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Trial registered on ANZCTR


Registration number
ACTRN12619000443190
Ethics application status
Approved
Date submitted
18/12/2018
Date registered
18/03/2019
Date last updated
18/03/2019
Date data sharing statement initially provided
18/03/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study to evaluate the effect of food on the pharmakokinetics and cardiac function in male and female healthy volunteers who have been administered cannibidiol.
Scientific title
A double-blind, randomized, two-period, two treatment, fixed sequence, crossover (fed versus fasted) study to evaluate the effect of food on pharmacokinetics of CBD with robust ECG monitoring in Healthy Volunteers (HVs)
Secondary ID [1] 296894 0
None
Universal Trial Number (UTN)
KAL07
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Graft Versus Host Disease 310844 0
Condition category
Condition code
Inflammatory and Immune System 309585 309585 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A double-blind, randomized, two-period, two treatment, fixed sequence, crossover (fed versus fasted) study.

The Cannabidiol (CBD) and placebo will be administered orally as a liquid solution according to the pre-determined randomization scheme. The final administration volume for all CBD doses and placebo will be supplied as 6mL/vial (fill volume), where the deliverable volume is 5mL, wherein 4 vials will constitute one dose of either 600mg CBD or 1200mg CBD or placebo

Screening: Days -28 to -2
Fasted Period
Randomization: Days -1 or 1
PK sampling & Holter monitoring/Single Dose Administration: Days 1, 9 and 15
1st Washout: Days 2-8
Multiple Dosing (two times per day): Days 10 to 15
2nd Washout: Days 16 to 29

Fed Period - Subjects crossover to fed period (during Fed period subjects will receive a high calorie meal in the morning, 30 minutes prior to administration of the Investigational Medicinal Product (IMP)
Pharmacokinetic (PK) sampling & Holter monitoring/Single Dose Administration: Days 30, 38 and 44
3rd Washout: Days 31 to 37
Multiple Dosing Administration (two times a day): Days 38-44
End of Study: Day 45
Safety Follow Up: Day 51 (phone call)

Fasted state:
Beginning on Day 1 with a single dose administration. A 7-day washout period will follow. On Days 9 and 15 subjects will be administered the total daily dose (i.e. 600mg, 1200mg or placebo) as a single morning dose after being fasted for a minimum of 10 hours. On Days 10-14 subjects will be administered IMP or placebo twice-daily (BID) with the first daily dose administered post a minimum of 10 hour fast. At least 8 hours should lapse between multiple daily doses (±2 hours). The second daily dose should be administered post a minimum 2-hour fast.14-day washout period will commence post Day 15.

Fed state:
On day 30 subjects will be administered a high calorie/high fat meal 30 minutes prior to receiving a single dose of CBD or placebo. This will be followed by a 7-day washout period. On day 38 subjects will receive a high calorie/high fat meal 30 minutes prior to Cannabidiol (CBD) or placebo dosing. On Days 30 and 38 subjects will receive a single morning dose of IMP or placebo (i.e. 600mg, 1200mg or placebo) 30 minutes after starting the consumption of a high calorie/high fat meal. and continue on this meal and dosing regimen for 7 days (until day 44).

The Phase 1 unit will provide subjects with written email/text reminders of fasting requirements and periods. This is also well documented in the participant information and consent form.
Intervention code [1] 313179 0
Treatment: Drugs
Comparator / control treatment
The control group is Placebo (Olive oil)
Control group
Placebo

Outcomes
Primary outcome [1] 308477 0
Frequency and severity of adverse events (AEs), including clinically significant laboratory abnormalities after administration of the study drug based on vital signs, 12 lead ECGs and physical examinations
Timepoint [1] 308477 0
From time of consent until End of Study/Day 45.
Primary outcome [2] 308478 0
Changes from baseline in QT interval
Timepoint [2] 308478 0
Holter Monitoring assessments on Days 1, 9, 15, 30, 38 & 44
Secondary outcome [1] 355110 0
Changes in CBD bioavailability in fasting and fed conditions
Timepoint [1] 355110 0
The PK of CBD will be determined from plasma and urine specimens in each of the two phases of the study (fasted and fed phases), on Day 1 (72-hours) Day 15 (48-hours), Day 30 (72-hours) and Day 44 (48-hours).

Eligibility
Key inclusion criteria
1. Healthy adult subjects =18 – 60 years of age
2. Body Mass Index (BMI) of 18 to 30 kg/m2 inclusive and a minimum weight of at least 50 kg at screening and not more than 100 kg at screening
3. Non-users of tobacco or nicotine-containing products (minimum of 4 weeks from admission)
4. Subjects with reproductive potential required to practice abstinence or be using and willing to continue using a medically acceptable form of birth control for at least one month prior to screening (at least 3 months for oral contraceptives) and for at least 60 days after the last study drug administration.
5. Free from any clinically significant abnormality based on medical history, vital signs, physical examination, ECG, and laboratory evaluation at screening and admission to the treatment session, as judged by the investigator or designee.
6. Systolic blood pressure between 90 to 140 mmHg and diastolic blood pressure between 50 and 90 mmHg at screening and admission to the treatment session.
7. Male Participants who agree to the following during their participation in this study and for at least 1 month after the last dose of study intervention: Refrain from donating sperm PLUS either:
o Be abstinent from heterosexual [or homosexual] intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR Must agree to use contraception/barrier as detailed below:
o Agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak) when having sexual intercourse with a woman of childbearing potential who is not currently pregnant
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
o Is not a woman of childbearing potential (WOCBP) OR
o Is able to abstain from heterosexual intercourse if it is in keeping with her preferred and usual lifestyle (such as participants with same-sex partners)
OR
o Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), during the intervention period and for at least 30 days plus 30 days (a menstrual cycle) after the last dose of study intervention [and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.]. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
o A WOCBP must have a negative pregnancy test [ serum] as required by local regulations) within [24 hours] before the first dose of study intervention.
9. Subjects must be able to speak, read and understand English sufficiently to understand the nature of the study and provide written informed consent
10. Subjects must be capable of giving signed informed consent and agree to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
11. Subjects must have understood and provided written informed consent prior to initiation of any protocol-specific procedures.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, and renal or other major disease as determined by the Investigator and/or Sponsor’s Medical Monitor
2. Evidence of disease that may influence the outcome of the study within 4 weeks before dosing as determined by the Investigator and/or Sponsor’s Medical Monitor
3. Any history of gastrointestinal surgery that may affect the pharmacokinetic profile of the study drug
4. Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, ECG findings or laboratory test results that requires medical treatment at Screening or Baseline
5. History of any medical condition which, in the opinion of the Investigator, may interfere with study procedures or compromise subject safety (e.g. psychiatric illness, disability or social situation)
6. Known history of clinically significant drug allergy (including to study drugs or any of their excipients) at Screening or Baseline
7. Known history of clinically significant food allergies or presently experiencing significant seasonal or perennial allergy at Screening or Baseline
8. Active viral hepatitis (B or C) and HIV as demonstrated by positive serology at Screening
9. Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones)
10. Alanine transaminase (ALT) >1.5x upper limit of normal (ULD)
11. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if fractionated and direct bilirubin <35%)
12. Persistent systolic blood pressure (BP) > 140 mmHg or < 90 mmHg and diastolic BP >90mmHg or <40mmHg at Screening or Baseline
13. Heart rate <50 or >100 beats/minute at Screening
14. History of prolonged QT/QTc interval
15. A history of risk factors for torsade de pointes or the use of concomitant medications that prolong the QT/QTc interval
16. Corrected QT interval (QTc) >450 milliseconds (msec) (for males) or >470 msec (for females)
• The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or manually over-read
• The specific formula that will be used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the trial.
• For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used
17. A history of additional risk factors for TdP (e.g. heart failure, hypokalemia, family history of Long QT Syndrome)
18. History of myocardial infarction or active ischemic heart disease
19. History of clinically significant arrhythmia or uncontrolled arrhythmia
20. Intake of caffeinated beverages or food within 72 hours before dosing
21. Intake of nutritional supplements, juice, and herbal preparations or other foods or beverages that may affect the various drug metabolizing enzymes and transporters (e.g. grapefruit, grapefruit juice, apple or orange juice, vegetables from the mustard green family) within 1 week before dosing. Alcohol within 72 hours of dosing.
22. Intake of herbal preparations containing St. John’s Wort within 4 weeks before dosing
23. Past or intended use of over-the-counter (OTC) or prescription medications 2 weeks before first dosing unless agreed by the Investigator and Sponsor’s Medical Monitor to not be clinically relevant
24. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study
25. Regular alcohol consumption within 3 months prior to the study defined as:
• An average weekly intake of >14 units for males and females. One unit is equivalent to 8g of alcohol: pot of beer (~240mL), 1 glass (125mL) of wine or 1 (25mL) measure of spirits
26. History of drug or alcohol dependency or abuse within the 2 years before Screening, or who have a positive urine drug or alcohol test at Screening or Baseline
27. Engagement in strenuous exercise within 72 hours before dosing
28. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during the participation in the study.
29. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days preceding informed consent
30. A subject who, in the opinion of the investigator or designee, is not considered to be suitable and is unlikely to comply with the study protocol for any reason.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
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
Crossover
Other design features
Two-period, two treatment, fixed sequence, crossover study.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Sample size is based on the FDA (CDER) Guidance for Industry - Food-Effect Bioavailability and Fed Bioequivalence Studies guidance document. A total of 30 subjects will be randomized to 3 arms (2:2:1):
Arm 1: 600 mg (n=12), Arm 2: 1200 mg (n=12), Arm 3: Placebo (n=6)

All subjects who enrolled in the study and received at least one dose of study drug will be included in the Safety Population. This will be the population for the safety analyses and for summarization of baseline/demographic characteristics.

Adverse events will be coded using the MedDRA classification system. Treatment-emergent AEs will be defined as any AEs, regardless of relationship to investigational product, that occur after the dose of investigational product. All AEs will be summarized by group at AE onset for the overall number of AEs and the percentage of subjects who experience them. The total number of AEs will be summarized by group and overall. Listings for the subsets of SAEs and treatment-related SAEs will be provided. The number of SAEs will be summarized. The incidence of AEs will also be summarized by system organ class and preferred term.

Clinical laboratory results, vital sign measurements (systolic and diastolic blood pressure and heart rate), and 12-lead ECG results will be summarized by change from baseline. Clinical laboratory values that are outside of the reference ranges will be flagged and evaluated for clinical significance by the investigator. Any ECG abnormalities, including but not limited to a QTc greater than 500 msec or increase in QTc from the baseline ECG of greater than or equal to 60 msec, will be summarized by group.

Pharmacokinetic Analyses
Plasma concentration-time data will be analyzed using non-compartmental methods. Based on the individual concentration time data the following parameters will be estimated:
Cmax Maximum plasma concentration
tmax Time of maximum plasma concentration
Tlag Absorption lag-time defined as the time of the first concentration greater than or equal to limit of quantitation (LOQ)
AUC(0-t) The area under the plasma concentration-time curve up to the last quantifiable concentration (LOQ; limit of quantitation) from time of administration (t equals 0) up to the selected interval after dosing, calculated by the linear trapezoidal method
AUC(0-infinity) The area under the plasma concentration-time curve extrapolated to infinity, calculated as: AUC 0-infinity equals AUC0-t + Clast/lamdaz, where Clast is the last measurable concentration
Lamdaz Elimination rate constant determined by linear regression of the terminal points of the ln-linear plasma concentration-time curve

t½ Terminal elimination half-life, defined as 0.693/lamdaz

fu Fraction excreted in urine unchanged

PK data will be listed and may be presented in graphical form and will be summarized descriptively.
The PK parameters (except Tmax and Tlag) will be loge-transformed and separately analyzed using a mixed effects model. For the analysis of repeated CBD effect, the model will include a fixed effect term for treatment (CBD 300mg/600mg/Placebo) and condition (fed versus fasted) and a random effect term for subject. Point estimates and their associated 90% CIs will be constructed for the differences in PK parameter values.
Tmax and Tlag of study treatment will be separately analyzed with the non-parametric Wilcoxon matched pair method to compute point estimates and associated 90% confidence intervals for the median differences between test and reference treatments.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
12/03/2019
Date of last participant enrolment
Anticipated
24/05/2019
Actual
Date of last data collection
Anticipated
31/07/2019
Actual
Sample size
Target
32
Accrual to date
10
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12770 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 25210 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 301465 0
Commercial sector/Industry
Name [1] 301465 0
Kalytera Australia Pty Ltd.
Country [1] 301465 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Kalytera Australia Pty Ltd
Address
Level 4, 68 Georges Terrace
Perth, WA 6000
Australia
Country
Australia
Secondary sponsor category [1] 301169 0
None
Name [1] 301169 0
Address [1] 301169 0
Country [1] 301169 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302200 0
Bellberry Limited
Ethics committee address [1] 302200 0
Ethics committee country [1] 302200 0
Australia
Date submitted for ethics approval [1] 302200 0
18/12/2018
Approval date [1] 302200 0
20/02/2019
Ethics approval number [1] 302200 0

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

Contacts
Principal investigator
Name 89454 0
Dr Jason Lickliter
Address 89454 0
Nucleus Network
5th Floor
Burnet Tower
AMREP Precinct
89 Commercial Road
Melbourne 3004 VIC
Country 89454 0
Australia
Phone 89454 0
+61 3 9089 8226
Fax 89454 0
Email 89454 0
J.Lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 89455 0
Antu Mishra
Address 89455 0
Nucleus Network
5th Floor
Burnet Tower
AMREP Precinct
89 Commercial Road
Melbourne 3004 VIC
Country 89455 0
Australia
Phone 89455 0
+61 3 8593 9259
Fax 89455 0
Email 89455 0
a.mishra@nucleusnetwork.com.au
Contact person for scientific queries
Name 89456 0
Jason Lickliter
Address 89456 0
Nucleus Network
5th Floor
Burnet Tower
AMREP Precinct
89 Commercial Road
Melbourne 3004 VIC
Country 89456 0
Australia
Phone 89456 0
+61 3 9089 8226
Fax 89456 0
Email 89456 0
J.Lickliter@nucleusnetwork.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified participant data included in the Clinical Study report/publication will be made available upon completion of the study.
When will data be available (start and end dates)?
November 2019 - November 2025
Available to whom?
Publicly available for anyone who wishes to access it.
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Via contact request from Sponsor website: https://kalytera.co/contact/


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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