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Trial registered on ANZCTR


Registration number
ACTRN12621001181897
Ethics application status
Approved
Date submitted
2/08/2021
Date registered
2/09/2021
Date last updated
2/09/2021
Date data sharing statement initially provided
2/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I study to measure the absorption of cannabidiol (CBD) in healthy volunteers after consumption of an oral CBD soft-gel capsule
Scientific title
A Phase I, open label, randomised, single dose, two-way crossover study in healthy volunteers to determine the pharmacokinetics of two doses of an oral cannabidiol soft-gel capsule.
Secondary ID [1] 304934 0
Avecho Biotechnology protocol number (AVE045-20)
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Insomnia 323084 0
Condition category
Condition code
Neurological 320659 320659 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment A and Treatment B will be ingested in clinic under monitoring from trial staff.

Treatment A:
Single soft-gel capsule containing oil based formulation with 75 mg cannabidiol and 75 mg tocopheryl phosphate mix (TPM).

Treatment B:
Two soft-gel capsules containing oil based formulation with a total of 150 mg cannabidiol (2 x 75 mg) and 150 mg (2 x 75 mg) tocopheryl phosphate mix (TPM).

Treatment A and Treatment B will be separated by a minimum of 7 days.
Intervention code [1] 321329 0
Treatment: Drugs
Comparator / control treatment
This study will compare the pharmacokinetics of two different doses of the same product in a cross-over design. Each dose (Treatment A or Treatment B) will be compared against the other. Subjects will be randomized to either treatment sequence AB or BA.

Neither of the doses are considered a reference comparator dose in this first study. Based upon the results generated here, one of the doses may become focus of future studies, and act as the reference in these future trials.
Control group
Dose comparison

Outcomes
Primary outcome [1] 328477 0
CBD will be quantified in blood samples and used to calculate the following pharmacokinetic parameters for each dose:
- Cmax: Maximum observed concentration
- tmax: Time to reach the maximum concentration
- AUC0-last: Area under the plasma concentration-time curve from the time of the dose administration to the time of the last measurable concentration calculated by the linear up log down trapezoidal method.
- AUC0-inf: Area under the concentration-time curve from the time of the dose administration to time infinity calculated by the linear up log down trapezoidal method.
- t1/2: Elimination half-life associated with the terminal slope (kel) of the semilogarithmic concentration-time curve, calculated as 0.693/kel.
- CL/F: The apparent total clearance.
- Vz/F: The apparent total volume of distribution.
Timepoint [1] 328477 0
For each dosing period, blood samples will be taken at: pre-dose and 0.5, 1, 2, 3, 4, 6, 9, 12, 24 and 48 hours post-dose for the characterisation of the CBD PK
Secondary outcome [1] 399140 0
To evaluate the single dose safety and tolerability of cannabidiol absorbed from two doses of an oral formulation. Mild to severe adverse health events will be monitored by the in-clinic physician each day. Vital signs and ECG will be performed at approximately 1, 2, 8 and 24 hours post each dose as well as the follow up visit. Blood biochemistry will be assessed at check-in for each dose, as well as the follow up visit.
Timepoint [1] 399140 0
Mild to severe adverse health events will be monitored by the in-clinic physician each day during the subject's stay in clinic (Day -1 to Day 2). Vital signs and ECG will be performed at approximately 1, 2, 8 and 24 hours post each dose as well as the follow up visit. Blood biochemistry will be assessed at check-in for each dose, as well as the follow up visit.
Secondary outcome [2] 399141 0
To evaluate the systemic exposure of the two primary excipients of the oral CBD formulation. In addition to the CBD, TP and T2P (the components of TPM) will be assayed in all collected blood samples to estimate the pharmacokinetics of each molecule. In addition, tocopherol will also be assayed in subjects blood samples, as a possible metabolite of both TP and T2P. PK assessments for TP, T2P and tocopherol will be identical to those calculated for CBD;
- Cmax: Maximum observed concentration
- tmax: Time to reach the maximum concentration
- AUC0-last: Area under the plasma concentration-time curve from the time of the dose administration to the time of the last measurable concentration calculated by the linear up log down trapezoidal method.
- AUC0-inf: Area under the concentration-time curve from the time of the dose administration to time infinity calculated by the linear up log down trapezoidal method.
- t1/2: Elimination half-life associated with the terminal slope (kel) of the semilogarithmic concentration-time curve, calculated as 0.693/kel.
- CL/F: The apparent total clearance.
- Vz/F: The apparent total volume of distribution.
Timepoint [2] 399141 0
For each dosing period, blood samples will be taken at: pre-dose and 0.5, 1, 2, 3, 4, 6, 9, 12, 24 and 48 hours post-dose for the characterisation of the TP, T2P and tocopherol PK

Eligibility
Key inclusion criteria
1. Aged greater than or equal to 18 years and less than or equal to 55 years (inclusive).
2. Participant is free from clinically significant (in the opinion of the Investigator) illness or disease as determined by their medical and surgical history, physical examination, 12-lead ECG, vital signs and clinical laboratory determinations.
3. Body Mass Index (BMI) greater than or equal to 18.0 and less than or equal to 27 kg/m2 at Screening.
4. Weight > 50.0 kg at Screening.
5. Adequate venous access in both arms for collection of a number of blood samples.
6. Capable of understanding the purposes and risks of the study and able to provide written informed consent before any study-specific screening procedures are performed.
7. Willing and able to adhere to all protocol requirements.
8. Female participants must be abstinent or agree to use effective contraception (i.e., pill, condom) during the study period (from the time of first check in until completion of the final study visit).
9. Male participants that are not surgically sterile (i.e. vasectomy) must be abstinent or agree to use effective barrier contraception (i.e., condom) during the study period (from the time of first check in until completion of the final study visit).
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of coronary disease, peripheral vascular disease, cerebrovascular accident, transient ischaemic attack, uncontrolled hypertension or signs/symptoms of ischaemic heart disease.
2. Have a rested systolic blood pressure of < 90 mmHg or > 160 mmHg and/or diastolic blood pressure of < 50 mmHg or > 95 mmHg or radial pulse rate at rest of < 45 beats per minute (bpm) or > 100 bpm at Screening or Check-In (Day -1). Blood Pressure (BP) or heart rate may be re-tested two times in the rested position at intervals of five minutes. The elevation is considered sustained if any values are outside the stated limits after three assessments or judged as clinically significant by the Investigator and the participant may not be enrolled.
3. History of acute or severe bronchial asthma (excluding childhood or exercise induced asthma), diagnosed obstructive sleep apnoea, hypoxia, hypoxaemia, hypercarbia, or other obstructive airway disease or any condition that may increase the risk for respiratory depression.
4. History of neurologic conditions such as seizures or convulsive disorders (including epilepsy), severe head injury or increased intracranial pressure.
5. Presence of current psychiatric condition or psychiatric condition requiring pharmacological management within the last two years.
6. A calculated creatinine clearance of < 85 mL/minute at Screening or Check-In (Day -1) according to the equation using Cockcroft and Gault.
7. Liver function tests showing values for ALT or AST > 1.5 times ULN at Screening
8. Evidence or history of clinically significant (in the opinion of the Investigator) other cardiovascular, pulmonary, neurologic or renal disorders or hepatic, gastrointestinal, oral (difficulty swallowing / taking oral medication), haematological, endocrine, or psychiatric impairment/disorders.
9. Have undergone surgery requiring, or have received (for any reason) anaesthetic within 30 days of Day 1.
10. Use of CNS depressants including: opioids, sedative, anxiolytics, hypnotics, neuroleptics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines or cimetidine within 30 days of Day 1.
11. Use of macrolide antibiotics (e.g., Erythromycin), azole antifungal agents (e.g., Ketoconazole) or protease inhibitors (e.g., Ritonavir) within 30 days of Day 1.
12. Use of any prescription medication within 14 days of Day 1 and for duration of study, unless approved by both the Investigator and the Medical Monitor (in writing). If necessary, paracetamol (acetaminophen) or ondansetron (or other 5-HT3 receptor antagonist) may be administered with the approval of the Investigator.
13. Use of any over the counter product, herbal product, diet aid, or hormone supplement, with a particular regard to hemp or products containing cannabidiol, within 14 days of Day 1 and for duration of study, unless approved by both the Investigator and Medical Monitor (in writing).
14. Known intolerance, allergy or hypersensitivity reactions to medicinal cannabis.
15. Positive screening test for Human Immunodeficiency Virus (HIV) antibodies, Hepatitis B surface antigen or Hepatitis C antibody.
16. Evidence or history of substance or alcohol abuse (drink more than 4 standard units of alcohol per day or >10 standard units per week), including positive results for the urine drugs of abuse test or a positive alcohol breath test at Screening or at Check-In (Day -1).
17. Unwilling or unable to abstain from recreational drug/substance use, alcohol, from check-in until discharge.
18. Unwilling or unable to abstain from caffeine or other xanthine-containing products from check-in until discharge in each study period.
19. Participants who are not willing to refrain from smoking 48 hours before check-in until discharge in each study period.
20. Consumption of grapefruit, grapefruit juice or any products containing CYP3A4 inhibitors and inducers within 14 days of Day 1 and through to completion of the study.
21. Any known contraindication to blood sampling.
22. Currently participating in another clinical study involving another IP or extensive blood sampling, or recent study participation ending within 3 months of Day 1.
23. Donation or loss of more than 500 mL of blood within 3 months of Day 1 and/or not willing to refrain from donating blood/extensive blood sampling for 12 weeks after study completion.
24. Participants that have or are planning to discontinue effective contraceptive precautions during the study period.
25. Any issues that, in the opinion of the Investigator, would render the participant unsuitable for study participation.


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)
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)
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Not yet 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)
SA

Funding & Sponsors
Funding source category [1] 309314 0
Commercial sector/Industry
Name [1] 309314 0
Avecho Biotechnology
Address [1] 309314 0
Unit A8, 2A Westall Road, Clayton, VIC 3168
Country [1] 309314 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Avecho Biotechnology
Address
Unit A8, 2A Westall Road, Clayton, VIC 3168
Country
Australia
Secondary sponsor category [1] 310287 0
None
Name [1] 310287 0
Address [1] 310287 0
Country [1] 310287 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309142 0
Bellberry Human Research Ethics Committee E
Ethics committee address [1] 309142 0
123 Glen Osmond Road, Eastwood, South Australia, 5063
Ethics committee country [1] 309142 0
Australia
Date submitted for ethics approval [1] 309142 0
Approval date [1] 309142 0
12/04/2021
Ethics approval number [1] 309142 0

Summary
Brief summary
Cannabidiol is a phytocannabinoid found naturally in the Cannabis sativa plant. Despite CBD’s long history of use, its medicinal properties have been somewhat anecdotal. There are very few pharmaceutically approved products on market, and these are limited to rare clinical indications (i.e. Epidiolex® for rare childhood epilepsy).
Cannabidiol is being developed for a range of medicinal applications. These applications typically require CBD at high purity, which can be extracted and purified from Cannabis sativa, or synthetically manufactured. High purity CBD is a white to pale yellow crystalline solid that is insoluble in water. Consequently, CBD is usually administered in an oil vehicle. The limited aqueous solubility of CBD leads to poor oral bioavailability, which has been reported as between 3-8%.
CBD has been selected for clinical development in a formulation containing TPM. It is believed that CBD TPM formulations may have improved bioavailability when compared to CBD alone, which would allow for lower doses administered to patients, or the targeting of therapeutic indications that would ordinarily need CBD doses that are so large as to be prohibitive.
The proposed Phase I clinical study will evaluate the PK, safety and tolerability of an oral CBD soft-gel capsule. The PK profile of the capsule will be compared at two separate doses.
Results from this study will support further clinical development of the CBD soft-gel product, with a focus on indications that can be treated with low-dose CBD.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113134 0
Prof Sepehr Shakib
Address 113134 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace
Adelaide SA, Australia 5000
Country 113134 0
Australia
Phone 113134 0
+61 8 8222 2763
Fax 113134 0
Email 113134 0
Sepehr.Shakib@cmax.com.au
Contact person for public queries
Name 113135 0
Ms Francesca Bell
Address 113135 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace
Adelaide SA, Australia 5000
Country 113135 0
Australia
Phone 113135 0
+61 8 7088 7900
Fax 113135 0
Email 113135 0
francesca.bell@cmax.com.au
Contact person for scientific queries
Name 113136 0
Prof Sepehr Shakib
Address 113136 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace
Adelaide SA, Australia 5000
Country 113136 0
Australia
Phone 113136 0
+61 8 8222 2763
Fax 113136 0
Email 113136 0
Sepehr.Shakib@cmax.com.au

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 other documents available
Summary results
No Results