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Trial registered on ANZCTR


Registration number
ACTRN12619000037101
Ethics application status
Approved
Date submitted
10/01/2019
Date registered
14/01/2019
Date last updated
17/12/2019
Date data sharing statement initially provided
14/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study that evaluates the effectiveness of oral combined THC/CBD for people with advanced cancer experiencing a range of symptoms.
Scientific title
Oral Medicinal cannabinoids to Relieve Symptom Burden in the Palliative care of Patients with Advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of 1:1 delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)
Secondary ID [1] 297030 0
NIL
Universal Trial Number (UTN)
Trial acronym
MedCan 2 - THC/CBD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 311007 0
Fatigue 311008 0
Nausea 311009 0
Breathlessness 311010 0
Appetite 311011 0
Psychological effects 311012 0
Condition category
Condition code
Cancer 309658 309658 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients with advanced cancer will participate in a double-blind, placebo controlled, and randomisation clinical trial. Each participant will follow a dose titration schedule for 14 days and a follow on stable dose for a further 14 days. Participants will be allocated into a treatment arm according to a block randomisation schedule held by a central registry. There will be one active arm (THC/CBD) and an inert oral oily liquid (placebo).

Concentration of medication:
THC/CBD (delta-9-tetrahydrocannabinol)/(cannabidiol) 10mg/mL oral oily liquid (dose range 2.5mg/2.5mg - 30mg/30mg/day)

Dosing schedule:
Dose titration (days 0 - 14) will be confirmed by the treated doctor with doses starting at:
Days 0 & 1 – 1 dose/day = total daily dose 2.5mg/2.5mg (0.25mL)
Day 2 & 3 – 1 dose/day = total daily dose 5mg/5mg (0.5mL)
Day 4 & 5 – 2 dose/day = total daily dose 10mg/10mg (1mL)
Day 6 & 7 – 3 doses/day = total daily dose 15mg/15mg (1.5mL)
Day 8 & 9 – 3 doses/day = total daily dose 20mg/20mg (2mL)
Day 10 & 11 – 3 doses/day = total daily dose 25mg/25mg (2.5mL)
Day 12 & 13 – 3 doses/day = total daily dose 30mg/30mg (3mL)
Day 14 – 28 – Continue on final dose reached

Each participant will be advised to increase their dose according to the dosing schedule until they are satisfied with symptom improvement and no unacceptable side effects (according to the CTCAE graded >4 (confusion, somnolence, personality change, paranoia, anxiety, mood change, psychosis, hypertension, tachycardia, sweating, nausea, vomiting, abdominal pain). The patient then will be given the option of remaining on the cannabinoid preparation for continuing assessment of efficacy and adverse events for a further 14 days totaling 28 days on the study drug.
Patients will have the choice of lowering their dose according to symptom improvement. Dose titration downwards will be in consultation with the doctor.
Participants will be required to return empty/unused bottles each clinic visit to receive a further supply.
Intervention code [1] 313308 0
Treatment: Drugs
Comparator / control treatment
The placebo will be an excipient-matched oral oil solution with no active drug in a 50mL bottle
Control group
Placebo

Outcomes
Primary outcome [1] 318626 0
Change from baseline of total ESAS TSDS
Timepoint [1] 318626 0
Assessed at baseline and day 14
Secondary outcome [1] 365535 0
Patient determined effective dose of the 1:1 THC/CBD formulation
Timepoint [1] 365535 0
Defined as the dose that achieves symptom relief with acceptable side-effects by day 14
Secondary outcome [2] 365536 0
Combined physical and emotional (pain, tiredness, nausea, shortness of breath, drowsy, appetite, anxiety, depression, wellbeing) will be totalled together at each time point. Each symptom will be rated from 0-10 on the ESAS. Scores will be collected at each time point
Timepoint [2] 365536 0
Assessed at days 7, 14, 21 and 28
Secondary outcome [3] 365537 0
Oral morphine equivalent (OME). Conversion of various opioids to an equianalgesic dose of oral morphine (mg/24hr). OME will be assessed by review of medical records. 24hr opioid consumption will be measured as oral morphine equivalents. Opioid conversion e.g. Oxycodone multiplication of a factor 1.5; fentanyl is a multiplication of a factor of 0.3
Timepoint [3] 365537 0
Average used assessed at baseline and days 7, 14, 21 and day 28
Secondary outcome [4] 365539 0
Clinical Global Impression (CGI) scales
Timepoint [4] 365539 0
Assessed at baseline and compared at days 7, 14, 21 and 28
Secondary outcome [5] 365540 0
DASS-21 score assessing combines depression, anxiety and stress
Timepoint [5] 365540 0
Assessed at baseline and compared at days 7, 14, 21 and 28
Secondary outcome [6] 365541 0
Quality of Life using questionnaire EORTC QLQ-C15 PAL
Timepoint [6] 365541 0
Assessed at baseline and compared at days 7, 14 and 28
Secondary outcome [7] 365542 0
Adverse Events (AE) recorded using Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0) All AE's will be recorded at baseline until end of study (day 28).Particular attention will be given to: mood change, dizziness, somnolence, confusion, concentration, feeling "high" warm/tingle feeling, exaggerated sense of well-being, anxiety, headache, insomnia, clumsiness, lack of coordination, weakness, unsteadiness, red yes, dry mouth, nausea, vomiting, diarrhoea, stomach/abdominal pain, personality change, paranoia, psychosis, hypertension, tachycardia, sweating
Timepoint [7] 365542 0
Assessed at baseline and compared at days 2, 4, 7, 9, 11, 14, 21 and 28

Eligibility
Key inclusion criteria
Patients with advanced histologically proven cancer (metastatic or locally advanced) known to the palliative care team of the recruiting centre who:

- have an ESAS TSDS greater than 10 for cancer-related symptoms*
- at least one individual ESAS score greater than 3
- AKPS score >30
- aged >25yrs and above. English speaking (or have interpreter available)
- have a negative pregnancy urine test at eligibility (only if of reproductive potential) and
agree to avoid pregnancy during the study and 12 weeks following the last dose of the
study drug. Males must agree to avoid fathering a child and to not donate sperm during
the study and for at least 12 weeks following the last dose of the study drug
- have a negative THC urine test
- able to tolerate oral medication
- willing to receive standard palliative care
- comply with trial requirements; agree to attend scheduled clinic appointments, adhere to dose
titration schedule as directed
- agree to use no other cannabis based products for the duration of the trial
- understand it is illegal to drive whilst taking THC containing cannabis products, to take
cannabinoid products outside of Australia or to endorse legal documents whilst taking THC
containing cannabis products
- provide fully informed consent
*physician assessed
Minimum age
25 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with:

- a history of hypersensitivity to any cannabinoid product
- unstable untreated cardiovascular disease (hypertension, ischemic heart disease, congestive
cardiac failure)
- severe hepatic impairment (total bilirubin >1.5 times the upper limit of the institution's normal
range. Asparate aminotransferase (AST), and alanne aminotransferase (ALT) >3.0 time the upper
limit of the institution's normal range; subjects with liver metastasis may have an AST and ALT of
>5.0 times the upper limit of normal
- severe renal impairment (eGFR <20mls/min/1.73m2)
- history of psychiatric disorders (severe depression or anxiety, personality disorder, psychosis,
schizophrenia, first degree relative with schizophrenia and/or suicidal ideation)
- cognitive impairment (SLUMS - St Louis University Mental Status) examination <20/30
- known substance use disorder (ASSIST - Alcohol, Smoking and Substance Involvement Screening
Test) examination score >27+
- history that drug diversion may be a risk for them or their family/carers
- females who are pregnant or lactating
- concurrent or participation of a new clinical entity with the last 28 days
- treatment with a new specific anticancer agent (chemotherapy, targeted or hormonal therapy) or
radiation within the last 7 days

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)
An independent centre (Mater Research Office) will establish a randomisation schedule. Randomisation will be allocated according to a block randomisation schedule held by the central registry. Block randomisation within each centre will ensure even allocation across each treatment arm. Active and placebo treatments will be labeled and coded by Mater Research Office and will not be revealed to investigators or the participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
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
Each participant will complete a 28 day period of treatment, receiving either the active or placebo drug.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The sample size is based on previous work by Hui et al., who determined the minimal clinically important difference in the TSDS to be 5.7 (2). As such we have elected to use an improvement of =6 in the TSDS as the primary outcome measure. Allowing 20% for attrition, and with improvement of =6 for CBD compared to placebo, it is anticipated that 144 participants (72 per arm) should be randomized to achieve a sample size of 60 participants per arm, assuming 80% power, a simple random sampling scheme and a Type 1 error of 5% (two-tailed), and a standard deviation of 11.6. The superiority of each medicinal cannabis arm compared to placebo will be tested by comparing the response to each arm after 14 days, relative to baseline.

Descriptive analyses and frequency distributions will be generated from participants’ demographic and clinical characteristics, with all variables explored using graphical methods and summary statistics. In univariate analysis, T tests or the corresponding non-parametric tests (Wilcoxon Rank Sum) will be used to test for differences in change in total symptom distress scores of CBD versus placebo. Generalised estimating equation models with the appropriate link function will be developed to assess the effect of treatment and confounders and/or modifying factors on the primary and secondary outcomes and account for within subject correlation where required. This study is powered to detect superiority of CBD over placebo. If the CBD is shown to be superior to placebo, subsequent studies will need to be undertaken to determine which particular combination (or dose) is superior.

An interim analysis will be performed after one third of the participants have completed 14 days of the trial. The analysis will be performed by a biostatistician blinded for the treatment allocation and reported to the investigators and the DSMB. The purpose of the interim analysis is primarily to monitor and ensure safety of participants rather than evidence of such benefit that early stopping of the trial is justified. AEs and SAEs will be stratified by type and severity. The frequency of AEs and SAEs will be compared between treatment groups using chi-square test and logistic regression if indicated to adjust for any baseline differences between groups.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 12853 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [2] 12854 0
Mater Private Hospital - South Brisbane
Recruitment hospital [3] 12855 0
St Vincent's Hospital Brisbane - Kangaroo Point
Recruitment hospital [4] 12856 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 12857 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [6] 12858 0
Gold Coast Hospital - Southport
Recruitment postcode(s) [1] 25330 0
4101 - South Brisbane
Recruitment postcode(s) [2] 25331 0
4169 - Kangaroo Point
Recruitment postcode(s) [3] 25332 0
4029 - Herston
Recruitment postcode(s) [4] 25333 0
4102 - Woolloongabba
Recruitment postcode(s) [5] 25334 0
4215 - Southport

Funding & Sponsors
Funding source category [1] 301600 0
Government body
Name [1] 301600 0
National Health and Medical Research Council (NHMRC)/Medical Research Future Fund (MRFF)
Address [1] 301600 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 301600 0
Australia
Primary sponsor type
Hospital
Name
Mater Misericordiae Limited
Address
Mater Misericordiae Ltd
Raymond Terrace
South Brisbane Qld 4101
Country
Australia
Secondary sponsor category [1] 301303 0
Hospital
Name [1] 301303 0
Mater Misericordiae Limited
Address [1] 301303 0
Mater Misericordiae Ltd
Raymond Terrace
South Brisbane Qld 4101
Country [1] 301303 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302326 0
Mater Misericordiae Ltd Human Research Ethics Committee (MML HREC)
Ethics committee address [1] 302326 0
Raymond Terrace
South Brisbane Qld 4101
Ethics committee country [1] 302326 0
Australia
Date submitted for ethics approval [1] 302326 0
29/11/2018
Approval date [1] 302326 0
14/01/2019
Ethics approval number [1] 302326 0
HREC/MML/49348

Summary
Brief summary
The purpose of this study is to assess whether delta-9-tetrahydrocannabinol (THC) and cannabidoil (CBD) can be used to reduce total symptoms in patients with advanced cancer in palliative care.

Who is it for?

You may be eligible for this study if you are over 25 years of age and have been diagnosed with advanced cancer.

Study details

Participants will be randomly assigned to one of two treatment groups; either THC/CBD or a placebo medication.

Participants will be asked to take increasing doses of the study medication for 14 days, with the dose increasing until participants are satisfied with the symptom improvement and are experiencing no unacceptable side effects. After these 14 days, participants will be asked to take a steady dose of the medication for another set of 14 days.

During the 28 days of the study you will be required to have routine bloods and urine test which will be used as part of the eligibility and post trial analysis

It is hoped that this research will show a positive effect of THC/CBD on symptoms for patients suffering with advanced cancer and thus provide an option in helping manage symptoms.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89834 0
Prof Janet Hardy
Address 89834 0
Medical Director Mater Cancer Care Centre
Director Palliative and Supportive Care Services
Mater Misericordiae Ltd
Raymond Terrace
South Brisbane, Qld 4101
Country 89834 0
Australia
Phone 89834 0
+61 7 3163 2775
Fax 89834 0
+61 7 3163 2701
Email 89834 0
Janet.Hardy@mater.org.au
Contact person for public queries
Name 89835 0
Ms Georgie Cupples
Address 89835 0
Clinical Trial Coordinator
Palliative and Supportive Care
Mater Misericordiae Ltd
Raymond Terrace
South Brisbane, Qld 4101
Country 89835 0
Australia
Phone 89835 0
+61 7 3163 6057
Fax 89835 0
+61 7 6163 1588
Email 89835 0
Georgie.Cupples@mater.org.au
Contact person for scientific queries
Name 89836 0
Prof Janet Hardy
Address 89836 0
Medical Director Mater Cancer Care Centre
Director Palliative and Supportive Care Services
Mater Misericordiae Ltd
Raymond Terrace
South Brisbane, Qld 4101
Country 89836 0
Australia
Phone 89836 0
+61 7 3163 2775
Fax 89836 0
+61 7 3163 2701
Email 89836 0
Janet.Hardy@mater.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a double blinded trial, nil data will be provided at this time
What supporting documents are/will be available?
No other documents available
Summary results
No Results