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Trial registered on ANZCTR


Registration number
ACTRN12617001287325
Ethics application status
Approved
Date submitted
29/08/2017
Date registered
6/09/2017
Date last updated
24/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2 Randomised, Double Blind Clinical Trial assessing the Tolerability of Two different Ratios of Medicinal Cannabis in patients with Glioblastoma multiforme (GBM).
Scientific title
A Phase 2 Double-Blind Randomised-Controlled Clinical Trial assessing the Tolerability of Two different ratios of medicinal Cannabis in patients with Glioblastoma multiforme (GBM).
Secondary ID [1] 292764 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma multiform 304554 0
Condition category
Condition code
Cancer 303876 303876 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Medicinal cannabis imported from overseas.
NB: CBD is cannabidiol, THC is Delta-9– tetrahydrocannabinol.

The administration of this drug will be for 12 weeks per participant and it is an oil which will be ingested orally. The drug will be self administered or by a carer/family member/appointed person.

Arm 1: Standard treatment[1] plus CBD:THC (1:1) (6mg/mL:6mg/mL)
Arm 2: Standard treatment plus CBD:THC (1:4) (3.8mg/mL:15mg/mL)

[1] Standard treatment is defined as chemotherapy, radiation, immunotherapy, or any other cancer related treatment requested by the participants medical specialists and including best supportive and palliative care.

Dosing for this trial will start at 0.25 ml (of either arm 1 or 2 of the combined THC:CBD whole plant extract oil) of the oral medicinal cannabis oil per day and titrated up according to participant’s weight and symptoms. As oral ingestion has to be processed by the liver, effects will be slower than smoking or vaporizing of cannabis. It can take anywhere from 1-1.5 hours for effects to be noticed and can take 2-4 hours to reach its peak effect.

Dose will start at 0.25mL at night. If the person is able to function normally the next day, the dose will be increased 0.3mL, if they were not able to function as normal, the dose will be decreased to 0.2mL next night. Each night, the dose will either go up or down by 0.05mL depending on how the participant feels. The research nurse/assistant will be phoning the participant each morning to assess how the person is feeling to determine if they should titrate up or down or stay at that dose.

Previous trials on oral administration of medicinal cannabis have shown that dose escalation or titration is best choice for the participants. Previous trials, although not on patients with cancer have documented the first dose as 2.7mg THC:2.5mg CBD. These trials increased a dose every 2-3 hours over 24 to 48 hour period till the person felt they were affected by the dose. The dose is then stabilized at that amount for that person and the dose documented. The maximum dose documented in this trial was 48 administrations over 24 hour period.

Adherence or fidelity will be assessed by blood pathology tests for THC and CBD levels in the blood at 4 weeks, 8 weeks and 12 weeks. The blood pathology results will be assessed by the primary investigator and the research team. If there is poor adherence or fidelity, the research team will contact the participant to inquire about taking the dose.
Intervention code [1] 299001 0
Treatment: Drugs
Comparator / control treatment
There will be no active control group for this trial. This trial will be a comparison of one treatment compared to another treatment. A retrospective analysis will form the basis of a historical control group. During the trial and for 6 months after the completion of the trial, the research nurse will have access to Dr Teo's client files and match age, gender, disease status and no medicinal cannabis use to the participants recruited for this trial. MRI's must have been conducted three months apart for comparison to occur to see if medicinal cannabis was beneficial compared to no medicinal cannabis.
Control group
Dose comparison

Outcomes
Primary outcome [1] 303232 0
Changes in quality of life (QoL) as quantified by the FACT-Br between the two medicinal cannabis groups from baseline (week 0) to 12 weeks.
Timepoint [1] 303232 0
A comparison of scores for the FACT-Br will be conducted for baseline (week 0) and week 12.
Secondary outcome [1] 338303 0
Changes in blood pathology markers within the blood. (FBC, ELFT, THC, CBD)
Timepoint [1] 338303 0
0 weeks, 4 weeks, 8 weeks, 12 weeks
Secondary outcome [2] 338304 0
Assess the difference of response rate to two different cannabinoid ratio dosages using the RANO criteria,
Timepoint [2] 338304 0
12 weeks
Secondary outcome [3] 338305 0
Analysis the absorption of the oral medicinal cannabis oil (THC and CBD concentrations) in by analysis of CBD and THC levels from blood pathology tests.
Timepoint [3] 338305 0
0 weeks, 4 weeks, 8 weeks, 12 weeks (12 weeks per patient)

Blood tests for the start of dosing will not be conducted until week 4. Daily phone calls to ensure the right dose based on subjective measures will be conducted until the participant has the right dose.
Blood tests taken on week 4, 8 and 12 will be conducted 12-14 hours post last dose of the medicinal cannabis.
Secondary outcome [4] 338306 0
Changes in quality of life (QoL) as quantified by the FACT-Br between the two medicinal cannabis groups every 4 weeks from baseline (week 0) to 12 weeks (T0, T4, T8, T12).
Timepoint [4] 338306 0
O weeks, 4 weeks, 8 weeks, 12 weeks (12 weeks complete)
Secondary outcome [5] 338307 0
Assessing the difference of response rate to the two different cannabinoid ratio dosages on Tumour measurements according to the RANO criteria from MRI results (ie. sum of products of diameters (SPD). At 12 weeks, participants will be categorised based on their SPD (ie. change in SPD (from baseline to 12 weeks) is =25% or <25%).
Timepoint [5] 338307 0
Assessing the changes from baseline to week 12.
Secondary outcome [6] 338308 0
Cost effectiveness will be assessed via the QoL measure - FACT-Br.
Costs that will be measured include conventional standard care costs, both prescribed medications, chemotherapy, radiation, consultation fees etc. These costs will be calculated based on whole costs including both to government to the individual. However, full cost to individual such as lost time at work, waiting time will not be included in this calculation.
Timepoint [6] 338308 0
12 weeks
Secondary outcome [7] 342628 0
Treatment related toxicity. [Time frame: monthly for 12 weeks] Treatment related toxicity will be according to NCI CTC Version 4.0. This will be recorded throughout the treatment. A patient with a grade 3 or more treatment related toxicity or adverse events will be taken off the study and appropriate medical attention and intervention provided.
Timepoint [7] 342628 0
Baseline, 4 weeks, 8 weeks and 12 weeks

Eligibility
Key inclusion criteria
Diagnosis: Recurrent Glioblastoma multiforme (GMB)
* Recurrent Cancer Definition: Cancer that has recurred (come back), usually after a period of time during which the cancer could not be detected. The cancer may come back to the same place as the original (primary) tumor or to another place in the body. Also called recurrence. (National Cancer Institute Dictionary for Cancer)

1. Have been diagnosed with a recurrent brain malignancy (GBM): MRI revealing recurrent tumour growth
2. Greater than or equal to 18 years of age
3. Patient status:
a) Liver function: Total bilirubin less than or equal to 2 ULN, ALT or AST is less than or equal to 2.5 ULN (or less than 5 in case of liver impairment).
b) Serum creatinine is less than or equal to 1.5 ULN
4. Willing to consider participating in a clinical trial using oral medicinal cannabis
5. Diagnosis of recurrent tumour progression
6. Individuals who have no history of substance abuse within the last 2 years
7. Pregnancy:
a) Negative test in women of childbearing potential
b) Use of effective contraceptive method during the whole treatment and up to 3 months post completion of the treatment in both males and females
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant or breast feeding women.
2. Severe cognitively impaired patients who are unable to understand or comprehend the participation in the trial
3. Individuals who have severe mental illness e.g. bipolar disorder, schizophrenia
4. Non-English speaking individuals
5. Severe bacterial, viral or fungal infection (Grade great than 2 NCI-CTCAE v 4.0)
6. Participation in another interventional clinical trial
7. Individuals who have a past history of cannabis addition or major substance abuse (dependence on cannabis)
8. Past history of adverse events from cannabis
9. Individuals who have had an adverse event from past cannabis use
10. Individuals who have had a past history of myocardial infarctions (MI) or angina pectoris.
11. Severe liver and kidney disease.
12. Continued use of another medicinal cannabis product during the trial

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)
Envelope concealment
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be conducted by the PI of the trial. All other researchers will be blinded to the allocation. The randomization will be conducted using the website, Research Randomizer: https://www.randomizer.org/. The randomization will be conducted for two sets randomised for 46 participants. Further allocation if required for attrition will be conducted on another 8 count divided into two sets.
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
A historically matched cohort study will follow the interventional trial which will retrospectively audit clinical records to match suitable controls. Retrospective data will be collected from medical records at the Centre for Minimally Invasive Neurosurgery. Patients will be matched to participants recruited from the trial for age, gender, and disease status. MRI results and descriptive information will be collected for the comparison. An analysis will then be conducted comparing the retrospective data as a control to each group in the medicinal cannabis trial. If there is no statistical differences in the primary efficacy outcomes of the interventional trial, then both interventional groups will also be analyzed as one cohort against the collected retrospective data.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
All available data will be conducted on an intention-to-treat basis. The statistical program utilized will be STATA. For the primary outcome measure, a difference between two proportions will be used to determine if the intervention groups significantly differ. The difference in change between groups, for the secondary outcome measures, will be tested using Analysis of Covariance (ANCOVA). Groups will be compared at baseline ie. Age, tumour size, other comorbidities, gender etc and if difference(s) is/are ascertained, the variable(s) will be entered into the regression model to appropriately adjust the analyses.

Interim analysis will be conducted every 6 months during the trial. If interim results indicate that termination is required, then the trial will be terminated at that time.

Interim analysis: if at interim analysis, approximately 15% of the participants experienced a major adverse event able to be proven medically to be related to the investigation drugs, the trial will be terminated. All adverse events will be monitored by the advisory safety board to determine if the major adverse event was due to the investigation drug or other causes. Each case will be assessed individually and if any major adverse event is deemed extreme (causing death), the trial can be terminated. In addition, progression free survival statistics will be conducted to evaluate efficacy. This will be analysed using the test of proportions of participants experiencing longer progression free survival between treatment groups at each time point. Changes in SPD (from baseline to 12 weeks) will be categorised into two possible outcomes: greater than 25% or less than 25%. Logistic regression will be conducted on the change of scores if there are differences noted from baseline. (Scores will be based on the measurement scores from the RANO criteria - SPD)


End of trial statistical analysis will incorporate the following:

1. Scores of QoL measures between participants: The FACT-Br scores will be analsyed for changes from baseline to week 12 using paired T tests.

2. Scores of QoL measures between participants: The FACT-Br scores will be obtained at baseline, 4 weeks, 8 weeks, and 12 weeks. The medicinal cannabis groups will be compared against each other. Bivariate analyses of FACT-Br scores against group will be conducted at each time point using either an Independent Samples t-test (or Mann-Whitney U test if data is non-normal). For the analysis of changes in the FACT-Br scores over time, a longitudinal mixed model will be used, which will allow us to adjust for potential confounders.

3. Comparison of Participants to Retrospective Historical data: Each medicinal cannabis participant will be compared to matched historical controls stratified by gender and age. This will be analysed using longitudinal mixed model analysis (adjusting for confounders) based on time, MRI results and FACT-Br results if they have completed them. (Scores will be based on the measurement scores from the RANO criteria – SPD. If the RANO score was not used, the MRI results will be referred to a radiographer to determine the RANO score for that MRI.

4. Comparison of toxicity results between participants: The medicinal cannabis groups will be compared against each other. This will be analysed using the test of proportions of people experiencing minor and severe toxicity between treatment groups from baseline to week 12.

5. Comparison of adverse events between participants (severe and minor): The medicinal cannabis groups will be compared against each other. Independent samples t-test (or Mann-Whitney U test if data is non-normal) will be used to compare severity of adverse events between groups. For the analysis of changes in the severity over time, a longitudinal mixed model will be used, which will allow us to adjust for potential confounders.

6. Comparison of Tumour growth and re-growth between participants: The medicinal cannabis groups will be compared against each other using the test of proportions of participants experiencing changes in tumour size and/ or tumour re-growth. Changes in SPD (from baseline to 12 weeks) will be categorised into two possible outcomes: greater than 25% or less than 25%. Logistic regression will be conducted on the change of scores if there are differences noted from baseline. (Scores will be based on the measurement scores from the RANO criteria - SPD).

7. Scores of blood pathology markers: Full blood count, blood glucose, renal and liver function tests, anti-convulsant therapeutic drugs levels (if participant is on an anti-convulsant medication) will be measured at baseline, 4 weeks, 8 weeks and 12 weeks. Either a repeated measures ANOVA will be utilized for analysis or a longitudinal mixed model will be used, which will allow us to adjust for potential confounders between the two arms over time periods.


8. Dose response: The dose of each participant will be recorded and any changes noted over the 12 weeks. The MCP-Mod methodology which is modeling technique in Dose-response studies. Repeated measure ANOVA will also be conducted to confirm dose range.

9. Cost utility analysis: Health related QoL weights will be calculated. Extrapolated to QALY which will then be able to inputs from publically available health cost data.

10. Cost effectiveness analysis: Comparison between groups based on quality of life and tolerability will be used to determine incremental cost effectiveness ratios from publically available health cost data. This will be based on the FACT-Br QoL questionnaire.


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
Recruitment hospital [1] 8909 0
Prince of Wales Private Hospital - Randwick
Recruitment postcode(s) [1] 17155 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 297398 0
Commercial sector/Industry
Name [1] 297398 0
FIT - BioCeuticals Pty Ltd
Address [1] 297398 0
Unit 1, Level 1, 85 O’Riordan St, Alexandria, NSW 2015
Country [1] 297398 0
Australia
Primary sponsor type
University
Name
Endeavour College of Natural Health
Address
Level 2, 269 Wickham St
Fortitude Valley Qld 4006
Country
Australia
Secondary sponsor category [1] 296387 0
None
Name [1] 296387 0
Address [1] 296387 0
Country [1] 296387 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298497 0
NSW Government Health South Eastern Sydney Local Health District
Ethics committee address [1] 298497 0
Research Support Office
G71, East Wing
Edmund Blacket Building
Prince of Wales Hospital
Randwick NSW 2031
Ethics committee country [1] 298497 0
Australia
Date submitted for ethics approval [1] 298497 0
08/09/2017
Approval date [1] 298497 0
12/07/2018
Ethics approval number [1] 298497 0
18/028
Ethics committee name [2] 298498 0
University of Technology Sydney HREC
Ethics committee address [2] 298498 0
City Campus
15 Broadway
Ultimo NSW 2007
Ethics committee country [2] 298498 0
Australia
Date submitted for ethics approval [2] 298498 0
25/10/2017
Approval date [2] 298498 0
Ethics approval number [2] 298498 0
Ethics committee name [3] 298500 0
Endeavour HREC
Ethics committee address [3] 298500 0
269 Wickham St
Fortitude Valley
Qld 4006
Ethics committee country [3] 298500 0
Australia
Date submitted for ethics approval [3] 298500 0
16/11/2017
Approval date [3] 298500 0
Ethics approval number [3] 298500 0

Summary
Brief summary
The purpose of this study is to investigate the efficacy of two strengths of oral medicinal cannabis oil in patients who have been diagnosed with recurrent glioblastoma multiforme (GBM).

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with a recurrent brain malignancy (GBM): MRI revealing recurrent tumour growth.

Study details
Participants will be randomised to receive one of two different CBD:THC strains for 12 weeks. Each participant will have a MRI at baseline and at 12 weeks. Blood work will be conducted at baseline, 4 weeks, 8 weeks and 12 weeks.

How this study will contribute to research and/or Treatment
This research will assist medical doctors and patients understanding if medicinal cannabis can assist their treatment in slowing glioma tumour re-growth or growth in conjunction with standard treatment and dosage of medicinal cannabis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77282 0
Dr Janet Schloss
Address 77282 0
Office of Research
Endeavour College of Natural Health
Level 2, 269 Wickham St
Fortitude Valley Qld 4006
Country 77282 0
Australia
Phone 77282 0
+61 7 32539579
Fax 77282 0
Email 77282 0
janet.schloss@endeavour.edu.au
Contact person for public queries
Name 77283 0
Dr Janet Schloss
Address 77283 0
Office of Research
Endeavour College of Natural Health
Level 2, 269 Wickham St
Fortitude Valley Qld 4006
Country 77283 0
Australia
Phone 77283 0
+61 7 32539579
Fax 77283 0
Email 77283 0
janet.schloss@endeavour.edu.au
Contact person for scientific queries
Name 77284 0
Dr Janet Schloss
Address 77284 0
Office of Research
Endeavour College of Natural Health
Level 2, 269 Wickham St
Fortitude Valley Qld 4006
Country 77284 0
Australia
Phone 77284 0
+61 7 32539579
Fax 77284 0
Email 77284 0
janet.schloss@endeavour.edu.au

No data has been provided for results reporting
Summary results
Not applicable