Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001424291
Ethics application status
Approved
Date submitted
2/08/2018
Date registered
27/08/2018
Date last updated
1/08/2019
Date data sharing statement initially provided
1/08/2019
Date results information initially provided
1/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigation of the safety, tolerability and pharmacokinetics of Cannabidiol in Healthy Volunteers
Scientific title
A Phase 1, Randomised, Placebo-controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Healthy Volunteers
Secondary ID [1] 295069 0
NTA1701
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe Intractable Epilepsy 308114 0
Condition category
Condition code
Neurological 307155 307155 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A total of 24 healthy volunteers will be enrolled in this study and divided into 3 cohorts.

Eight participants in every cohort will receive a single oral dose of either Cannabidiol (CBD) oil or placebo oil, such that 6 participants will receive CBD and 2 will receive placebo. The volume given will be calculated based on the participants weight and Cohort group assigned. The oil will be administered following a minimum of 10 hours of overnight fasting (no food or drink, other than water up to 1 hour before dosing) and 30 minutes after commencing a high fat breakfast.

Participants should start the meal 30 minutes prior to CBD/placebo oil administration and complete it at least 5 minutes before dosing. No food is allowed for at least 4 hours post-dose. Water is allowed as desired except for one hour before dosing. Immediately following dosing, 240 mL of water will be provided.

The content of the high fat breakfast will follow US FDA/Centre for Drug Evaluation and Research (CDER) Guidance regarding caloric content and composition. An example of a high fat breakfast would be two eggs fried in butter, two strips of bacon, two slices of toast with butter, 4 ounces (approximately 115 g) of hash brown potatoes and 8 ounces (approximately 230 g) of whole milk.

Dosing syringes will be capped and weighed pre and post product administration and participants observed during dosing to confirm volume of product delivered. Syringes will be retained until inspected and monitor verified.

Three increasing doses of CBD will be investigated: 5mg/kg (Cohort 1), 10mg/kg (Cohort 2) and 20mg/kg (Cohort 3).

A Safety Review Commitee will undertake a dose-escalation review of all available safety data up to Day 8 following every cohort, and prior to participants commencing the next dose.

Sentinel dosing will be implemented in the first 2 participants (1 CBD and 1 placebo) of Cohort 1. Twenty-four hour safety data will be reviewed and if no significant safety concerns, the remaining 6 participants in the cohort will then be dosed. Sentinel dosing may be implemented for Cohorts 2 and 3 if deemed necessary by the Safety Review Committee.
Intervention code [1] 301400 0
Treatment: Drugs
Comparator / control treatment
The placebo oil will be composed of the same excipients as the Cannabidiol oil (without the active ingredient, CBD) and will be identical in appearance to maintain the blind. The volume of oil administered will be based on participant weight and cohort group assigned.
Control group
Placebo

Outcomes
Primary outcome [1] 306128 0
To determine the safety and tolerability of CBD following a single oral dose in healthy volunteers to support use in patients with severe intractable epilepsy.

This will be measured by evaluating the incidence of adverse events and changes from baseline of relevant parameters including, vital signs, clinical laboratory assessments, 12-lead ECG data and concomitant medications.



Timepoint [1] 306128 0
Day 15 post-dose

Adverse events will be recorded for study duration, to Day 15 post dose (final visit). All AEs will be followed until resolution, until the condition stabilises, until the event is otherwise explained, or until the subject is lost to follow-up.

Vital signs will be measured Day 1: within 60 minutes prior to dosing, 2 hours, 4 hours, 8 hours and 12 hours post dose; Day 2: 24 hours and 36 hours post dose; Day 3: 48 hours post dose and on Day 8 (168h post dose).

Clinical laboratory samples will be collected and measured on Day -1 and Day 3: 48 hours post dose and Day 8 (168h post dose).

12-Lead ECG's will be undertaken within 60 minutes prior to dosing on Day 1, 4 hours post dose and daily on Day 3 and Day 8 (168h) post dose

Concomitant medication information will be collected throughout the study to Day 15 post-treatment (final visit).
Secondary outcome [1] 347639 0
To assess the Pharmacokinetics of CBD following a single oral dose in healthy volunteers.

The PK of CBD, plasma concentration of CBD will be evaluated by:
- AUClast – area under the plasma concentration versus time curve from time zero to the last quantifiable concentration
- AUCinf – area under the plasma concentration versus time curve extrapolated to infinite time
- Cmax – maximum observed plasma concentration
- Tmax – time of maximum observed plasma concentration
- Kel – apparent terminal elimination rate constant
- T1/2 – apparent terminal elimination half-life
Timepoint [1] 347639 0
Day 8 post-dose

Blood samples for PK analysis will be collected Day 1: within 60 minutes prior to dosing, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post dose; Day 2: 24 hours and 36 hours post dose; Day 3: 48 hours post dose, Day 4 (72 hours post dose), Day 6 (120h post dose) and on Day 8 (168h post dose).

Eligibility
Key inclusion criteria
1. Male or females aged between 18 - 49 years (inclusive);
2. Body mass index between 18 and 30 kg/m2 (inclusive);
3. Negative screen for drugs of abuse, alcohol, hepatitis B surface antigen, Hepatitis C Virus and Human Immunodeficiency Virus;
4. Negative screen for drugs of abuse and alcohol pre-dose on Day -1;
5. Clinical laboratory values within the normal limits as defined by the clinical laboratory, unless the results are deemed as not clinically significant by the investigator
6. Be in general good health without clinically significant medical history;
7. Ability to provide written informed consent;
8. Willing and able to follow study instructions and likely to complete all study requirements;
9. Females of childbearing potential must agree to use an established oral, injected or implanted hormonal method of contraception throughout the study (Screening to Day 15) and for 90 days after receiving the study drug.
10. Males must agree to use adequate methods of contraception throughout the study (Screening to Day 15) and for 90 days after receiving study drug, excluding sterilized males (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate)
11. Suitable venous access.
Minimum age
18 Years
Maximum age
49 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Positive screening result for cannabis use;
2. Current smoker, or a history of regular (more than weekly) use of tobacco- or nicotine-containing products (including e-cigarettes) within 2 months prior to screening; cotinine (nicotine) test to be performed at screening;
3. History of excessive alcohol intake (more than four standard drinks daily, on average) or use of recreational drugs within the last 3 months prior to screening;
4. Use of prescription or over the counter medications within 7 days of investigational product administration, except for hormonal contraception, simple analgesics such as paracetamol, oral non-steroidal anti-inflammatory drugs and vitamins unless approved by the sponsor medical monitor and study doctor;
5. Consumption of grapefruit, grapefruit juice and Seville oranges within 1 week prior to study drug dose or the use of CYP3A inducers/inhibitors within 2 weeks prior to study drug dose, until completion of the study (Day 15 visit). Study doctor will advise what these inducers/inhibitors are..
6 Standard donation of blood within 30 days of investigational product administration;
7. Participation in any investigational drug study within 30 days prior to screening;
8. Females who are pregnant or breastfeeding;
9. Clinically significant (as judged by the investigator) presence of acute illness (e.g. gastrointestinal illness, infection such as influenza, upper respiratory tract infection) at admission to the study unit;
10. Anticipated need for surgery or hospitalisation during the study;
11. History of brady- or tachy-dysrhythmias;
12. History of heart failure or heart disease;
13. Sensitivity to CBD;
14. Allergy to soybeans or any of the excipients in the IP or placebo preparation.
15. Any condition, which in the investigator’s opinion, puts the subject at significant risk, could confound the study results or may interfere significantly with the subject’s participation in the study.

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)
This is a double-blind study and thus the investigator, site staff (other than pharmacists), sponsor, sponsors delegates (if applicable) and subjects are all blinded to treatment.

Prior to study start, the unblinded study statistician will generate a treatment assignment list. This list will detail the treatment (CBD or placebo) for every randomised participant and will be provided to the unblinded pharmacist to be stored securely at the pharmacy with access restricted to the unblinded staff only
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated randomisation schedule will be prepared by an unblinded statistician prior to the start of the study
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
All safety data will be summarised using descriptive statistics (mean, median, standard deviation, minimum and maximum) or frequency counts and percentages, as appropriate to the type of data. Presentation of quantitative safety data will include change from baseline, where baseline will be defined as the last available, valid, non-missing assessment prior to dosing.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
5/09/2018
Actual
6/09/2018
Date of last participant enrolment
Anticipated
Actual
12/10/2018
Date of last data collection
Anticipated
Actual
2/11/2018
Sample size
Target
24
Accrual to date
Final
24
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11062 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 22864 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 299723 0
Government body
Name [1] 299723 0
Victorian State Government
Country [1] 299723 0
Australia
Primary sponsor type
Government body
Name
Victorian State Government
Address
Victorian State Government
Department of Health and Human Services
50 Lonsdale Street
Melbourne Victoria 3000
Australia
Country
Australia
Secondary sponsor category [1] 298980 0
Other
Name [1] 298980 0
Neuroscience Trials Australia
Address [1] 298980 0
Melbourne Brain Centre
245 Burgundy Street
Heidelberg VIC 3084
Country [1] 298980 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300549 0
Alfred Hospital Ethics Committee (EC00315)
Ethics committee address [1] 300549 0
55 Commercial Rd, 
Melbourne VIC 3004
Ethics committee country [1] 300549 0
Australia
Date submitted for ethics approval [1] 300549 0
01/12/2017
Approval date [1] 300549 0
05/12/2017
Ethics approval number [1] 300549 0
308/17

Summary
Brief summary
This study is a Phase 1, randomised, dose escalation, double-blind, placebo-controlled study of cannabidiol (CBD) in healthy volunteers. The study is designed to evaluate the safety, tolerability and pharmacokinetics (PK) of a single dose of Cannabidiol in healthy volunteers.

A total of 24 subjects will be enrolled in this study. Eight subjects in each cohort will be randomised to receive either CBD or placebo in a 3:1 ratio, so that 6 subjects receive CBD and 2 subjects receive placebo:
Cohort 1: 5mg/kg
Cohort 2: 10mg/kg
Cohort 3: 20mg/kg.

Sentinel dosing will be implemented in the first 2 subjects (1 CBD and 1 placebo) of Cohort 1; the rest of the subjects in the cohort will then be dosed if there are no significant safety concerns identified in the sentinel participants within at least the first 24 hours after administration of the oral dose (CBD or placebo). Sentinel dosing may be implemented for subsequent cohorts if deemed appropriate by the Safety Review Committee (SRC).

The study will be conducted at a single study centre. Each participant will be involved in the study for a maximum of 15 days (screening period (up to 28 days); treatment period (3 days); follow-up visits (Days 4, 6 and 8) and telephone contact (Day 15).

The SRC will undertake a dose-escalation review of all available safety data up to Day 8, approximately 2 weeks after the final subject in a cohort has been dosed and prior to subjects commencing the next dose.

The primary objective of the study is to:
• Assess the safety and tolerability of CBD following a single oral dose in healthy volunteers

The secondary objective of the study is to:
• Assess the PK of CBD following a single oral dose in healthy volunteers

The primary endpoints to be evaluated in the study are:
• Safety and tolerability of CBD, including review of:
- adverse events
- vital signs
- 12-lead ECG
- clinical laboratory assessments
- concomitant medications.

The secondary endpoints to be evaluated in the study are:
• The PK of CBD, plasma concentration of CBD and PK parameters including:
- AUClast – area under the plasma concentration versus time curve from time zero to the last quantifiable concentration
- AUCinf – area under the plasma concentration versus time curve extrapolated to infinite time
- Cmax – maximum observed plasma concentration
- Tmax – time of maximum observed plasma concentration
- Kel – apparent terminal elimination rate constant
- T1/2 – apparent terminal elimination half-life

The CBD to be manufactured for this study will be prepared as an oil for oral administration. Dosing will be based on subject body weight and the assigned dose cohort.

The matching placebo will be composed of the same excipients as the study drug (without the CBD).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84026 0
Dr Jason Lickliter
Address 84026 0
Nucleus Network
Level 5 Burnet Building AMREP Precinct
89 Commercial Rd
Melbourne VIC 3004
Country 84026 0
Australia
Phone 84026 0
+ 61 3 9076 8960
Fax 84026 0
+ 613 9076 8911
Email 84026 0
[email protected]
Contact person for public queries
Name 84027 0
Dr Katherine Ong
Address 84027 0
Office of Medicinal Cannabis
Department of Health and Human Services
50 Lonsdale Street, Melbourne VIC 3000
Country 84027 0
Australia
Phone 84027 0
+ 61 3 9096 1760
Fax 84027 0
Email 84027 0
[email protected]
Contact person for scientific queries
Name 84028 0
Dr Katherine Ong
Address 84028 0
Office of Medicinal Cannabis
Department of Health and Human Services
50 Lonsdale Street, Melbourne VIC 3000
Country 84028 0
Australia
Phone 84028 0
+ 61 3 9096 1760
Fax 84028 0
Email 84028 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
Data will not be shared at this time.


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
SourceTitleYear of PublicationDOI
EmbaseA Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers.2020https://dx.doi.org/10.1007/s13318-020-00624-6
N.B. These documents automatically identified may not have been verified by the study sponsor.