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Trial registered on ANZCTR


Registration number
ACTRN12616000516482
Ethics application status
Approved
Date submitted
12/04/2016
Date registered
21/04/2016
Date last updated
27/02/2019
Date data sharing statement initially provided
27/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Medicinal Cannabis for Anorexia in Advanced Cancer
Scientific title
Phase I/II, dose ranging study of the pharmacokinetics dose-response parameters, and feasibility of vaporised botanical cannabis flower bud in advanced cancer
Secondary ID [1] 288121 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 296995 0
Anorexia 296996 0
Condition category
Condition code
Cancer 297248 297248 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Botanical cannabis flower bud (Bedrobinol, Bedrocan) administered via inhalation by vaporiser, taken 3 times a day, 1 hour before meal times.at study site under supervision of trials staff. Each dose level is administered for either one or two days as indicated below in a specific order which is the same for all participants, namely:

50 mg Placebo leaf, 0 mg Delta-9-tetrahydrocannabinol (THC) (one day)
8 mg Bedrobinol (dose 1) mixed with 42 mg placebo leaf, 1.08 mg THC (one day)
16 mg Bedrobinol (dose 2) mixed with 34 mg placebo leaf, 2.16 mg THC (one day)
32 mg Bedrobinol (dose 3) mixed with 18 mg placebo leaf, 4.32 mg THC (two days)
50 mg Bedrobinol (dose 4), 6.75 mg THC (two days)
Intervention code [1] 293430 0
Treatment: Drugs
Comparator / control treatment
Placebo cannabis (Bedrocan) (terpene content is alpha-2-pinene (2 mg/g), beta-2-pinene (@0.75 mg/g), myrcene (10 mg/g), R-limonene (@0.2 mg/g), cis-ocimene (@0.6 mg/g) and BCP (1 mg/g).)
Control group
Dose comparison

Outcomes
Primary outcome [1] 296831 0
Plasma concentrations of delta 9-Tetrahydrocannabinol
Timepoint [1] 296831 0
trough (pre-dose), and at 1, 5, 20, 40 and 60 minutes and 4 hours post inhalation after morning dose at each dose level
Primary outcome [2] 296832 0
Numerical rating scale - Appetite
Timepoint [2] 296832 0
1, 5, 10, 20, 40 and 60 minutes and 4 hours post inhalation of every dose, and 30 minutes prior to subsequent dose
Secondary outcome [1] 319482 0
Plasma levels of Cannabidiol
Timepoint [1] 319482 0
trough (pre-dose), and at 1, 5, 20, 40 and 60 minutes and 4 hours post inhalation
Secondary outcome [2] 322783 0
Satiety Labelled Intensity Magnitude (SLIM scale)
Timepoint [2] 322783 0
5 minutes before each of the three meals on the baseline day (day 1) and on day 7
Secondary outcome [3] 322784 0
Hunger, Taste and Smell Survey
Timepoint [3] 322784 0
baseline and study end (day 7)
Secondary outcome [4] 322785 0
Quality of Life (functional assessment of anorexia-cachexia subscale)
Timepoint [4] 322785 0
baseline and study end (day 7)
Secondary outcome [5] 322786 0
Global Impression of Change
Timepoint [5] 322786 0
day 8 and day 14
Secondary outcome [6] 322787 0
Daily food intake (self - reported using my fitness PAL)
Timepoint [6] 322787 0
daily (day 1 - 7 of treatment)
Secondary outcome [7] 322788 0
Adverse effects will be assessed using participant self-report on 4-point numerical rating scale and NCI common terminology for adverse events V4.03 (adverse events of interest include neurological (confusion, somnolence), psychiatric (personality change, paranoia, anxiety, mood changes, psychosis), cardiovascular (hypertension, tachycardia), systemic (sweating), and gastrointestinal (nausea, vomiting, abdominal pain)
Timepoint [7] 322788 0
prior to each dose, and at 1, 5, 10, 20, 40 and 60 minutes and 4 hours after each dose administration
Secondary outcome [8] 322789 0
Anxiety and depression symptoms (composite outcome, PHQ-9 and GAD-7)
Timepoint [8] 322789 0
baseline and day 7
Secondary outcome [9] 322790 0
Inpatient resource utilisation (composite outcome) by review of case record forms (total duration of admission, additional days of admission due to toxicity)
Timepoint [9] 322790 0
daily from day 1 to day 7 of study treatment, and day 8 - 14 of follow-up.
Secondary outcome [10] 322791 0
Feasibility (Number of participants continuing on study/day by review of daily case record forms)
Timepoint [10] 322791 0
daily from day 1 to day 7 of treatment
Secondary outcome [11] 322792 0
Feasibility (number of participants who complete 7 days of study intervention by review of completion case record form)
Timepoint [11] 322792 0
day 7
Secondary outcome [12] 322793 0
Feasibility (Percentage completion of all measures at all time points by review of case record form completion)
Timepoint [12] 322793 0
daily from day 1 to day 7 of treatment
Secondary outcome [13] 322794 0
Feasibility of vaporisation (report of treating trials nurse on completeness of vaporisation, presence of cough during vaporisation)
Timepoint [13] 322794 0
each dose three times a day from day 1 to day 7 of treatment
Secondary outcome [14] 322843 0
Plasma levels of cannabidiol metabolite 7-OH-CBD
Timepoint [14] 322843 0
trough (pre-dose), and at 1, 5, 20, 40 and 60 minutes and 4 hours post inhalation
Secondary outcome [15] 322844 0
Plasma levels of 11-hydroxy-delta 9-tetrahydrocannabinol (11-OH-THC)
Timepoint [15] 322844 0
trough (pre-dose), and at 1, 5, 20, 40 and 60 minutes and 4 hours post inhalation
Secondary outcome [16] 322845 0
Plasma levels of 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH))
Timepoint [16] 322845 0
trough (pre-dose), and at 1, 5, 20, 40 and 60 minutes and 4 hours post inhalation
Secondary outcome [17] 322846 0
Quality of Life (EORTC-Pal 15)
Timepoint [17] 322846 0
baseline and study end (day 7)

Eligibility
Key inclusion criteria
1) Age 18 years or above;
2) Advanced cancer;
3) Anorexia for at least 2 weeks (defined as numeric rating scale [0 no appetite – 10 best possible appetite] score less than or equal to 4) unresponsive to the optimisation of treatment of causative medical conditions
4) English-speaking (or have an interpreter available);
5) Performance status (Australia-modified Karnofsky Scale score) of 40 or above;
6) Written informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Hepatic impairment (Child’s Stage B)
2) Renal impairment (estimated glomerular filtration rate of <10 mL/min)
3) Cognitive impairment (Montreal Cognitive Assessment (MOCA score<26);
4) Psychiatric disorders (severe depression or anxiety, personality disorder, history of psychosis, schizophrenia, and/or suicidal ideation);
5) Acute delirium or delirium within < 30 days;
6) Unstable cardiovascular disease (uncontrolled hypertension, unstable ischaemic heart disease, unstable congestive cardiac failure);
7) Impaired pulmonary function which prohibits use of vaporiser;
8) Prior adverse reaction to botanical cannabis/pharmaceuticals containing cannabinoids;
9) Pregnant, breastfeeding or unwillingness to use oral contraceptives;
10) Substance use disorder (ICD-10 criteria (abuse, dependence)) to alcohol, opioids, benzodiazepines or simulants (excluding caffeine, tobacco).
11) Recent use of cannabis or cannabinoids within < 30 days (based on self-report and urine drug screen at eligibility).
12) Prescribed opioid, benzodiazepine, antidepressant, antipsychotic, corticosteroid, progestin, omega fatty acids and/or dietary supplements, which do not meet the criteria for therapies allowed at eligibility assessment
13) Participation in a clinical trial of another chemical entity.
14) Conditions causing irreversible or blood transfusion dependent anaemia where the volume of blood sampling required for this study is contraindicated in the opinion of the treating clinician.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Single group
Other design features
Dose-ranging pharmacokinetic study. Participants will be administered increasing doses of vaporised botanical cannabis flower bud (Bedrobinol 13.5% THC) for a period of 7 days, administered by vaporisation three times daily 60 minutes before meals, with dose increments daily
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Pharmacokinetic and pharmacodynamic endpoints:
Pharmacokinetic assays will use high-performance liquid chromatography (HPLC). Plasma concentrations and efficacy parameters (NRS appetite) will also be used to develop a population pharmacokinetic-pharmacodynamic model using NONMEM (Registered Trademark) VII software, which incorporates inter-individual and residual unexplained variability. Patient factors contributing to the parameter variability will be modelled using standard forward-inclusion/backward deletion methods. Model section 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. The developed model will be utilised to determine the relationship between dose-concentration-effect and the factors influencing this. Monte Carlo simulations will be conducted to simulate dosing regimens and target exposure values and will identify appropriate dosing strategies for employment in the proposed phase III study that are most likely to meet therapeutic targets.

Feasibility endpoints;
feasibility data will be summarised by descriptive statistics for all endpoints. Frequency counts and percentages will be used for categorical variables, and mean, range, interquartile range and 95 % confidence interval of mean for continuous variables. Outcomes and complications will be summarised across the range of concentrations seen in this study.

Sample size:
Statistical comparisons of pharmacokinetic parameters between patients classified as “therapeutic” and “non-therapeutic” (according to appetite and Quality of Life (QoL efficacy assessments) will be conducted in order to determine the relationship between drug exposure and effect; a sample size of 30 patients has been selected to examine this objective. Previous research has indicated that 36% is a reliable estimate of inter-subject variability in THC area-under-the-curve values; therefore, in order to detect a 40% difference in exposure (area under the curve) between the groups, at 80% power and an a-level of 0.05, a sample size of 30 patients is considered sufficient, allowing for a 90% retention rate.
Based on the proposed Phase III sample size (n=246), and using published methods to determine feasibility study sample sizes, a sample size of 30 for this phase I/II study also allows reasonable estimation of feasibility and percentage completion of study protocol and measures

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)
NSW
Recruitment hospital [1] 5209 0
Sacred Heart Hospice - Darlinghurst
Recruitment hospital [2] 5593 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 12678 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 292793 0
Government body
Name [1] 292793 0
New South Wales Government Ministry of Health
Address [1] 292793 0
Ministry of Health, 73 Miller Street North Sydney New South Wales 2060, Australia
Country [1] 292793 0
Australia
Primary sponsor type
University
Name
University of New South Wales
Address
Anzac Parade, Kensington NSW 2052
Country
Australia
Secondary sponsor category [1] 292156 0
None
Name [1] 292156 0
Address [1] 292156 0
Country [1] 292156 0
Other collaborator category [1] 278943 0
Other Collaborative groups
Name [1] 278943 0
Palliative Care Clinical Studies Collaborative
Address [1] 278943 0
University of Technology Sydney, Building 10, 235 Jones Street Ultimo New South Wales 2007
Country [1] 278943 0
Australia
Other collaborator category [2] 278944 0
Other Collaborative groups
Name [2] 278944 0
IMPACCT:NSW - Improving Palliative Care Through Clinical Trials
Address [2] 278944 0
Ingham Institute of Applied Medical Research
1 Campbell Street Liverpool, New South Wales, 2164
Country [2] 278944 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294287 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 294287 0
Locked Bag No 1
New Lambton NSW 2305
Ethics committee country [1] 294287 0
Australia
Date submitted for ethics approval [1] 294287 0
27/09/2015
Approval date [1] 294287 0
15/12/2015
Ethics approval number [1] 294287 0

Summary
Brief summary
The primary purpose of this trial is to evaluate whether a vaporised form of medicinal cannabis is feasible and effective in increasing appetite in cancer patients with anorexia.
Who is it for? You may be eligible for this trial if you are aged 18 or over, have an advanced cancer and have been suffering from anorexia for at least two weeks.
Study details: Participants will receive a range of doses of vaporised botanical cannabis flower bud one hour before your meals (three times a day) for 7 days unless side effects occur. Each dose may be different from the previous dose, but they will all be made up to the same weight of plant material by adding different amounts of inactive plant material (‘placebo’, which has the same characteristics of leaf cannabis with the active components removed). Participants will have blood samples taken at multiple timepoints up to 4 hours following each morning dose and will complete a number of questionnaires and a daily food record to determine the concentration of the drug in the blood, and to monitor its effect on appetite, mood and other factors.
It is hoped that the findings from this trial will provide information on whether inhalation of medicinal cannabis is feasible for achieving a safe and effective blood concentration for the treatment of anorexia in cancer patients.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62126 0
Prof Meera Agar
Address 62126 0
Ingham Institute of Applied Medical Research
1 Campbell Street,
Liverpool NSW 2170
Country 62126 0
Australia
Phone 62126 0
+61 0295144232
Fax 62126 0
+61-2-8738 9149
Email 62126 0
meera.agar@sswahs.nsw.gov.au
Contact person for public queries
Name 62127 0
Prof Meera Agar
Address 62127 0
Ingham Institute of Applied Medical Research
1 Campbell Street,
Liverpool NSW 2170
Country 62127 0
Australia
Phone 62127 0
+61 0295144232
Fax 62127 0
+61-2-8738 9149
Email 62127 0
meera.agar@sswahs.nsw.gov.au
Contact person for scientific queries
Name 62128 0
Prof Meera Agar
Address 62128 0
Ingham Institute of Applied Medical Research
1 Campbell Street,
Liverpool NSW 2170
Country 62128 0
Australia
Phone 62128 0
+61-2-8738 9149
Fax 62128 0
Email 62128 0
meera.agar@sswahs.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
early phase trial
What supporting documents are/will be available?
Study protocol
Summary results
No Results