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Trial registered on ANZCTR


Registration number
ACTRN12617001480370
Ethics application status
Approved
Date submitted
13/10/2017
Date registered
19/10/2017
Date last updated
4/02/2020
Date data sharing statement initially provided
6/02/2019
Date results information initially provided
4/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The buccal administration of a Cannabis sativa L./Cannabis indica L. extract as an adjunct to opioid analgesia for the management of intractable pain in patients diagnosed with advanced cancer: a safety, tolerability and exploratory end-point pilot study.
Scientific title
The buccal administration of a Cannabis sativa L./Cannabis indica L. extract as an adjunct to opioid analgesia for the management of intractable pain in patients diagnosed with advanced cancer: a safety, tolerability and exploratory end-point pilot study.
Secondary ID [1] 290700 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 301255 0
Condition category
Condition code
Cancer 301014 301014 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The aim of this project is to conduct a safety, tolerability and exploratory end-point pilot study assessing the administration of a cannabis extract containing approximately 2.5 mg of cannabidiol (CBD) and approximately 2.5 mg delta-9-tetrahydrocannabinol (THC) compounds extracted from cannabis sativa L. per dose (300 micro litres) delivered in a micellised oro-buccal spray as an adjunct to opioid analgesia for the management of intractable pain in patients with a positive diagnosis of advanced cancer. This is an open label pharmacokinetic and dose escalation study, comprising of two stages:
STAGE 1 (n= 5 people with advanced cancer):
Procedures:
Day -14 to -1:
• Sign informed consent
• Assessment of eligibility
• Study related assessments (e.g., urine sample collection for THC/pregnancy detection, participants to complete questionnaires in the booklet provided: BPI-SF, EORTC QLQ-C30 and NPRS Score).
• Study staff to record MMeq doses and breakthrough analgesia (analgesia administered the day prior to screening day) and concomitant medications.
Day 1 (+/- 3 day window):
• Admission into RNSH for overnight stay for 2 nights.
• Commence a buccal administered prescribed standard dose of the cannabis medicine containing the THC:CBD extract as two actuations of the drug delivery pump (2.5 mg THC+2.5 mg of CBD/0.3 mL) one time only.
• Safety and tolerability assessments.
• Blood sample collections to measure plasma THC and CBD and 11-hydroxy-THC and 11-nor-9-carboxy-COOH-THC concentrations at the following time points: (baseline) 0, 30, 60, 90, 120, 150, 180, 240, 360 minutes and 24 hours. Blood draws have a +/- 10 minute window.
• Participants to complete questionnaires in the booklet provided: BPI-SF, EORTC QLQ-C30 and NPRS Score.
• Study staff to record MMeq doses and breakthrough analgesia administered (if applicable).
• Note: These sampling times align with the expected PK profile of cannabinoids of interest after Sativex buccal delivery (seen in the paper by Karschner et al. Clin Chem 2011).

Day 2 (consecutive):
• Participants commence buccal administered 3 prescribed doses (6 actuations of the pump delivering 7.5 mg THC+7.5 mg CBD/0.9 mL) of the cannabis product. First dose at 0 minutes, second dose at 2 minutes and third dose at 4 minutes.
• Safety and tolerability assessments.
• Blood sample collections to measure plasma THC and CBD and 11-hydroxy-THC and 11-nor-9-carboxy-THC concentrations at the following time points: (baseline) 0, 30, 60, 90, 120, 150, 180, 240, 360 minutes and 24 hours. Blood draws have a plus or minus 10 minutes window.
• Participants to complete questionnaires in the booklet provided: BPI-SF, EORTC QLQ-C30 and NPRS Score.
• Study staff to record MMeq doses and breakthrough analgesia administered (if applicable).
• Note: that the PI will oversee the patient admitted for two nights of stage 1 and may keep the patient in hospital if deemed relevant beyond the mandatory admission (2 nights) based on adverse changes to the investigative drug.
Participants discharged from RNSH after 48 hours. Eligible participants who report future opioid intolerance will be invited to participate in Stage 2 of the Dose Escalation and Treatment phases of the study.

DSMB to review safety and tolerability data before continuation to the next stage.

STAGE 2 (n= 25 participants with advanced cancer and intractable pain not responsive to opioid analgesic medicines):
Consists of (i) dose escalation phase; (ii) dose treatment phase;
(iii) follow-up phase.

(i) Dose escalation phase:
• Day -28 to 0: Participants assessments and on satisfying inclusion and exclusion criteria and completion of signed informed consent. Baseline urine sample collection (THC and pregnancy detection).
• On Days 1 to 3: Pharmacy dispenses new cannabis vial. Participants are instructed to administer 1 spray (delivering 1.25 mg THC+ 1.25 mg CBD in 0.15 mL) every 4 hours (unless asleep), repeat for the next two days. Participants are instructed on how to complete questionnaires in the booklet provided (BPI-SF, EORTC QLQ-C30 and NPRS Score) as well as a medication diary at the end of each study day.
• Day 4 to 6: Participants return to RNSH on day 4 and return used cannabis medicine vial. Pharmacy dispenses new cannabis vial. Blood sample collection. Increase dose to two sprays (delivering 2.5 mg THC+ 2.5 mg CBD in 0.3 mL) every 4 hours (unless asleep), repeat for the next two days.
• Day 7 to 9: Participants return to RNSH on day 7 and return used cannabis medicine vial. Pharmacy dispenses new cannabis vial. Blood sample collection. Increase dose to three sprays (delivering 3.75 mg THC + 3.75 mg CBD in 0.45 mL) every 4 hours (unless asleep), repeat for the next two days.
(ii) Treatment phase (ongoing):
• Day 10 to 12: Participants return to RNSH on day 10 and return used cannabis medicine vial. Participants undergo dosage review by the PI. Pharmacy to dispense new cannabis vial. Administer either one, two or three sprays every 4 hours for the next two days (unless asleep) as indicated by the PI. Participants will provide 2 blood samples, 1 hour apart (participants to administer prescribed IP dose at the visit, after the first blood sample is collected).
• Day 13 to 15: Participants return to RNSH on day 13 and return used cannabis medicine vial. Pharmacy to dispense new cannabis vial. Participants will provide 2 blood samples, 1 hour apart (participants to administer prescribed IP dose at the visit, after the first blood sample is collected). Continue administration of cannabis medicine at the same dose as directed by clinician. Final dose of investigative product will occur at the end of day 15.
• Day 16: Participants return to RNSH and return used cannabis medicine vial. Blood sample collection.
NOTES:
1. Outpatient visits have a plus or minus 1-day window to avoid weekend visits.
2. Participants are instructed to omit dose/s if intoxicated.
3. The 4 hours timeframe between doses is intended as the minimum amount of time before the prescribed dose can be repeated.
4. If a patient is unable to tolerate a dose increase during the dose escalation phase and/or the dose treatment phase, the PI may decide to keep the participant on the currently tolerated dose or reduce the prescribed dose by 1 spray and review, and to keep decreasing the dose by 1 spray until a tolerable dose is achieved.

(iii) Follow-up phase:
• Day 30: Participants return to RNSH. Participants will be followed-up after completing dose escalation and treatment phases 2-weeks post completion. Participants to return completed questionnaires booklet (BPI-SF, EORTC QLQ-C30 and NPRS Score) and medication diary. A final blood sample is collected.

DSMB second meeting to review all data before completing report.
Intervention code [1] 296589 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Active

Outcomes
Primary outcome [1] 300433 0
Composite Primary Outcome
To investigate the safety, tolerability and pharmacokinetics (PK) of a cannabis (THC:CBD) extract by buccal administration in people with advanced cancer measured by:
- Clinical assessment including: recorded adverse events;
- The European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30) Version 3;
- Laboratory assessments including pharmacokinetic data.
Timepoint [1] 300433 0
- Participants will be monitored for adverse events by the Principal Investigator and/or research nurse throughout study period.
- EORTC QLQ-C30 Questionnaire to be completed daily by study participants in study stages 1 and 2.
- Blood samples collection for PK analysis at the following time points:
Stage 1
Day 1 - Baseline (0), 30, 60, 90, 120, 150, 180, 240, 360 minutes and 24 hours.
Day 2 - Baseline (0), 30, 60, 90, 120, 150, 180, 240, 360 minutes and 24 hours.
Stage 2
Blood samples collection (10 ml) on days 0, 4, 7, 10, 13, 16, 30
Secondary outcome [1] 329975 0
Composite Secondary Outcome
Exploratory pilot study to evaluate the analgesic effects of a THC:CBD extract as an adjunct to opioid analgesia in the management of pain in patients with moderate to severe cancer-related pain measured by:
- Numerical Pain Rating Scale (NPRS);
- Brief Pain Inventory, Short Form;
- MMeq doses;
- Rescue analgesia (opioid) requirement.
Timepoint [1] 329975 0
- Numerical Pain Rating Scale (NPRS) to be completed daily by study participants in study stages 1 and 2.
- Brief Pain Inventory, Short Form to be completed daily by study participants in study stages 1 and 2.
- Morphine Milligram Equivalent doses to be recorded by study nurse daily on study stage 1 and on days 1, 4, 7, 10, 13, 16, 30 on study stage 2.

Eligibility
Key inclusion criteria
Inclusion criteria Stage 1
1. Patient aged greater than 18 years.
2. Patient able to give informed consent and comply with study procedures.
3. Patient that has been diagnosed with an incurable malignancy.
4. Patient willing and able to receive an oro-buccal mucosa delivered medicine.
5. Patient willing to take a medication, which may exhibit psychoactive effects.
6. Patient agrees to abstain from using cannabis medicines other than the experimental drug for the duration of the clinical trial.
7. Patient agrees to not partake in any other interventional clinical treatments other than the ones that the treating clinical team are already aware of for the duration of the study.
8. Patient consents to provide blood samples for analysis throughout the duration of the clinical trial, whether participation is for Stage 1 only and or Stage 2.
9. Patient agrees to disclose that they are receiving an experimental medication to treating medical professionals who might be unaware of this fact.
10. Female of childbearing potential, agrees to use an effective form of birth control during the study participation.
11. Patient consents to having a baseline test for pregnancy if applicable.
12. Patient consents to having baseline tests for recent illicit substance use.
13. Patient agrees to still take regular doses of an opioid analgesic as prescribed. Patient should not cease opioid medications.
14. Patient agrees not to drive a car or other motor vehicle or operate any type of heavy machinery for 72 hours after the last dose of study medication.

Inclusion Criteria Stage 2
1. Patient aged greater than 18 years.
2. Patient able to give informed consent and comply with study procedures.
3. Patient that has been diagnosed with an incurable malignancy.
4. Patient reported experiencing moderate to severe pain.
5. Patient has been using strong opioid analgesics for at least one week to relieve pain associated with incurable malignancy (one-week prior use of opiate treatment is sufficient duration because it would represent established opioid treatment and most patients would have developed tolerance after one week, especially if it is given around the clock at a total daily dose of at least 60 mg of oral morphine or equivalent) and/or patient is on a low dose opioid regimen and still experiencing pain and is unable to increase the opioid dose due to poor tolerance as confirmed by the GP/specialist.
6. Patient report pain severity that is scored to be greater than a rating of 4 within a 0-10 Numerical Rating Scale (NRS) assessment tool.
7. Patient willing and able to receive an oromucosal delivered medicine.
8. Patient willing to take a medication, which may exhibit psychoactive effects.
9. Patient agrees to abstain from using cannabis medicines other than the experimental drug for the duration of the clinical trial.
10. Patient agrees to not partake in any other interventional clinical treatments other than the ones that the treating clinical team are already aware of for the duration of the study.
11. Patient consents to provide blood samples for analysis throughout the duration of the clinical trial, whether participation is for Stage 1 only and or Stage 2.
12. Patient agrees to disclose that they are receiving an experimental medication to treating medical professionals who might be unaware of this fact.
13. Female of childbearing potential, agrees to use an effective form of birth control during the study participation.
14. Patient consents to having a baseline test for pregnancy if applicable.
15. Patient consents to having baseline tests for recent illicit substance use.
16. Patient agrees to still take regular doses of an opioid analgesic as prescribed. Patient should not cease opioid medications.
17. Patient agrees not to drive a car or other motor vehicle or operate any type of heavy machinery while administering the study medication and for 7 days after the last dose of study medication.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient engaged in medicinal or recreational use of any cannabinoid containing substance, in any form within the past 30 days.
2. Patient has a cognitive impairment or intellectual disability.
3. Patient has a history of primary psychotic disorder, bipolar affective disorder, bipolar disorder with psychotic features, depressive disorder with psychotic features, borderline personality disorder, antisocial personality disorder, or a positive family history (first degree relative) of psychotic disorder or bipolar affective disorder.
4. Patient has any history of allergic or hypersensitivity reaction to any herbal product, including cannabinoids.
5. Patient reports a prior sensitivity reaction to an oromucosal administered medicine or supplement (e.g., Liposomes).
6. Patient diagnosed with a head, neck, or oropharyngeal cancer will be considered for participation in the study at the discretion of the PI.
7. Patient has undergone any radiotherapy to the mouth or oral cavity.
8. Patient presents with any new unstable cardiovascular disorders (Coronary artery disease; heart attack; abnormal heart rhythms or arrhythmia; heart failure; heart valve disease; congenital heart disease; heart muscle disease; pericardial disease; aorta disease; vascular disease) that the PI assesses to be unsafe for the trial.
9. Patient has a history of epilepsy (or a previous history of seizures).
10. Patient has any clinically significant hepatic or renal impairment.
11. Patient diagnosed with brain metastasis will be considered for participation in the study at the discretion of the PI.
12. Patient is pregnant, lactating or partaking in sexual contact, which may result in pregnancy without adequate contraception.
13. Patient has received epidural analgesia within 48 hours of the baseline assessment
14. Patient has received any radiotherapy within two weeks of the initial baseline assessment.
15. Patient is currently administering Levodopa, Sildenafil (or any other PDE5s), anticonvulsants and/or Cannabinoids
16. Patient is currently receiving ketamine.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis
For the two secondary efficacy variables (i.e., NRS pain score and use of breakthrough medication), the Hochberg (1) method will be used to test the global hypothesis for a treatment effect on pain. The null hypothesis will be rejected if either secondary variable produce a two-sided P<= 0.025 or both produce a P<= 0.05. The pre dose NRS score will be the average of the 3 NRS scores on any given day. The pain NRS score will be the mean of the first 12 hours post dose assessments. The change in mean NRS pain score from baseline (all days in run-in period) to the post dosing will be analyzed using analysis of covariance (ANCOVA), with baseline pain as a covariate and grouped study and treatment as factors (2,3). The proportions of responders (patients with >= 30% improvement from baseline to end of study NRS pain score) will be compared. Use of breakthrough medication) will be analyzed
using logistic regression with a cumulative logit model. In addition, the change from baseline in mean number of doses of escape medication will be analyzed using ANCOVA.
The study will be powered assuming an underlying treatment difference of 1 point on an NRS and a standard deviation (SD) of 1.6 (estimated from previous studies), with 80% power and two-sided 5% significance.

1. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988;75:800e802.
2. Conover WJ, Inam RL. Analysis of covariance using the rank transformation. Biometrics 1982;38:715e724.
3. Hodges JL Jr, Lehmann EL. Estimates of location based on rank tests. Ann Math Statist 1963;34:598e611.

Recruitment
Recruitment status
Completed
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] 9186 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 17836 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 295607 0
Commercial sector/Industry
Name [1] 295607 0
Medlab Clinical
Address [1] 295607 0
66 McCauley Street, Alexandria New South Wales 2015
Country [1] 295607 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Medlab Clinical
Address
66 McCauley Street, Alexandria New South Wales 2015
Country
Australia
Secondary sponsor category [1] 294442 0
None
Name [1] 294442 0
Address [1] 294442 0
Country [1] 294442 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296926 0
The Kolling Research Office - Northern Sydney Local Health District HREC
Ethics committee address [1] 296926 0
Level 13, Kolling Building, Royal North Shore Hospital, Pacific Highway, St. Leonards, NSW 2065
Ethics committee country [1] 296926 0
Australia
Date submitted for ethics approval [1] 296926 0
30/01/2017
Approval date [1] 296926 0
16/06/2017
Ethics approval number [1] 296926 0
HREC/16/HAWKE/496

Summary
Brief summary
Medlab Clinical is currently sponsoring an early phase clinical study evaluating the safety and efficacy of a new Cannabis formulation containing THC 8.33 mg/ml and CBD 8.33mg/ml in the form of an oro-buccal spray, for the management of severe pain in advanced cancer patients as an adjunct to opioid analgesia. The formulation is a 1:1 mixture of two distinct cannabis oil extracts produced from cultivated Cannabis sativa L. and Cannabis indica L. plants.

Who is it for?
Males and females aged 18+ diagnosed with advanced cancer who are experiencing intractable pain and are currently administering opioid analgesia. It is a requirement that participants continue to administer the prescribed opioid analgesia while on the study. Participants will not be allowed to drive while administering the study drug. Patients wishing to participate in the study will need a referral from their threating physician.

Where?
The study is taking place at a major Sydney metro hospital. Recruiting is now open.

Study details
This study will be conducted in two stages. During the first stage, participants will be enrolled and remain under clinical supervision in hospital for 48 hours. On day 1, a ‘standard dose’ of 2.6 mg delta-9-tetrahydrocannabinol (THC) and 2.4 mg cannabidiol (CBD) in 0.3 mL will be administered using a buccal spray delivery system. On day 2, three ‘standard doses’ will be administered. Participants will be monitored for any adverse events during hospital stay.

Stage 2 of study will involve a dose escalation over 7 days commencing with one ‘standard dose’ every 4 hours and three ‘standard doses’ every 4 hours by day 7 which are then maintained until day 15. Several assessments are conducted over administration period and on day 30 post intervention commencement.

Participants will be required to self-administer the drug for 15 consecutive days and visit the study site for a total of 8 visits within 30 days. Each visit is approximately 1 hr in duration. There are no overnight stays. In addition, participants will be required to provide a blood sample at each visit and complete daily questionnaires about their pain while on the study.

This study may greatly contribute to the research into the pharmacokinetic and medicinal properties of the Cannabis plant, in particular C. sativa L. and C. indica L. strains. The treatment may be beneficial for the treatment of intractable pain in cancer patients in conjunction with the conventional opioid treatment.

In the event that the medication is efficacious over the two-week period of the study, Medlab Clinical will make available the medication free of charge after the study to those trial participants that the Principal Investigator deems clinically appropriate to do so in consultation with their treating clinician.
Trial website
https://www.medlab.co/research/clinical-trials
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 70998 0
Prof Stephen Clarke
Address 70998 0
Department of Medical Oncology, Royal North Shore Hospital, Reserve Rd, St Leonards NSW 2065
Country 70998 0
Australia
Phone 70998 0
+61294631172
Fax 70998 0
Email 70998 0
stephen.clarke@sydney.edu.au
Contact person for public queries
Name 70999 0
Ms Serena Dal Forno, RN
Address 70999 0
Medlab Clinical. 66 McCauley Street, Alexandria, NSW, 2015
Country 70999 0
Australia
Phone 70999 0
+61281880311 ext. 120
Fax 70999 0
Email 70999 0
serena_dalforno@medlab.co
Contact person for scientific queries
Name 71000 0
Prof Luis Vitetta
Address 71000 0
Medlab Clinical. 66 McCauley Street, Alexandria, NSW, 2015
Country 71000 0
Australia
Phone 71000 0
+61281880311
Fax 71000 0
Email 71000 0
luis_vietta@medlab.co

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary