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Trial registered on ANZCTR


Registration number
ACTRN12622001294741
Ethics application status
Approved
Date submitted
14/09/2022
Date registered
6/10/2022
Date last updated
6/10/2022
Date data sharing statement initially provided
6/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Does taking cannabidiol (CBD) oil with food affect the amount we absorb?
Scientific title
Crossover design pharmacokinetics investigation of Australian Natural Therapeutics Group (ANTG) CBD medium chain triglycerides (MCT) oil with and without fasting in healthy volunteers
Secondary ID [1] 307966 0
Nil known
Universal Trial Number (UTN)
U1111-1279-6908
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Irritable bowel syndrome 327628 0
Condition category
Condition code
Oral and Gastrointestinal 324716 324716 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is the oral administration of a single dose of cannabidiol (100mg) in coconut oil (1ml). The participants will consume a 'meal effect' breakfast according to FDA guidelines (Food-Effect Bioavailability and Fed Bioequivalence Studies, 2002). This will be approximately 965 calories with 560 calories from fats. The meal will be consumed 30min prior to the dose and the dose followed by 240ml of water. The meal and dose will be supervised by a member of the research team. Participants will have free access to water excluding 1h prior to and 1h after the dosage. There will be a 6-week washout period before the fed vs fasted cross-over. All participants will complete the fasted condition (comparator) first, followed by the intervention condition (fed) 6 weeks later.
Intervention code [1] 324424 0
Treatment: Drugs
Comparator / control treatment
The fasted group will act as the active control. Participants will be required to fast (no food, no drink except water) for 10h prior to the study. They can freely consume water except for 1h prior, till 1h after the dosage. They will receive the dosage in the same manner as the fed group excluding the meal.
Control group
Active

Outcomes
Primary outcome [1] 332535 0
Blood concentrations of phytocannabinoids and their metabolites will be determined at predetermined time points.. Particularly cannabidiol (and its metabolites) and tetrahydrocannabinol, to assess efficacy and safety. For each pharmacokinetic profiles including maximum concentration (Cmax), area-under-the-curve from zero to infinity (AUC0-8), and time-to-maximum concentration (Tmax) will be calculated. The confidence intervals (CIs) for log-transformed Cmax and AUC0-8 ratios between fed and fasting states will also be calculated.
Timepoint [1] 332535 0
Pre-first dose (fasted), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12 and 30 hours post-first dose.
Pre-second dose (fed), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12 and 30 hours post-second dose.
Secondary outcome [1] 413844 0
Incidence of adverse events accessed using the case report form- Sampling and Adverse (designed specifically for this trial).

Very common side effects of CBD include feeling drowsy or sleepy, decreased appetite, diarrhoea, fever, feeling tired, and vomiting. Common side effects include lack of energy, sore throat, respiratory tract infection, a blood test showing increased liver enzymes, shaking, irritability, difficulty sleeping, cough, rash, increased appetite, weight loss, drooling, urinary tract infection, agitation, and abnormal behaviour. Serious side effects include changes to mental status or personality (depression or thoughts of suicide), rapid or irregular heartbeat, low blood pressure, seizures or convulsions, shortness of breath, wheezing or difficulty breathing, swelling of face, lips, tough or other body parts, rash and hives or swelling on the skin.

Heart rate (measured using pulse oximeter), blood pressure (systolic/diastolic; measured using sphygmomanometer), respiratory rate (measured by physical examination) and irritation at the cannulation site (assessed using the Phlebitis Grading Scale) will be assessed by the clinical nurses.

Palpitations, sinus tachycardia, hypertension, cough, dyspnoea, syncope, presyncope, dizziness, blurred vision, amnesia, ataxia, confusion, headache, somnolence, concentration impairment, depressed level of consciousness, lethargy, personality change, cognitive disturbance, memory impairment, anxiety, depression, delirium, hallucinations, euphoria, dysphoria, restlessness, dysarthria, psychosis, suicidal ideation, suicidal attempt, dry mouth, vomiting, stomach pain, diarrhoea, constipation, chills, hyperhidrosis, flushing, conjunctivitis, allergy, anaphylaxis and malaise will be monitored using the adverse event study specific questionaire.
Timepoint [1] 413844 0
Pre-first dose (fasted), 1, 3, 6 12 and 30 hours post-first dose and then at 1 week post-first dose.
Pre-second dose (fed), 1, 3, 6 12 and 30 hours post-first dose and then at 1 week post-first dose.

Eligibility
Key inclusion criteria
Healthy individuals with normal cardiovascular, hepatic, and renal function are required because this study is the initial determination of pharmacokinetics.
- Aged 18 to 45 years old at the time of consent.
- Able and willing to comply with all study procedures.
- Willing and able to give informed written consent.
- Fluent English speaking.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Tobacco smoker, current or former.
- Binge drinker, current or former (defined as more than 4 standard drinks in a single session OR more than 10 standard drinks in a week.
- Takes ANY prescription medication, especially blood thinners/anti-thrombotic agents, anti-inflammatory drugs, hypoglycemics, H2 blockers, proton pump inhibitors, and immunosuppressants.
- Frequent use (more than twice weekly) of any non-prescription NSAIDs (including ibuprofen and diclofenac).
- Diagnosis of metastatic cancer and in active treatment (including chemo/radio/hormonal/immunotherapy) or with recurrence on last follow-up with oncologist.
- Pregnant, breastfeeding, plan to conceive within 6 months (both women and men) or unwillingness to use oral contraceptives.
- History of psychiatric disorders (including suicide attempt, schizophrenia, severe depression or anxiety, personality disorder, or history of psychosis).
- History of cognitive impairment, seizures, or epilepsy.
- History of gastric, small bowel or colonic surgery.
- History of liver or renal disease, hyperacidity, gastric/duodenal ulcers, gallbladder problems, or hyperglycaemic, haemophiliac diseases.
- History of Type 1 or 2 diabetes, impaired glucose tolerance or with fasting blood sugar level <5.5 mmol/L.
- History of substance use disorder (ICD-10 criteria (abuse, dependence)) to alcohol, opioids, benzodiazepines or simulants (excluding caffeine, tobacco).
- Had taken cannabinoids for a cannabinoid-based medicine within 6 months prior to the study, or provided a blood sample that tests positive for cannabinoids at the initial timepoint before administration.
- Severe unstable heart disease (unstable angina or ischaemic heart disease, heart failure >NYHA Grade 2; uncontrolled hypertension/hypotension);
- Allergies to MCT oil (as derived from coconut oil) or cannabidiol.
- Vegan, vegetarian, or religiously required to abstain from meat and/or dairy products included in the standardised fat-rich fast-food breakfast meal.
- Participation in a clinical trial of another chemical entity.
- Conditions causing irreversible or blood transfusion dependent anaemia where the volume of blood sampling required for this study is contraindicated in the opinion of the clinician PI.
- Currently on a weight loss program, or ketogenic diet unless it had been stable for 4 weeks before the initial assessment visit and throughout the entire trial period
- Participants will be excluded if according to the judgment of their physician they might be vulnerable to drug addiction or mental instability.
- Not willing to abstain from recreational drug use (excluding caffeine and alcohol that is not recognised as binge drinking) during the study.
- Not a student of or employed by a member of the research team

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Fasting vs feed, pharmacokinetics study
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Bioanalytical Method
Technical directions for the sample preparation and analysis are as follows. Plasma samples will be defrosted immediately prior to analysis. 500ul of plasma will be analysed with the addition of 30ul of deuterated internal standards and 300ul acetonitrile. The mixture will be vortexed and cold sonicated for 5 min. The partitioning will be facilitated by the addition of Quechers salt and centrifuged at 18000g for 5 min. The upper organic layer (150ul) will be removed to a low recovery insert and mixed with equal volume MS grade water. This solution shall be analysed by LC-MS/MS for CBD, THC, and related metabolites (7-OHCBD and 7-COOH-CBD) using MRM monitoring and quantification of concentration in comparison to a freshly prepared standard curve.
Plasma analysis will be undertaken at the NICM Health Research Institute’s Herbal Analysis and Pharmacology Laboratory, Western Sydney University (Sydney, NSW, Australia) in accordance with Good Laboratory Practice and related guidelines. Specifically, the LC-MS/MS method used was previously validated for the clinical trial ACTRN12617001287325. The method will be revalidated ahead of the proposed use in this trial. Instrument control, data acquisition, and Analysis Report generation shall be performed using Shimadzu LabSolutions software. The automatically generated Analysis Report for each run will be printed, signed, and collated into an Analysis File envelope for each participant ID. Quantitative data will also be exported to .csv and/or .xlsx file formats, which can be traceably compared to the Analysis File. These de-identified digital files will be securely kept on the Cloudstor system.

Quantitative data will be processed using non-compartmental analysis in third party PK software packages, examples of which include the proprietary NONMEN ® (v 7.5, ICON Early Phase) software package and GraphPad Prism in conjunction with PK Solver. Outcome variables will principally include: the maximum plasma concentration, the time at the maximum concentration, and the area under the concentration time curves. Relative bioavailability of CBD under the fasted state against the fed state may be computed from the ratio of the areas under the curves. Individual and aggregate results will be produced and interpreted.


Statistical Analysis
Third party software packages shall be used for statistical analysis, examples of such software include SPSS and GraphPad. Descriptive summaries of results will be provided as mean and standard deviation (SD). A Paired Hotelling T-Square test will be performed to determine statistically significant differences in the sets of PK parameters (TMAX, CMAX, and AUC) between the fed and fasted states. A p value less than 0.05 will be deemed statistically significant for the main analysis. If there exists a significant difference, individual PK parameters will be tested by conventional paired t-tests, where a p value less than 0.05 divided by the number of hypotheses (outcome parameters tested).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
10/10/2022
Actual
Date of last participant enrolment
Anticipated
17/10/2022
Actual
Date of last data collection
Anticipated
12/12/2022
Actual
Sample size
Target
16
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 38514 0
2145 - Westmead
Recruitment postcode(s) [2] 38515 0
2150 - Parramatta

Funding & Sponsors
Funding source category [1] 312234 0
Commercial sector/Industry
Name [1] 312234 0
Australian Natural Therapeutics Group (ANTG)
Country [1] 312234 0
Australia
Funding source category [2] 312235 0
Government body
Name [2] 312235 0
NSW government Tech Voucher Scheme through Investment NSW
Country [2] 312235 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Australian Natural Therapeutics Group (ANTG)
Address
59 Cattai Road, Pitt Town, NSW 2756
Country
Australia
Secondary sponsor category [1] 313769 0
None
Name [1] 313769 0
Address [1] 313769 0
Country [1] 313769 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311612 0
Western Sydney University Human Research Ethics Committee
Ethics committee address [1] 311612 0
Ethics committee country [1] 311612 0
Australia
Date submitted for ethics approval [1] 311612 0
04/07/2022
Approval date [1] 311612 0
24/08/2022
Ethics approval number [1] 311612 0
H15050

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

Contacts
Principal investigator
Name 121714 0
Dr Mitchell Low
Address 121714 0
NICM Health Research Institute (HRI), 158 Hawkesbury Road, Westmead, NSW 2145
Country 121714 0
Australia
Phone 121714 0
+61 431067086
Fax 121714 0
+61 2 9685 4760
Email 121714 0
mitchell.low@westernsydney.edu.au
Contact person for public queries
Name 121715 0
Mitchell Low
Address 121715 0
NICM Health Research Institute (HRI), 158 Hawkesbury Road, Westmead, NSW 2145
Country 121715 0
Australia
Phone 121715 0
+61 2 9685 4700
Fax 121715 0
+61 2 9685 4760
Email 121715 0
mitchell.low@westernsydney.edu.au
Contact person for scientific queries
Name 121716 0
Mitchell Low
Address 121716 0
NICM Health Research Institute (HRI), 158 Hawkesbury Road, Westmead, NSW 2145
Country 121716 0
Australia
Phone 121716 0
+61 431067086
Fax 121716 0
+61 2 9685 4760
Email 121716 0
mitchell.low@westernsydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Commercially sensitive and was not part of our protocol for ethics approval.


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.