 3775
Fax 111156 0
Email 111156 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
To ensure confidentiality and prevent possible identification of individual participants; due to the small sample size, IPD will not be available.


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.