Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001302842
Ethics application status
Approved
Date submitted
14/04/2021
Date registered
27/09/2021
Date last updated
29/08/2022
Date data sharing statement initially provided
27/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
NanaBis™ an Oro-Buccal Administered delta9-Tetrahydrocannabinol (d9-THC) and Cannabidiol (CBD) Medicine For The Management of Chronic Pain From Metastatic Bone Cancer
Scientific title
NanaBis™ an Oro-Buccal Administered Equimolar d9-THC and CBD Formulation As Monotherapy For The Management of Opioid-Requiring Chronic-Pain Due To Metastatic Cancer: A Phase 3 Multi-Centre, Double Blind, Randomized-Withdrawal Active And Placebo Controlled Clinical Study
Secondary ID [1] 302188 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 318858 0
Bone Metastases 322712 0
Pain Management 323059 0
Condition category
Condition code
Cancer 316862 316862 0 0
Bone
Anaesthesiology 320953 320953 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
NanaBis™ is a nanoparticle water soluble equimolar solution of d9-THC and CBD administered through the oro-buccal membrane. One dose is equivalent to 2 actuations of the pump delivering 280 µL volume containing 2.5 mg d9-THC and 2.5 mg CBD. The dose administered will be 2-3.5 doses (2 sprays to 7 sprays) per 4 hours unless asleep.
To avoid and adapt participants to potential adverse effects of NanaBis™, NanaBis™ will be started at a low dose, which will be gradually escalated. The titration phase that involves cessation of pre-trial analgesia will only commence once NanaBis™ has reached expected therapeutic levels. The dose of sprays and tablets will be transiently or permanently reduced as required to alleviate adverse reactions.

The study consists of:
- Screening
- Pre-Titration (1 Week)
- Titration (1 Week)
- Maintenance (4 Weeks)
- Open Label Extension (12 Weeks)

The medicine will be accounted for by the Research Site’s Pharmacy (e.g., GenesisCare). The pharmacy will be responsible for stock management, dispensing and control of all of the investigational drug vials as well as ensure drug storage and environmental monitoring under drug S8 conditions.
Participant compliance will be measured from the participant medication diary and exploring the accurate reporting, interpretation verification and validity of the recorded data and that of missing data.

This study has three arms:
1. Double-Placebo Arm: Each participant receives both spray-placebo and tablet-placebo.
2. NanaBis™ Treatment Arm: Each participant receives both NanaBis™ and tablet-placebo.
3. Oxycodone Controlled Release (CR) Comparator Arm: Each participant receives both Oxycodone CR and spray-placebo.

Oxycodone Controlled Release (CR) used as the comparator will be Oxycontin oral tablets 10 mg – 70 mg twice per day for a duration of 6 weeks.

All arms will have Oxycodone Immediate Release (IR) available as required and not limited by the study, except that excessive use in the MAINTENANCE Phase will lead to forced discontinuation. Participants will be allowed 3 days to transition off their prior analgesia at the start of the TITRATION phase. The amount of Oxycodone IR used and the time require to transition off the prior analgesia (0-3 days) will be determined by the treating physician; however, it is recommended that participants showing symptoms or signs of opiate withdrawal be considered for using Oxycodone IR at regular intervals during the TITRATION phase.

After the one week TITRATION phase, absence of any opioid withdrawal symptoms will be confirmed with the Subjective Opioid Withdrawal Scale (SOWS). The emergence of opiate withdrawal symptoms due to cessation of all prior analgesics should be prevented by the use of Oxycodone IR; however, to further minimise discontinuations of participants due to opiate withdrawal issues rather than pain control issues, the Double-Placebo Arm will split off the NanaBis™ Treatment Arm after the TITRATION Phase and all participants will be started on either the NanaBis™ Treatment Arm or Oxycodone Controlled Release (CR) Comparator Arm. Best practice for treatment with NanaBis™ is to commence with a sub-therapeutic dose and escalate to a therapeutic dose over a week, which minimises adverse reactions. This study will use a one week PRE-TITRATION SPRAY ADAPTATION phase that will allow escalation of the spray to a therapeutic level before starting the TITRATION phase.

If participants have a TITRATION SOWS score greater than 10 points above their START SOWS Score then entry into the MAINTENANCE phase will be postponed until the a TITRATION SOWS score is less than or equal to 10 points above their START SOWS Score.
The procedure for down-titration of pre-trial opioid medication will largely be determined at the principal investigator’s discretion, however oxycodone IR as use as breakthrough analgesia is strongly recommended to minimise withdrawal issues, where appropriate. Furthermore, withdrawal issues will be monitored through use of SOWS measure in conjunction with factors such as drowsiness and other opioid-toxicity symptoms with amount of time taken to properly down-titrate the participant also dependant on both baseline duration of opioid treatment and withdrawal response observed, respectively.
OPIATE WITHDRAWAL: All participants will have Oxycodone IR available as required for pain and avoidance of opiate withdrawal. Oxycodone IR may need to be prescribed regularly, at least initially, if participants are showing signs or symptoms of opiate withdrawal. Absence of opiate withdrawal will be confirmed with the SOWS before commencing the MAINTENANCE Phase and entry into the MAINTENANCE phase postponed until the a TITRATION SOWS score is less than or equal to 10 points above their START SOWS Score.

FORCED DISCONTINUATION: Applies if any of the below criteria are met in any consecutive 3-day period commencing on or after day 10 of the TITRATION period:
(i) Pain severity (NPRS) is greater than 5
(ii) Breakthrough Oxycodone is greater than 1/6 of the SCREENING period’s
equivalent average daily opioid use and greater than 20 mg /day Oxycodone.
DEFINITIONS:
• Responder: Participate fulfilling all following criteria:
(i) Average pain score (NPRS) less than or equal to 5
(ii) Average breakthrough Oxycodone used is less than or equal to 1/6 of the SCREENING period equivalent average daily opioid use or 20 mg of Oxycodone (whichever is greater).
(iii) No discontinuation for efficacy or tolerability reasons.

OPEN LABEL EXTENSION (12 weeks):
• While there is no evidence during the trial to contradict current data that NanaBis™ is safe and tolerable, open label extension of NanaBis™ will be offered to all participants.
• Other analgesics such as pre-trial analgesics to be used as required.
• A three day randomised withdrawal study will occur at the end of the 12 week extension, with a 1:1 randomisation of participants to NanaBis™ or Spray Placebo and stable maintenance of all other analgesia. Pain relapse will be determined by a 30% increase in the NPRS score or a greater than 50% increase in breakthrough analgesia use over the three day period.
Intervention code [1] 318488 0
Treatment: Drugs
Comparator / control treatment
Double-Placebo Arm - Each participant receives both spray-placebo and tablet-placebo:

Spray placebo is a nanoparticle water soluble solution without cannabinoids containing pharmacologically inactive hemp seed oil (for fragrance purposes only) as defined by Australian ODC (https://www.odc.gov.au/hemp-products). One dose is equivalent to 2 actuations of the pump delivering 280 µl volume.

Tablet placebo will be identical to the Oxycontin tablets without active pharmaceutical ingredient with a composition usually akin to a polysaccharide such as glucose/maltodextrin.

1:1 RANDOMISATION of NanaBis™ Treatment Arm:
Half the participants in the NanaBis™ Treatment Arm are changed to the Double-Placebo Arm (spray-placebo and tablet-placebo)*. The other half remain in the NanaBis™ Treatment Arm (NanaBis™ and tablet-placebo).
* As observed in the pilot trial, majority of participants abruptly ceased NanaBis™ with no ill effects. Throughout abrupt cessation during this trial, participants will be monitored closely by the principal investigator and via formal measures such as the SOWS.
Control group
Placebo

Outcomes
Primary outcome [1] 324970 0
The primary endpoint is the proportion of patients who respond to study treatment at the end of the 6-week study period.

A ‘responder’ is defined as a participant who completes the maintenance phase with an acceptable level of pain (NPRS is equal to 5) and without requiring excessive amounts of rescue (breakthrough analgesia) medication. Unlimited breakthrough analgesia (Oxycodone) is allowed throughout the study; however, excessive use will result in discontinuation.
Participants who discontinue due to excessive Oxycodone use will be classified as ‘non-responders’.
Timepoint [1] 324970 0
The NPRS is completed twice daily by the participant throughout the entire 18 weeks of the study.
Secondary outcome [1] 386378 0
Proportion of responders in the Oxycodone CR group compared to the placebo group determined by pain levels recorded using NPRS. A responder is defined as a participant who completes the maintenance phase with an acceptable level of pain (NPRS is equal to 5) and without requiring excessive amounts of rescue (breakthrough analgesia) medication.
Timepoint [1] 386378 0
The NPRS is completed twice daily by the participant throughout the entire 18 weeks of the study.
Secondary outcome [2] 387871 0
Proportion of responders in the NanaBis group compared to the Oxycodone CR group determined by pain levels recorded using NPRS.
Timepoint [2] 387871 0
The NPRS is completed twice daily by the participant throughout the entire 18 weeks of the study.
Secondary outcome [3] 387872 0
Quality of life as assessed by the EORTC-QLQ-C30 validated questionnaire.
Timepoint [3] 387872 0
The EORTC-QLQ-C30 validated questionnaire is answered by participants on study start day 1 and weekly during the maintenance phase of the study.
Secondary outcome [4] 392846 0
Safety and tolerability will be assessed via standardised adverse events, Serious adverse events, Deaths, UKU Scale, Local Adverse Events Charts and patient medical records.

Adverse events, serious adverse events and deaths will be summarised by treatment arm.
Timepoint [4] 392846 0
Monitored continuously for the duration of the study (18 weeks).
Secondary outcome [5] 400235 0
Proportion of participants in the NanaBis group who prefer further treatment with NanaBis in the open label extension phase assessed by audit of signed consent forms from participants.
Timepoint [5] 400235 0
At the end of the 6-week study period.

Eligibility
Key inclusion criteria
At Screening Phase participants must fulfill all of the following criteria:
i. Prospective male and female participants that are
a. in the age range 18 to 65 years or
b. 65 to 75 years without significant co-morbidities (heart, lung, liver or renal failure, myocardial infarction, cerebral vascular accident, peripheral vascular disease, chronic obstructive pulmonary disease, dementia, connective tissue disease or diabetes mellitus with end-organ damage)
ii. Metastatic bone pain from a cancer diagnosis is the only major cause of pain.
iii. Pathology (imaging) confirmed metastatic bone cancer;
iv. Meet International Classification of Diseases, Tenth Revision (ICD-10) codes for pain management criteria (i.e., bone cancer pain);
v. During the screening period, the participant is on stable opioid pain management and pain severity (NPRS) is less than or equal to 8 with a maximum variation of plus or minus 1.
vi. Pain Detect score is greater than 18
vii. Participant willing and able to provide informed consent and follow study procedures
a. including agreeing to not drive or operate heavy machinery; and
b. females of child-bearing potential agree to use reliable contraception during the duration of the clinical trial;
viii. Patient deemed tolerable to Oxycodone and NanaBis™ determined by medical history of allergies to cannabinoids or opioids
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i. History of epilepsy or recurrent seizures;
ii. Moderate to severe medical conditions such as
a. Severe hepatic, cardiovascular, pulmonary or renal impairment; or
b. Psychiatric disorders (i.e., unstable schizophrenia, recent drug-induced psychosis, severe mood disorders), that would be assessed at the medical screen;
iii. If patients have been diagnosed with a substance abuse disorder.
iv. Women who are pregnant, lactating or planning to become pregnant;
v. Identified concerns by the nursing / medical team relevant to the safe storage of medications (i.e., NanaBis™ or standard medical therapy);
vi. Participants who may not be available for follow up (i.e., planned or expected travel or other);
vii. Participants plan to undergo any treatment that will substantially reduce the burden of disease (and therefore bone pain) during the screening, titration or maintenance phase of the clinical trial such as radiotherapy or cytotoxic chemotherapy;
viii. Participants who are unable to withhold all analgesia (apart from that which is part of this trial) during the titration and maintenance phase of the study, including bisphosphonates. Medications such as bisphosphonates may be coordinated so they are given either side of the excluded period that covers the titration and maintenance phases

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)
Phase 3 Multi Centre, Double-Blind, Randomized-Withdrawal Active and Placebo Controlled Clinical Study

The Independent statistician (i.e., Dr Belinda Butcher) will conduct the randomisation procedure and the codes for all participants that will be eligible to participate will be delivered and held by each research site’s hospital pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The participant will receive a study enrolment number, and this will be documented in the participant’s medical record and on all study documents.

An intention to treat analysis with all randomised participants.

The method of sequence generation is: 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
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Placebo response to analgesic agents is highly variable and may range between 0 and 40%. With alpha set at 0.05 and power set at 80%, we assumed that the proportion of responders to NanaBis™ would be 30% more than that of placebo. The FDA dictates a minimum number of participants for a phase 3 study on n=300. Allowing for approximately 17% drop out, we will recruit n=120 per arm.
All data will be summarized descriptively using n, mean (+/-) standard deviation, or median (25–75% IQR), and frequency and percent for categorical data. Unadjusted comparisons between arms in the proportion of participants meeting the primary endpoint at the end of the study at week-7 will be made using Chi-square tests.
The proportion of responders in each treatment arm will be summarized along with a 95% confidence interval. Differences in the proportion of responders will be analysed using multivariate logistic regression, including treatment arm, baseline NPRS score and sex as covariates in the model.
The non-inferiority of NanaBis™ compared to Oxycodone will be determined if the lower bound of the 95% confidence interval for the difference between the proportion of responders in the NanaBis™ arm compared to the control arm will have an upper bound greater than zero.

An intention to treat analysis with all randomised participants.

In demonstrating that the proportion of responders at the end of the 6-week study period is significantly greater in the NanaBis™ group than in the placebo group a significant reduction in pain and that for at least 50% of the patients in the NanaBis™ group, both the change in pain severity and the NPRS is the same or better over 6 weeks. Hence in outpatient treatment of metastatic bone pain, a total sample size of 360 participants (10 or 20 per test or control groups depending on the number of participants at each specific site) will be required to achieve at least a 20% improvement in responders and or pain scores at 6-weeks for the standard treatment group (as ascertained by an approximate average improvement in pain with NanaBis™ that was administered in a previous pilot clinical trial). Thus, achieving 50% responders to NanaBis™ treatment with a statistically significant improvement in pain scores.

Sample size calculation.
The primary endpoint is the proportion of patients who respond to study treatment at the end of the 6-week study period.
Placebo response to analgesic agents is highly variable and may range between 0 and 40%. With alpha set at 0.05 and power set at 80%, we assumed that the proportion of responders to NanaBis™ would be 30% more than that of placebo. The FDA dictates a minimum number of participants for a phase 3 study on n=300. Allowing for approximately 17% drop out, we will recruit n=120 per arm, then the study will have the following power:
Proportion of responders in placebo arm : Proportion of responders in NanaBisT™ arm : Power
0.2 : 0.5 : 99.7%
0.3 : 0.6 : 99.4%
0.4 : 0.7 : 99.4%

Power calculations performed using PASS v2020 using the two proportion procedure.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2023
Actual
Date of last participant enrolment
Anticipated
1/12/2025
Actual
Date of last data collection
Anticipated
1/06/2026
Actual
Sample size
Target
360
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 17818 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [2] 18022 0
GenesisCare St Leonards - St Leonards
Recruitment postcode(s) [1] 31671 0
4101 - South Brisbane
Recruitment postcode(s) [2] 31992 0
2065 - St Leonards
Recruitment outside Australia
Country [1] 22911 0
United States of America
State/province [1] 22911 0
Country [2] 22912 0
United Kingdom
State/province [2] 22912 0

Funding & Sponsors
Funding source category [1] 306611 0
Commercial sector/Industry
Name [1] 306611 0
Medlab Clinical Ltd
Country [1] 306611 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Medlab Clinical Ltd
Address
Unit 5-6/11 Lord Street
Botany, NSW
Australia 2019
Country
Australia
Secondary sponsor category [1] 308239 0
None
Name [1] 308239 0
Address [1] 308239 0
Country [1] 308239 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307615 0
Bellberry limited
Ethics committee address [1] 307615 0
Ethics committee country [1] 307615 0
Australia
Date submitted for ethics approval [1] 307615 0
12/04/2021
Approval date [1] 307615 0
01/07/2021
Ethics approval number [1] 307615 0
2021-01-001

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105050 0
Prof Stephen Clarke
Address 105050 0
Level 1/38 Pacific Hwy St Leonards, NSW 2065
GenesisCare, St Leonards, NSW, Australia
Country 105050 0
Australia
Phone 105050 0
+61 439 008 884
Fax 105050 0
Email 105050 0
[email protected]
Contact person for public queries
Name 105051 0
Larah Hall
Address 105051 0
Medlab Clinical Ltd.
Unit 5-6/11 Lord St, Botany, NSW Australia 2019
Country 105051 0
Australia
Phone 105051 0
+61 02 8188 0311
Fax 105051 0
Email 105051 0
[email protected]
Contact person for scientific queries
Name 105052 0
Jeremy Henson
Address 105052 0
Medlab Clinical Ltd.
Unit 5-6/11 Lord St, Botany, NSW Australia 2019
Country 105052 0
Australia
Phone 105052 0
+61 02 8188 0311
Fax 105052 0
Email 105052 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.