The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12619000265178
Ethics application status
Approved
Date submitted
31/01/2019
Date registered
21/02/2019
Date last updated
29/03/2019
Date data sharing statement initially provided
21/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Cannabinoids for Symptom Control in Advanced Cancer, an Open Label Prospective Clinical Trial in New South Wales (NSW)
Scientific title
Cannabinoids for Symptom Control in Advanced Cancer, an Open Label Prospective Clinical Trial in New South Wales (NSW)
Secondary ID [1] 297158 0
None
Universal Trial Number (UTN)
U1111-1227-1657
Trial acronym
CARE NSW
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 311188 0
Pain 311190 0
Anorexia 311191 0
Nausea 311192 0
Condition category
Condition code
Cancer 309810 309810 0 0
Any cancer
Anaesthesiology 310272 310272 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open label study to profile how advanced cancer patients use a range of cannabis medicines for symptom relief via the collection of prospective data on open label product, dose, efficacy, safety, pharmacokinetics and pharmacodynamics to provide preliminary safety, tolerability and efficacy evidence to guide future studies.

Each patient will be prescribed a cannabis medicine from a defined selection of products currently available in Australia that are compliant with TG093 and GMP regulations, manufactured both overseas and within Australia. The choice of study drug will be guided by the patient’s primary index symptoms and at the discretion of the doctor and supply.

Treatment will be oral oil liquids, either Delta-9-Tetrahydrocannabinol (THC) or a combination of THC and Cannabidiol (CBD) in near equal amounts.

Treatment will be given in addition to the usual medical treatments for advanced cancer and symptoms, including other medicines and radiotherapy.

Dosing guidance for this trial is to 'start low, go slow'and start at 2.5mg THC three times a day in cannabis naive patients, and 5 mg THC three times a day in previous users. Dose titration up or downwards will be in consultation with the doctor according to symptom control and reported side effects (measured on CTCAE v5.0). Maximal dosage of 30 mg THC per day, in line with TGA guidance, is advised.

Blood samples for pharmacokinetic profiles will be taken at the first assessment to measure THC and CBD levels.

Long term exposure of THC and CBD, and adherence to trial product, will be monitored by a single pharmacokinetic blood sample at each follow-up assessment timepoint (1-2 weeks, 6 weeks, 3 months, 6 months, then every 3 months until death or withdrawal).

Clinical assessments, along with validated patient reported outcome measures and an electronic patient diary will record outcomes and guide dose.

Patients will remain enrolled in this trial and continue to receive the prescribed cannabis medicines until they are no longer able to take it or withdraw from the trial.
Intervention code [1] 313419 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 319123 0
To describe preliminary efficacy of cannabis medicines products on overall quality of life in patients with advanced cancer measured by the validated patient reported outcome measure, the quality of life questionnaire EORTC QLQ-C30.
Timepoint [1] 319123 0
Assessed at baseline and compared at 1-2 weeks, 6 weeks (Primary Endpoint), 3 months, 6 months and every 3 months until patient no longer on trial. In this study, the primary outcome will be assessed at 6 weeks at main analysis, all time points will be assessed at final analysis.
Primary outcome [2] 319124 0
To characterise the preliminary pharmacological endpoints, including pharmacokinetics (Tmax, Cmax, bioavailability, AUC, T1/2), of a number of cannabis medicines formulations in a group of advanced cancer patients.
Timepoint [2] 319124 0
Pharmacokinetic samples will be taken at the time of first dose (primary timepoint) at 0, 30, 60, 120 and 240 mins to measure THC and CBD levels. Concentrations will be measured at each follow-up assessment timepoint (1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial.). In this study, the primary outcome will be assessed after day 1, all other time points will be assessed at final analysis.
Primary outcome [3] 319125 0
To determine the preliminary adverse effects of cannabis medicines products in an advanced cancer population. This will be assessed by recording the frequency, type and severity of the 15 commonly known associated side effects (Drowsiness, Nausea, Dizziness, Confusion, Vomiting, Tiredness, Anaemia, Pain, Weakness/ Asthenia, Diarrhoea, Headache, Dyspnea, Hallucinations, Anxiety, and any other which occur) using the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
Timepoint [3] 319125 0
CTCAE v5.0 will be completed and assessed at baseline and compared at 1-2 weeks, 6 weeks (primary timepoint), 3 months, 6 months and every 3 months until patient no longer on trial. In this study, the primary outcome will be assessed at 6 weeks at main analysis, all time points will be assessed at final analysis.
Secondary outcome [1] 367027 0
To describe the preliminary efficacy outcome of cannabis medicines products on overall symptoms in patients with advanced cancer, This is measured by the patients reported Treatment Satisfaction score and Global impression of change.
Timepoint [1] 367027 0
Assessed at baseline and compared at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [2] 367028 0
To describe preliminary efficacy of cannabis medicines products on daily life in patients with advanced cancer measured through a patient dairy which includes the Symptom Assessment Scale (SAS), used by the Palliative Care Outcomes Collaboration.
Timepoint [2] 367028 0
Assessed at baseline and compared at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [3] 367029 0
To describe preliminary efficacy of cannabis medicines products on the key index symptom of pain, in participants with advanced cancer, measured by the validated patient reported outcome measure, the Brief Pain Index.
Timepoint [3] 367029 0
Assessed at baseline and compared at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [4] 367030 0
To describe preliminary efficacy of cannabis medicines products on the key index symptom of nausea in participants with advanced cancer, measured by the validated patient reported outcome measure, the Functional Assessment of Anorexia/Cachexia (FAACT).
Timepoint [4] 367030 0
Assessed at baseline and compared at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [5] 367031 0
To describe preliminary efficacy of cannabis medicines products on the key index symptom of anorexia (lack of appetite) in participants with advanced cancer, measured by the validated patient reported outcome measure, the Functional Assessment of Anorexia/Cachexia (FAACT).
Timepoint [5] 367031 0
Assessed at baseline and compared at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [6] 367032 0
To determine the preliminary adverse effects of cannabis medicines products in an advanced cancer population on mental health (distress and anxiety). This will be assessed through the Depression, Anxiety and Stress Scale - 21 items (DASS-21).
Timepoint [6] 367032 0
DASS-21 will be completed and assessed at baseline and compared at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [7] 367033 0
To determine the preliminary development of tolerance to cannabis medicines products in an advanced cancer population. A bespoke version of the opioid related behaviours in treatment questionnaire (ORBIT), modified to describe use and tolerance of cannabis medicines, will be employed.
Timepoint [7] 367033 0
The modified ORBIT will be assessed at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [8] 367034 0
To determine the preliminary development of addiction ( cannabis use disorder) to cannabis medicines products in an advanced cancer population. A bespoke version of the opioid related behaviours in treatment questionnaire (ORBIT), modified to describe use and tolerance of cannabis medicines, will be employed.
Timepoint [8] 367034 0
The modified ORBIT will be assessed at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [9] 367035 0
To describe change in concomitant medication use during the study through descriptive analysis of the patient reported use of concomitant medications recorded in the daily diary and at follow-up assessments.
Timepoint [9] 367035 0
Assessed at baseline and compared at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [10] 367036 0
To improve our understanding of cannabis use in the advanced care patient and examine the change in self-reported illicit cannabis use, recorded in the daily diary and at follow-up assessments, following access to a prescribed cannabis medicine through descriptive analysis.
Timepoint [10] 367036 0
Assessed at baseline and compared at 1-2 weeks, 6 weeks, 3 months, 6 months and every 3 months until patient no longer on trial. The secondary outcome will be assessed at all timepoints.
Secondary outcome [11] 367037 0
To identify the resource use and costs associated with cannabis medicines in the advanced cancer population. The EORTC QLU-C10D multi-attribute utility instrument derived from the EORTC QLQ-C30 Quality of Life (QoL) instrument will be used to estimate the health outcomes and Quality Adjusted Life Years (QALYs). MBS and PBS data will be collected from those patients who separately consent to the provision of this data. The costs and QALYs will be compared with other medicines recommended by the Pharmaceutical Benefits Advisory Committee (PBAC)
Timepoint [11] 367037 0
Once all patients recruited are off trial.

Eligibility
Key inclusion criteria
1. Aged 18 years or older.
2. Has provided written Informed Consent for participation in this trial.
3. Confirmed advanced cancer (any) with or without stable disease.
4. Predicted life expectancy of 6 to 12 months at time of consent, as estimated by the study investigator and confirmed by an additional qualified clinician, independent of the trial.
5. Persistent symptoms of anorexia, nausea or refractory pain, which in the investigator’s opinion are not responsive to implementation of standard practice, and who are ineligible or not wishing to be involved in other clinical trials of cannabis medicines.
6. Willing and able, in investigator’s opinion, to comply with all trial requirements, including keeping a patient diary, completing clinical measurement scales and having pharmacokinetic samples collected as per Participant Information Sheet. Note: completion of these trial requirements is essential and intentional non-compliance may cease access to trial product and will be managed on a case-by-case basis. Non-compliance due to declining health is unintentional and it is hoped unintentional noncompliance due to declining health may be minimised through optional proxy completion of patient reported outcomes and patient diary.
7. Available to attend Trial Site for follow up and collection of investigational product.
8. Participants (and/or partners) capable of childbearing are using adequate contraception.

Participants are able to continue to receive standard concomitant care and interventions, such as chemotherapy and radiotherapy, and take medications for other conditions as usual in the advanced care population
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Lack of capacity to consent.
2. Unwilling to keep a Patient Diary, attend follow up appointments, complete clinical measurement scales or have pharmacokinetic samples.
3. History of schizophrenia, other psychotic illness, severe borderline personality disorder, or other significant psychiatric disorder other than depression or anxiety associated with underlying condition. Delirium is an excluded condition.
4. Previous severe adverse event to any cannabinoid product, such as cannabis related psychosis, panic attack, palpitations.
5. A diagnosed substance use disorder (ICD-10 criteria (abuse, dependence)) to alcohol, opioids, cannabis, benzodiazepines, or illicit stimulants. Nicotine and caffeine are excluded.
6. Known allergy to cannabis or other ingredient of cannabis medicine e.g. carrier oil.

Note: Prior access to authorised cannabis medicines or current use of illicit cannabis is not an exclusion, unless associated with a serious adverse event (SAE) or substance use disorder as per exclusion criteria above.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
The choice of study drug will be guided by the patient’s primary index symptoms and at the discretion of the doctor and supply. Patients will remain enrolled in this trial and continue to receive the prescribed cannabis medicines until they are no longer able to take it or withdraw from the trial.
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Continuous variables with normal distribution will be presented as means with standard deviation. Ordinary variables or continuous variables with non-normal distribution will be presented as medians with an interquartile range (IQR). Categorical variables will be presented as counts and percent of the total.
The CARE NSW Trial will use t-test for the analysis of the continuous variables with normal distribution. The non-parametric Wilcoxon test will be used whenever parametric assumptions cannot be satisfied.
Logistic regression will be used for the multivariate analysis of factors associated with treatment success. The following variables have been included in the models based on clinical considerations, including: age (dichotomized at 65), gender, weight, indication for cannabis treatment, presence of pain, number of chronic medications, hospitalisation in the past six months, employment, car use, previous experience with cannabis, cigarette smoking, quality of life at the baseline, and concerns about cannabis treatment as reflected in the intake form.
At time of analysis, a sensitivity test will be performed by comparing the outcomes with and without removing patients who report taking illicit cannabis. If a number of patients report such usage, the reported dose of illicit cannabis may be controlled for in subsequent analyses.
For each participant administered active treatment, non-compartmental analysis of plasma concentration-time data for each participant will be used to evaluate the following: area under the plasma concentration-time profile from time 0 to t, the dosing interval, where t = 4 h (AUCt,); area under the plasma concentration-time profile from time 0 extrapolated to infinite time (AUC inf, single-dose only); maximal plasma concentration (Cmax); time to Cmax (Tmax); terminal half-life (t½); apparent oral clearance (CL/F); and apparent oral volume of distribution (Vz/F).
Different products, different concentrations, different symptoms in this population that includes any type of advanced cancer introduces a high number of cofounders and small number of participants in each group. However, the focus is the relationship between pharmacokinetics and endpoint. The relationship between dose and effect is intermediarised via the exposure (Cmax and AUC) and the relationship between dose and PK will be extrapolated to provide preliminary guidance for prescribers and future studies.
All plasma concentrations of THC and CBD will also be used to develop a population pharmacokinetic model that incorporates inter- and intra-individual and residual unexplained variability. Participant factors contributing to the parameter variability will be modelled using standard forward-inclusion/backward deletion methods. Model selection will be based on the objective function value and standard diagnostic plots. The final model will be evaluated through visual predictive checks and bootstrap analysis.
To provide an indication of the relationship between pharmacokinetics and response (efficacy and toxicity), model predicted pharmacokinetic parameters in participants who are classified as “therapeutic” (e.g. complete anti-nausea response) and “non-therapeutic” will be statistically compared. A linear mixed effects analysis of variance (ANOVA) model will be used to perform statistical comparisons of Ln-transformed pharmacokinetic data. The residual error (error mean square) will be used to construct the 90% confidence intervals for the ratio of the dose level means.

Recruitment
Recruitment status
Not yet 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)
NSW

Funding & Sponsors
Funding source category [1] 301711 0
Government body
Name [1] 301711 0
NSW Ministry of Health
Address [1] 301711 0
Medical Advisor
Office of the Chief Health Officer, NSW Health
73 Miller Street North Sydney NSW 2060
Country [1] 301711 0
Australia
Primary sponsor type
Government body
Name
Health Administration Corporation acting through the NSW Ministry of Health
Address
Medical Advisor
Office of the Chief Health Officer, NSW Health
73 Miller Street North Sydney NSW 2060
Country
Australia
Secondary sponsor category [1] 301441 0
University
Name [1] 301441 0
University of Newcastle acting through the NHMRC Australian Centre for Clinical Cannabinoid Research Excellence (ACRE)
Address [1] 301441 0
Director, Research and Innovation,
University Drive, Callaghan, NSW 2308
Country [1] 301441 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302430 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 302430 0
Research Ethics and Governance Office
The Lodge, Rankin Park Campus
Lookout Road,
New Lambton NSW 2305
Ethics committee country [1] 302430 0
Australia
Date submitted for ethics approval [1] 302430 0
02/10/2018
Approval date [1] 302430 0
27/03/2019
Ethics approval number [1] 302430 0

Summary
Brief summary
The main purpose of this study is to determine what dose and frequency of medicinal cannabis is the best to relieve key symptoms in people with advanced cancer.

Who is it for?
You may be eligible to join this study if you are aged 18 years or more, have a confirmed diagnosis of advanced cancer, with significant symptoms of severe pain, and/or vomiting, and/or nausea and/or lack of appetite that are poorly controlled by usual treatments, and a predicted life expectancy of more than 6 months and less than 12 months.

Study details
All participants in the study will be prescribed one of a number of cannabis medicines. The cannabis product will be given in addition to the usual treatments for their advanced cancer symptoms. On the first day of treatment participants will have 5 blood samples collected over 4 hours to measure the levels of cannabis medicines in their blood. They will also complete some online questionnaires about how they feel and be monitored for side effects.

Participants will remain enrolled in this trial and receive the cannabis medication prescribed at no cost until they are no longer able to take it or withdraw from the trial. Participants will be asked to complete regular online questionnaires and have a single blood sample taken every few weeks when they see the trial doctor, until they no longer receive the product and/or withdraw from the trial.

It is hoped the information collected in this study will guide the use of cannabis medicines to control symptoms in people with advanced cancer.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90218 0
Prof Jennifer Martin
Address 90218 0
Head of Clinical Pharmacology, University of Newcastle.
Director of Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE).
C/- Hunter Medical Research Institute
Lot 1, Kookaburra Circuit, New Lambton Heights, NSW, 2305
Country 90218 0
Australia
Phone 90218 0
+61 2 40420908
Fax 90218 0
Email 90218 0
ACRE-CARE@newcastle.edu.au
Contact person for public queries
Name 90219 0
Dr Rachel Galettis
Address 90219 0
Clinical Trial Coordinator
ACRE
C/- Hunter Medical Research Institute
Lot 1, Kookaburra Circuit, New Lambton Heights, NSW, 2305
Country 90219 0
Australia
Phone 90219 0
+61 2 40420915
Fax 90219 0
Email 90219 0
ACRE-CARE@newcastle.edu.au
Contact person for scientific queries
Name 90220 0
Dr Rachel Galettis
Address 90220 0
Clinical Trial Coordinator
ACRE
C/- Hunter Medical Research Institute
Lot 1, Kookaburra Circuit, New Lambton Heights, NSW, 2305
Country 90220 0
Australia
Phone 90220 0
+61 2 40420915
Fax 90220 0
Email 90220 0
ACRE-CARE@newcastle.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
Nil individual participant data will be provided. A final cleaned non-identified data set of summary data will be available for dissemination.
What supporting documents are/will be available?
Study protocol
Clinical study report
How or where can supporting documents be obtained?
Type [1] 1132 0
Study protocol
Citation [1] 1132 0
Link [1] 1132 0
Email [1] 1132 0
Other [1] 1132 0
The CARE NSW Trial protocol is proposed to be made publically available through publication in a peer reviewed major medical journal. At a minimum, the protocol will be published online through the University of Newcastle Library and ACRE Website.
Attachment [1] 1132 0
Type [2] 1385 0
Clinical study report
Citation [2] 1385 0
Link [2] 1385 0
Email [2] 1385 0
Other [2] 1385 0
The final report of the results will be disseminated regardless of the magnitude or direction of effect. At a minimum, the report will be published online through the University of Newcastle Library and ACRE Website.
Attachment [2] 1385 0
Summary results
No Results