Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000404628
Ethics application status
Approved
Date submitted
29/03/2023
Date registered
19/04/2023
Date last updated
2/11/2023
Date data sharing statement initially provided
19/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised, Double-Blind, Placebo-Controlled, Parallel-Arm Study to Evaluate the Efficacy, Safety and Tolerability of 150 mg Sublingual Cannabidiol in Adults with Mild-to-Moderate Pain.
Scientific title
A Randomised, Double-Blind, Placebo-Controlled, Parallel-Arm Study to Evaluate the Efficacy, Safety and Tolerability of 150 mg Sublingual Cannabidiol in Adults with Mild-to-Moderate Pain.
Secondary ID [1] 308818 0
PH-CBD-AU-001
Universal Trial Number (UTN)
Trial acronym
PACT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mild to moderate pain 328785 0
Condition category
Condition code
Anaesthesiology 325795 325795 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, double-blind, placebo-controlled Phase 3 registration parallel arm study to evaluate the efficacy, safety and tolerability of 150 mg Promethean Health Cannabidiol (CBD) 3 times daily, in adults experiencing mild-to-moderate pain.

Promethean Health CBD Tablet is a plant-derived, highly purified CBD ((-) enantiomer (100%); minimum CBD content of greater than or equal to 98%), formulated as a nanoparticle encapsulation complexation tablet for sublingual delivery.

Participants will take Promethean Health CBD tablet as oral sublingual tablets three times a day for 30 days (150 mg total daily dose), with each dose taken approximately 6 hours (± 2 hours) apart. Doses will divided as follows:
• Dose 1: 2 x 30 mg tablets (60 mg total)
• Dose 2: 2 x 30 mg tablets (60 mg total)
• Dose 3: 1 x 30 mg tablet

A total of up to 172 participants will be randomised to receive Promethean Health CBD or placebo, at a ratio of 1:1. 86 participants will receive Promethean Health CBD.

During the treatment period, participants will be required to attend the clinic on days 1, 15 and 30 for study assessments. In addition participants will also be required to attend a telehealth appointment (or receive a phone call) on day 2, 8 and 22 to ascertain the use of concomitant medications and emergence of AEs, and to complete the BPI-SF, EQ-5D-5L and EQ-VAS questionnaires (Days 8 and 22 only). The end of study visit will be on Day 44.

At the discretion of the site (in consultation with the participant) Days 8 and 22 may be conducted as a phone call/telehealth appointment or an in-person clinic visit.

Clinical facility staff will administer the study drug only to participants included in this study following the procedures set out in this study protocol. Administration of study drugs will be recorded in the appropriate drug accountability records and the electronic case report form (eCRF). Participants will also maintain a diary to confirm the administration of the 3 doses of study drug each day. Each participant will only be given the study drug preparation carrying his/her study number.
Intervention code [1] 325274 0
Treatment: Drugs
Comparator / control treatment
Participants will receive up to 2 x placebo sublingual tablets, three times a day for 30 days and will be identical in appearance to the Promethean Health CBD tablet.
Placebo doses will be divided as follows:
• Dose 1: 2 tablets
• Dose 2: 2 tablets
• Dose 3: 1 tablet
The placebo tablet is a round (5mm high x 10 mm diameter) 500 mg, white tablet with no markings identical to the Promethean Health CBD tablet except that it does not contain CBD.

Microcrystalline cellulose
Gum arabic
Sucralose
Lemon (natural spray dried powder)
Peppermint (natural spray dried powder)
Salt (sodium chloride)
Citric acid
Control group
Placebo

Outcomes
Primary outcome [1] 333638 0
Mean change from baseline in brief pain inventory short form (BPI-SF) pain severity score on Day 30 in Promethean Health CBD treated participants compared to placebo.
Timepoint [1] 333638 0
BPI-SF will be completed pre dose at screening, day 1, day 8, day 15, day 22 and post dose at day 30 post commencement of intervention and early termination visit (ETV) if applicable.
Secondary outcome [1] 417838 0
Change in pain severity score assessed using the Brief Pain Inventory Short Form (BPI-SF)
Timepoint [1] 417838 0
BPI-SF will be completed pre dose at Screening, day 1, day 8, day 15, day 22 and post dose at day 30 post-commencement of intervention and early termination visit (ETV) if applicable.
Secondary outcome [2] 419081 0
To assess the safety and tolerability of three times a day dosing of Promethean Health CBD tablet (total daily dose 150 mg) over a 30-day period.

Change from baseline in: Incidence, type and severity of adverse events (AEs), The most commonly reportly adverse events associated with the use of CBD are tiredness, diarrhoea, changes in appetite/weight, transaminase elevation in the blood, sedation, sleep disturbances, infection and anaemia. Vital sign assessments (supine or semi-supine systolic and diastolic blood pressure, heart rate, body temperature, respiratory rate), Clinical laboratory assessments (haematology, serum chemistry and urinalysis) and use of concomitant pain medication.
Timepoint [2] 419081 0
1. AE's and Serious Adverse Events (SAE's) will be graded using the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events 5-point scale. AE's and SAE's will be continuously assessed as they are reported or observed and reviewed daily from Screening Visit until the End of Study (EOS) visit at Day 44 post-commencement of intervention.

2. Vital signs (Blood pressure, heart rate, body temperature and respiratory rate) are assessed at the Screening Visit and Day 1 (pre first dose of Promethean Health CBD/Placebo) then again at day 15 and post dose at day 30 and day 44 (EOS) visit post-commencement of intervention. - Blood pressure and Heart Rate will be assessed pre dose using a sphygmomanometer (blood pressure cuff) with the participant resting in a supine or semi-supine position for at least 5 minutes prior to and during measurement. - Body Temperature will be assessed pre dose using a tympanic thermometer. - Respiratory rate will be assessed pre dose by observing the number of breaths a participant takes.

3. Clinical laboratory assessments (haematology and serum chemistry) will be collected via venepuncture at the Screening Visit and Day 1 (pre first dose of Promethean Health CBD/Placebo) and then again at Day 15 and post dose at day 30 and day 44 (EOS) visit post-commencement of intervention.

4. Clinical laboratory assessments (Urinalysis) will be tested using a urine dipstick at the research site. If any abnormal findings are found on the urine dipstick, the urine sample will be sent to a local laboratory for a urine sediment microscopy to assess for blood or leukocyte esterase. Urinalysis will be performed at Screening Visit and Day 1 (pre first dose of Promethean Health CBD/Placebo) and then again at Day 15 and post dose at day 30 and day 44 (EOS) visit post-commencement of intervention.
Secondary outcome [3] 420647 0
Change in worst pain score assessed using the Brief Pain Inventory Short Form (BPI-SF Question 3)
Timepoint [3] 420647 0
BPI-SF worst pain score (Question 3) will be completed pre dose at Screening, day 1, day 8, day 15 day 22 and post dose day 30 post-commencement of intervention and early termination visit (ETV) if applicable.
Secondary outcome [4] 420648 0
Change in least pain score assessed using the Brief Pain Inventory Short Form (BPI-SF Question 4)
Timepoint [4] 420648 0
BPI-SF least pain score (Question 4) will be completed pre dose at Screening, day 1, day 8, day 15, day 22, and post dose day 30 post-commencement of intervention and early termination visit (ETV) if applicable.
Secondary outcome [5] 420649 0
Change in pain right now score assessed using the Brief Pain Inventory Short Form (BPI-SF, Question 6)
Timepoint [5] 420649 0
BPI-SF pain right now score (Question 6) will be completed pre dose at Screening, day 1, day 8, day 15, day 22, and post dose day 30 post-commencement of intervention and early termination visit (ETV) if applicable.
Secondary outcome [6] 420650 0
Change in pain relief score assessed using the Brief Pain Inventory Short Form (BPI-SF, Question 8)
Timepoint [6] 420650 0
BPI-SF pain relief score (Question 8) will be completed pre dose at Screening, day 1, day 8, day 15, day 22 and post dose day 30 post-commencement of intervention and early termination visit (ETV) if applicable.
Secondary outcome [7] 420651 0
Change in pain interference score assessed using the Brief Pain Inventory Short Form (BPI-SF, Question 9)
Timepoint [7] 420651 0
BPI-SF interference score (Question 9) will be completed pre dose at Screening, day 1, day 8, day 15, day 22 and post dose day 30 post-commencement of intervention and early termination visit (ETV) if applicable.
Secondary outcome [8] 420652 0
Change in health-related quality of life assessed using EuroQol 5 dimensions 5 levels index score (EQ-5D-5L)
Timepoint [8] 420652 0
EuroQol 5 dimensions 5 levels index score (EQ-5D-5L) will be completed pre dose at Screening, day 1, day 8, day 15, day 22 and post dose day 30 post-commencement of intervention and early termination visit (ETV) if applicable.
Secondary outcome [9] 420653 0
Change in self-perceived health assessed using EQ visual analogue scale (EQ-VAS),
Timepoint [9] 420653 0
EQ visual analogue scale (EQ-VAS) will be completed pre dose at Screening, day 1, day 8, day 15, day 22 and post dose day 30 post-commencement of intervention and early termination visit (ETV) if applicable.

Eligibility
Key inclusion criteria
1. Must have given informed consent, before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects.
2. Male or female 18 to 75 years of age
3. Body mass index (BMI) less than or equal to 35.0 kg/m2. Exceptions may be permitted at the discretion of the Investigator for healthy participants with a BMI > 35 mg/m2.
4. Presence of mild-to-moderate acute, subacute or chronic non-palliative pain for greater than or equal to 2 weeks (BPI-SF5 average pain score of 3-6) at the time of screening, and on Day 1, prior to dose administration. Pain may include, but is not limited to, pain due to injury, musculoskeletal pain, bone or joint-related pain, tendon or ligament-related pain, arthritis, fibromyalgia, bursitis, endometriosis etc .
5. Participant currently requires stable use (stable usage for at least 14 days, in the opinion of the Investigator) of non-opioid simple analgesia to manage pain symptoms at screening and on Day 1, prior to dose administration. Note: simple analgesia may refer to the use of non-opioid pain medications or non-pharmacological therapies (examples may include, but are not limited to, hydrotherapy, use of transcutaneous electrical nerve stimulation, walking and/or exercise).
6. With the exception of findings associated with the primary presentation of pain, participant is otherwise medically healthy, as determined by pre-study medical history and without clinically significant abnormalities at screening or on Day 1, prior to dose administration including:
a. Physical examination without any additional clinically relevant findings
b. Systolic blood pressure in the range of 90 to 160 mmHg and diastolic blood pressure in the range of 50 to 95 mmHg after 5 minutes in supine or semi-supine position.
c. Heart rate in the range of 45 to 100 beats/minute after 5 minutes rest in supine or semi-supine position.
d. Body temperature (tympanic), between 35.5°C and 37.7°C.
e. Electrocardiogram (ECG) without clinically significant abnormal findings.
7. No clinically relevant findings in clinical laboratory blood and urinalysis tests as judged by the PI (or delegate), including evidence of adequate hepatic function, as defined by AST and ALT less than or equal to 2.5 X upper limit of normal.
8. Female participants must be of non-child-bearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with postmenopausal status, per local laboratory guidelines), or, if of child-bearing potential:
a. Must have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test on Day 1, prior to dose administration.
b. Must agree not to donate ova or attempt to become pregnant from the time of signing consent until at least 31 days (30 days + a minimum of 5 x half-lives of Promethean Health CBD) after the last dose of study drug.
c. If not exclusively in a same-sex relationship, must agree to use adequate contraception (which is defined as use of a condom by the male partner combined with use of a highly effective method of contraception from one month prior to screening until at least 31 days after the last dose of study drug.
9. Male participants must:
a. Agree not to donate sperm from the time of signing consent until at least 91 days (90 days + minimum of 5 x half-lives of Promethean Health CBD) after the last dose of study drug.
b. If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use adequate contraception (defined as use of a condom plus a highly effective method of contraception from the time of signing consent until at least 91days after the last dose of study drug.
c. If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, must agree to use a condom from the time of signing consent until at least 91 days after the last dose of study drug.
10. Willing and able to comply with all scheduled visits, treatment plans, laboratory tests and other study procedures.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Hypersensitivity or other clinically significant reaction to the study drug or its active ingredients.
2. Participant is currently receiving treatment with an opioid analgesic, or any other Schedule 4, Schedule 8 or Schedule 9 analgesics listed in the most recent version of the Australian Therapeutic Goods Poisons Standard.
3. Participant is receiving current treatment with a neuroleptic medication.
4. Participant is receiving current treatment with selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs).
5. Participant has used cannabis (or its derivatives, synthetic or otherwise) within 28 days prior to first dose administration on Day 1.
6. Major surgery (in the opinion of the PI [or delegate]) within 28 days of study drug administration on Day 1, or minor surgical procedures within 7 days of Day 1.
7. In the opinion of the Investigator (or medically qualified designee), participant has any of the following:
a. A history of significant cardiac disease
b. Any current unstable serious illness or malignancy
8. Positive alcohol breath test at Screening or on Day 1, prior to dose administration.
9. Positive urine drugs of abuse test at Screening on Day 1, prior to dose administration.
10. Participant is breastfeeding or pregnant or planning to breastfeed or become pregnant during the study.
11. Known substance abuse or medical, psychological, or social conditions that, in the opinion of the PI (or delegate), may interfere with the participants inclusion in the clinical study or evaluation of the clinical study results.
12. Active infection requiring systemic antibiotic, antifungal, or antiviral medication within 14 days prior to first dose of study drug.
13. Active hepatitis B (Hep B), hepatitis C (Hep C), Epstein-Barr virus (EBV) or human immunodeficiency virus (HIV) infection.
14. Received any vaccination within 14 days prior to first dose administration on Day 1 or plans to receive a vaccination during the study.
15. Concurrent participation in another clinical trial, or participation in another clinical trial within 60 days prior to first dose administration on Day 1.
16. Any other condition or prior therapy that in the opinion of the Investigator (or delegate) would make the participant unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.

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)
Participants will be centrally randomized to study treatment using an electronic randomization and trial supply management system (RTMS). Before the study is initiated, the login information and directions for the RTMS (including directions for emergency unblinding) will be provided to each study center.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The allocation to Promethean Health CBD or placebo will be performed using a block randomisation algorithm to make sure the first block will have 30 participants per arm and will be documented in the study randomisation schedule. Randomisation numbers assigned will be in accordance with this randomisation schedule.
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
This is a Phase 3 registration study for Promethean Health CBD. The initial sample size of n=86 per arm is estimated to have approximately 90% power to detect a 1-point difference on the BPI-SF change from baseline in pain severity score between placebo and 150 mg Promethean Health CBD tablet with a minimum clinically important change from baseline of 2 points.

This calculation includes assumptions (inclusion criteria of BPI-SF pain severity score between 3-6 inclusive, indicative of mild-moderate pain; variance is the same in placebo and Promethean Health CBD treatment groups and that the SD is equal to 2). These assumptions will be evaluated when conducting the unblinded interim analysis and the sample size may be increased as a result.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
22/05/2023
Actual
5/07/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
172
Accrual to date
15
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD
Recruitment hospital [1] 24211 0
Paratus Clinical Research - Brisbane - Albion
Recruitment hospital [2] 24225 0
Paratus Clinical Pty Ltd Blacktown Trial Clinic - Blacktown
Recruitment hospital [3] 24226 0
Paratus Clinical Pty Ltd Kanwal Trial Clinic - Kanwal
Recruitment hospital [4] 24227 0
Paratus Clinical Research - Ochre Health Medical Centre Bruce - Bruce
Recruitment postcode(s) [1] 39763 0
2148 - Blacktown
Recruitment postcode(s) [2] 39764 0
2259 - Kanwal
Recruitment postcode(s) [3] 39765 0
2617 - Bruce
Recruitment postcode(s) [4] 39744 0
4010 - Albion

Funding & Sponsors
Funding source category [1] 313040 0
Commercial sector/Industry
Name [1] 313040 0
Promethean Health Pty Ltd
Country [1] 313040 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Promethean Health Pty Ltd
Address
9-15 Chilvers Road, Thornleigh, NSW, 2120
Country
Australia
Secondary sponsor category [1] 315088 0
Commercial sector/Industry
Name [1] 315088 0
Avance Clinical
Address [1] 315088 0
Level 1/2 Ann Nelson Dr, Thebarton SA 5031
Country [1] 315088 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312294 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 312294 0
123 Glen Osmond Road, Eastwood, South Australia, 5063, Australia
Ethics committee country [1] 312294 0
Australia
Date submitted for ethics approval [1] 312294 0
08/03/2023
Approval date [1] 312294 0
13/04/2023
Ethics approval number [1] 312294 0

Summary
Brief summary
Pain is extremely prevalent and highly impactful on quality of life. Both acute and chronic pain are routinely treated with paracetamol, non-steroidal anti-inflammatory drugs, monoamine reuptake inhibitors, anticonvulsant agents, and opioids. However, these treatments may have only modest efficacy in the treatment of pain and/or can have significant adverse effects that also interfere with quality of life (e.g., cognitive clouding, sedation, fatigue, weight gain).

The high prevalence and high burden of disease associated with pain, combined with ineffectual treatments or treatments with significant adverse effects defines a clear unmet need for new well tolerated and effective therapeutic treatments that are not prone to abuse/misuse. This extends to the management of mild-to-moderate non-palliative pain.
Cannabidiol (CBD) represents one such treatment for control of mild-to-moderate non-palliative pain. Three clinical trials and two observational studies demonstrated clear positive effects of chronic CBD dosing regimens on the management of a range of pain indications.

This is a first-in-human (FIH) study for the Promethean Health CBD tablet. However, CBD been extensively investigated in human clinical trials at doses ranging from < 10 mg/day to up to 6,000 mg/day.

The planned Promethean Health Pty Ltd clinical trial will investigate a total CBD daily dose of 150 mg/day for a period of 30 days. The dose level was selected within the TGA guidance for Schedule 3 registration (16). The 3 times a day dosing schedule was selected based on the half-life of the formulation (approximately 6 hours), with 3 times daily allowing the broadest dosing schedule that can be achieved through waking hours.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124142 0
Dr Sheetal Bull
Address 124142 0
Paratus Clinical Research Brisbane
Next Practice Albion, 6 Crosby Rd Albion QLD 4010
Country 124142 0
Australia
Phone 124142 0
+61 07 2111 9168
Fax 124142 0
Email 124142 0
sheetal.bull@paratusclinical.com
Contact person for public queries
Name 124143 0
Mr Alfonso Barraza
Address 124143 0
Promethean Health, 9-15 Chilvers Road, Thornleigh, NSW, 2120
Country 124143 0
Australia
Phone 124143 0
+61 1300 749 330
Fax 124143 0
Email 124143 0
Quality@PrometheanBiopharma.com
Contact person for scientific queries
Name 124144 0
Mr Alfonso Barraza
Address 124144 0
Promethean Health, 9-15 Chilvers Road, Thornleigh, NSW, 2120
Country 124144 0
Australia
Phone 124144 0
+61 1300 749 330
Fax 124144 0
Email 124144 0
Quality@PrometheanBiopharma.com

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


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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