NanaBis™ an Oro-buccal Administered delta9-Tetrahydrocannabinol (d9-THC) & Cannabidiol (CBD) Medicine for the Management of Bone Pain From Metastatic Cancers

Study Overview
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Brief Summary
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This is a multi-centre, long term, double blind, clinical protocol for NanaBis™ as a monotherapy treatment in participants 18-75 years of age with cancer related pain.

Detailed Description
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This trial uses an alternative method to demonstrate the analgesic efficacy of NanaBis™ as a monotherapy in cancer participants. Proving analgesic efficacy requires demonstrating that (i) the analgesic is significantly better than placebo and (ii) that the magnitude of the improvement is clinically important. The latter is standardly done by measuring the change in pain levels from a baseline (no analgesia) to the end of a treatment period. A 30% decrease in the Numerical Pain Rating Scale (NPRS) has been correlated with participants reporting a moderate improvement in their pain and this was adopted as the standard method of demonstrating a clinically important magnitude of improvement. In this strategy, the measure of analgesic efficacy is the proportion of participants in the treatment group whose pain is adequately treated (responders). A responder is defined as a patient who completes the treatment phase with an acceptable level of pain (NPRS ≤ 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. Comparison of the proportion of responders in the NanaBis™ arm and placebo arms will determine if NanaBis™ is significantly better than placebo. Demonstrating that the proportion of responders in the NanaBis™ arm is non-inferior to the Oxycodone controlled release (CR) comparator arm will determine if the magnitude of improvement (provided by NanaBis™) is clinically important because Oxycodone CR has been established as the benchmark analgesic that provides a clinically important effect.

Official Title
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NanaBis™ an Oro-buccal Administered Equimolar d9-THC & CBD Formulation as Monotherapy for Management of Opioid Requiring Bone Pain Due to Metastatic Cancer: Phase 3 Multi Centre Blinded Randomized Withdrawal Active & Placebo Controlled Trial

Conditions
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Cancer Related Pain

Intervention / Treatment
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* Drug: NanaBis™
* Drug: Oxycodone CR
* Drug: Placebo Spray
* Drug: Placebo Tablet
* Drug: Oxycodone IR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At Screening Phase Participants must fulfil all of the following criteria: Prospective male and female participants that are: in the age range 18-65 years or 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) Metastatic bone pain from a cancer diagnosis is the only major cause of pain. Documented proof (imaging) confirming the Metastatic Bone Disease at the current site of pain and that there has no been treatment since diagnosis Meet International Classification of Diseases, Tenth Revision (ICD-10) codes for pain management criteria (i.e., bone cancer pain) During the screening period, the participant is on stable opioid pain management and pain severity (NPRS) ≤ 8 with a maximum variation of ± 1 Pain Detect score > 18 Participant willing and able to provide informed consent and follow study procedures including agreeing to not drive or operate heavy machinery; and females of child-bearing potential agree to use reliable contraception during the duration of the clinical trial Patient deemed tolerable to Oxycodone and NanaBis™ determined by medical history of allergies to cannabinoids or opioids Patient must not be a participant in a clinical trial or study. Exclusion Criteria: At Screening Phase Participants will be excluded if they meet any of the following criteria that include: History of epilepsy or recurrent seizures Moderate to severe medical conditions such as Severe hepatic, cardiovascular, pulmonary or renal impairment or Psychiatric disorders (i.e., unstable schizophrenia, recent drug-induced psychosis, severe mood disorders), that would be assessed at the medical screen If participants have been diagnosed with a current substance abuse disorder Women who are pregnant, lactating or planning to become pregnant Identified concerns by the nursing / medical team relevant to the safe storage of medications (i.e., NanaBis™ or standard medical therapy) Participants who may not be available for follow up (i.e., planned or expected travel or other) 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 Participants who are unable to withhold all analgesia (apart from which is part of this trial) during the titration and maintenance phase of the study, including bisphosphonates, or are currently exceeding equivalence of 70mg BD Oxycodone CR. Medications such as bisphosphonates may be coordinated so they are given either side of the excluded period that covers the titration and maintenance phases Participants will NOT be excluded if they are being treated with maintenance pharmacotherapy to prevent progression of disease such as steroids and hormone therapy, which may be continued during the trial at a stable dose Participant will be excluded if they are participating in any other clinical trial or study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Double Placebo Arm<br>Spray Placebo + Tablet Placebo Spray Placebo is a nanoparticle water soluble solution without cannabinoids containing a small amount of hemp seed oil (for fragrance purposes only) as defined by Australian Office of Drug Control (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. | Drug: Placebo Spray<br>* Placebo comparator used against both NanaBis™ and Oxycodone depending on randomisation of arms.<br>* Other names: NanoCelle® Placebo Spray;Drug: Placebo Tablet<br>* Placebo comparator used against both NanaBis™ and Oxycodone depending on randomisation of arms.<br>Drug: Oxycodone IR<br>* Oxycodone immediate release (IR) tablet or capsule or oral solution used as breakthrough analgesia.<br>* Other names: Roxicodone®;|
| Experimental: Treatment NanaBis™ Arm<br>NanaBis™ + Tablet Placebo NanaBis™ is a nanoparticle water soluble equimolar solution of d9-THC and CBD. 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 1 - 3.5 doses (2 sprays to 7 sprays) per 4 hours unless asleep. | Drug: NanaBis™<br>* NanaBis™ is a nanoparticle water soluble equimolar solution of d9-THC & CBD. 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<br>* Other names: NanoCelle® d9-THC & CBD;Drug: Placebo Tablet<br>* Placebo comparator used against both NanaBis™ and Oxycodone depending on randomisation of arms.<br>Drug: Oxycodone IR<br>* Oxycodone immediate release (IR) tablet or capsule or oral solution used as breakthrough analgesia.<br>* Other names: Roxicodone®;|
| Active Comparator: Comparator (Oxycodone) Arm<br>Spray Placebo + Oxycodone CR Spray Placebo is a nanoparticle water soluble solution without cannabinoids containing a small amount of 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. Oxycodone controlled release (CR) used as a comparator will be Oxycontin tablets 10 mg - 70 mg po bd. | Drug: Oxycodone CR<br>* Oxycodone CR tablet is an opioid agonist supplied in 10 mg, 15 mg, 20 mg, 30 mg,40 mg, 60 mg and 80 mg tablets for oral administration. The tablet strengths describe the amount of oxycodone per tablet as the hydrochloride salt.<br>* Other names: Xtampza ER®;Drug: Placebo Spray<br>* Placebo comparator used against both NanaBis™ and Oxycodone depending on randomisation of arms.<br>* Other names: NanoCelle® Placebo Spray;Drug: Oxycodone IR<br>* Oxycodone immediate release (IR) tablet or capsule or oral solution used as breakthrough analgesia.<br>* Other names: Roxicodone®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Significant changes in responders with NanaBis™ spray over placebo (p<0.05) | To demonstrate that at the end of the 6-week study period the proportion of responders in the NanaBis™ group shows significant change than the proportion of responders in the placebo group. 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. NPRS Assessment [Time Frame: Baseline and then twice daily for the duration of the study]. The NPRS questionnaire is completed by the participant to determine their pain intensity. The NPRS is an 11-point scale scored from '0-10'. A score of '0' being no pain and a score of '10' being the most intense pain imaginable. Participants select the value that is most in line with the intensity of pain they have experienced in the last 24 hours. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparable efficacy in proportion of responders from NanaBis™ spray to the proportion of responders to Oxycodone CR | To demonstrate that at the end of the 6-week study period the proportion of responders in the NanaBis™ group is similar to the proportion of responders in the Oxycodone 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. NPRS Assessment [Time Frame: Baseline and then twice daily for the duration of the study]. The NPRS questionnaire is completed by the participant to determine their pain intensity. The NPRS is an 11-point scale scored from '0-10'. A score of '0' being no pain and a score of '10' being the most intense pain imaginable. Participants select the value that is most in line with the intensity of pain they have experienced in the last 24 hours. | 6 weeks | 
| Significant change in the Health-Related Quality of Life Scores with NanaBis™ spray over placebo (p<0.05) and comparable to Oxycodone CR | To demonstrate that at the end of the 6-week study period the Health-Related Quality of Life scores in the NanaBis™ treated group are significantly changed than in the Placebo group and is similar to the Oxycodone CR treated group. Quality of life as assessed by the EORTC-QLQ-C30 validated questionnaire [ Time Frame: Baseline and then weekly during the maintenance phase of the study and at then weeks 7 and 18 of the Open Label Extension]. The EORTC-QLQ-C30 is validated questionnaire answered by participants to assess the quality of life of cancer patients. It assesses important functioning domains (e.g. physical, emotional, role) and common cancer symptoms (e.g. fatigue, pain, nausea/vomiting, appetite loss). | 6 weeks | 
| Significant change in the NPRS score with NanaBis™ spray over placebo (p<0.05) and comparable to Oxycodone CR | NPRS Assessment [Time Frame: Baseline and then twice daily for the duration of the study]. The NPRS questionnaire is completed by the participant to determine their pain intensity. The NPRS is an 11-point scale scored from '0-10'. A score of '0' being no pain and a score of '10' being the most intense pain imaginable. Participants select the value that is most in line with the intensity of pain they have experienced in the last 24 hours. | 18 weeks | 
| NanaBis™ Adverse Events | To demonstrate that at the end of the 6-week study period that NanaBis™ is safe and tolerable. Safety and tolerability will be assessed via standardised adverse events, Serious adverse events, Deaths, UKU - Side Effects Rating Scale (UKU), Local Adverse Events Charts and patient medical records. Adverse events, serious adverse events and deaths will be summarised by treatment arm. Does the daily use of NanaBis™ oro-buccal spray reduce the severity of Treatment-Emergent Adverse Events (safety and tolerability). [Time Frame: Baseline and then weekly for the duration of the study]. Changes in validated UKU scale range is 0 to 3 for rating the degree of severity (mild, moderate or severe) and a second scale for the investigator that assigns a casual relationship of improbable, possible or probable. | 18 weeks | 
| Fifty percent or greater of the NanaBis™ treated group request compassionate extension with NanaBis™ spray | To demonstrate that at the end of the 6-week study period that after unblinding, half or more of the NanaBis™ treated group prefer further treatment with NanaBis™ in the open label extension phase (note that all participants will be all offered open label extension if appropriate). | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cannabis based medicine, d9-tetrahydrocannabinol, Cannabidiol, Cancer Pain, Cancer Bone Pain, Treatment, Monotherapy, Nanoparticle, Tetrahydrocannabinol