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Trial registered on ANZCTR


Registration number
ACTRN12619000623190
Ethics application status
Approved
Date submitted
20/07/2018
Date registered
26/04/2019
Date last updated
26/04/2019
Date data sharing statement initially provided
26/04/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
An open label, study to evaluate the safety of Cannabidiol (CBD) for the prevention of Acute Graft-Versus-Host Disease (GVHD) after allogeneic hematopoietic cell transplantation.
Scientific title
A Phase 2a, open label, multicenter, study to evaluate the pharmacokinetic (PK) profile, safety and efficacy of multiple doses of Cannabidiol (CBD) for the prevention of Acute Graft-Versus-Host Disease (GVHD) after allogeneic hematopoietic cell transplantation (HSCT)
Secondary ID [1] 295595 0
KAL05
Universal Trial Number (UTN)
U1111-1229-9861
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Graft Versus Host Disease 308909 0
Hematopoietic Stem Cell Transplantation 308910 0
Condition category
Condition code
Cancer 307813 307813 0 0
Other cancer types
Blood 307814 307814 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cannabidiol (CBD), Olive Oil Solution, 1.5% (15 mg/mL CBD)
Cannabidiol (CBD), Olive Oil Solution, 3% (30 mg/mL CBD)
Cannabidiol (CBD), Olive Oil Solution, 6% (60 mg/mL CBD)

Cannabidiol (CBD), dissolved in tocopherol and pharmaceutical grade olive oil, at concentrations of 1.5, 3 or 6%, will be administered orally at doses of 75, 150, or 300 mg twice a day, respectively, beginning on the day of the initiation of conditioning until Day 98 post-Hematopoietic Stem Cell Transplant (HSCT). The administration volume for all doses will be supplied as 5 mL per vial, wherein one dose is contained in a single vial.

36 subjects are planned to be enrolled into this study, distributed among 3 sequential cohorts. The first cohort of 12 subjects will be administered CBD at a dose of 75 mg orally, twice per day. Upon demonstration of safety for the first cohort (after DSMB examination of the safety data), a second cohort of 12 subjects will be administered CBD at a dose of 150 mg orally twice a day. Upon demonstration of safety for the second cohort, a final cohort of 12 subjects will be administered CBD at a dose of 300 mg orally, twice per day. No crossover will be allowed, and subjects will remain in the same dosing study arm until the end of the study. All subjects will receive standard acute GVHD prophylaxis consisting of a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate (MTX) on days 1, 3, and 6 post-HSCT.
All subjects will also receive anti-T cell globulin (ATG, Fresenius, Germany or Grafalon, Switzerland) at a dose of 5 mg/kg daily on Days -3 to -1 (prior to HSCT).

During this preconditioning period, CBD will be administered once at the beginning of the PK study day and then discontinued until the next study visit at Day -6 ± 3 (study visit 2). CBD will be administered at doses of 75, 150, or 300 mg orally twice a day from Days -6 to 98 post-HSCT (except for Day +7/study visit 4, the second PK sampling day, in which only the morning dose will be administered 15 minutes prior to first PK sampling of this visit).

STUDY RELATED ACTIVITIES PER STUDY VISIT:

Visit 0: Day -21 to -7 before HSCT, Baseline/Screening:
Informed consent form signed and countersigned, Inclusion/exclusion determination
Demographics, Physical examination, Medical history
Smoking and alcohol consumption status. NOTE: for alcohol consumption assessment, the following units will be used: number of cups of wine/beer/spirits a subject consumes per week. Lung function testing, Cardiac echocardiography or MUGA, HSCT-CI score evaluation
Concomitant medications (every day for 1 month after HSCT)
Vital signs will include temperature, peripheral arterial blood pressure, heart rate, and respiratory rate. Urine analysis, Biochemistry Panel, Hematology, Coagulation, Fibrinogen,
Reticulocytes & Endocrinology, Serology, including Hepatitis A, B, C Viruses (HAV, HBV, HCV), Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Venereal Disease Research Laboratory test (VDRL), HIV, Human T-Lymphotropic Virus (HTLV), Toxoplasma, Herpes Simplex (I & II). Urine pregnancy test: for all females of childbearing potential
Karnofsky scale assessment, Collect serum for cytokines/biomarkers.

Visit 1: Day -7 (±3) before HSCT, initial PK:
PK sampling day, only a single dose of CBD (i.e. one vial) to be given in the morning will be administered on that Day.
Plasma Sampling: Blood samples will be obtained immediately prior to dosing (Time = 0) and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after dosing of CBD
Urine Sampling: two urine samples (3 mL each) will be obtained: 1) prior to CBD dosing, and 2) as an aliquot derived from a total urine collection in the first 12 hours after CBD dosing.

Visit 2: Day -6, Conditioning and First full CBD Dose:

Physical examination, Concomitant medications, Vital signs, 12 lead ECG, Weight
Laboratory assessments: Biochemistry Panel: Liver Function Tests, Hematology Panel
Safety: AE/SAE assessment and EUPHORIA assessment - Euphoria-related terms to predict potential Abuse-Related Adverse Events in Clinical Studies (the following will be evaluated: euphoric mood, elevated mood, feeling abnormal, feeling drunk, feeling of relaxation, dizziness, thinking abnormal, hallucination)

Visit 3: Day 0 HSCT date: Physical examination, Concomitant medications
Vital signs, 12 lead ECG, Laboratory assessments, Biochemistry Panel: Liver Function Tests,
Hematology Panel, Coagulation, Cyclosporine trough levels, Dispensing and administration
AE/SAE and EUPHORIA assessments, Collect serum for cytokines/biomarkers

Visit 4: Day 7 post-HSCT:
Physical examination, Concomitant medications, Vital signs, Cyclosporine trough levels
GVHD evaluation, Dispensing and administration, AE/SAE and EUPHORIA assessments, PK sampling, Urine sampling

Visit 5: Day 14 post-HSCT: Physical examination, Concomitant medications, Vital signs
Laboratory assessments: Biochemistry, Hematology, CMV testing should start on day 14±3/Visit #5 and be carried out every 14 days, until study visit # 17 inclusively and on study visits 19-21
Cyclosporine trough levels, GVHD evaluation, IMP Dispensing and administration
AE/SAE and EUPHORIA assessments

Visit 6, 8, 10, 12 and 14: Days 21, 35, 49, 63 and 77) post-HSCT:
Physical examination, Concomitant medications, Vital signs, Laboratory assessments
Cyclosporine trough levels, GVHD evaluation, CBD Dispensing and administration
AE/SAE and EUPHORIA assessments, CMV reactivation (PCR)

Visit 7: Day 28, 1M post-HSCT: Physical examination, Concomitant medications
Vital signs, 12 lead ECG, Biochemistry, Hematolog, Cyclosporine trough levels
GVHD evaluation, Donor chimerism evaluation, CBD Dispensing and administration
Karnofsky scale assessment, AE/SAE and EUPHORIA assessments, CMV reactivation (PCR)
Collect serum for cytokines/biomarkers

Visit 9 and 13: Days 42 and 70 post-HSCT:

Physical examination, Concomitant medications, Vital signs, Biochemistry, Hematology, Cyclosporine trough levels, GVHD evaluation, CBD Dispensing and administration
AE/SAE and EUPHORIA assessments, CMV reactivation (PCR)

Visit 11: D56, 2M post-HSCT: Physical examination, Concomitant medications, Vital signs
12 lead ECG, Weight, Biochemistry, Hematology, Coagulation, Cyclosporine trough levels, GVHD evaluation, CBD Dispensing and administration, Karnofsky scale assessment, AE/SAE and EUPHORIA assessments, CMV reactivation (PCR), Collect serum for cytokines/biomarkers

Visit 12-14: Days 63, 70 and 77 post-HSCT: Physical examination, Concomitant medications
Vital signs, Biochemistry Panel, Hematology Panel, Cyclosporine trough levels
GVHD evaluation, CBD Dispensing and administration, AE/SAE and EUPHORIA assessments
CMV reactivation (PCR) at Visit 13/Day 77 ONLY

Visit 15: D84, 3M post-HSCT: Physical examination, Concomitant medications, Vital signs
Weight, Biochemistry, Hematology, Cyclosporine trough levels, GVHD evaluation, CBD Dispensing and administration, AE/SAE and EUPHORIA assessments

Visit 16: Day 91, Last CBD administration: Physical examination, Concomitant medications
Vital signs, 12 lead ECG, Biochemistry, Hematology, Cyclosporine trough levels
GVHD evaluation, CBD Dispensing and administration, AE/SAE and EUPHORIA assessments

Visit 17: Day 98/No IMP dosing:

Physical examination, Concomitant medications, Vital signs, Biochemistry, Hematology, Coagulation, Cyclosporine trough levels, GVHD evaluation, Donor chimerism evaluation in bone marrow or peripheral blood. Karnofsky scale assessment, AE/SAE and EUPHORIA assessments, CMV reactivation (PCR), Collect serum for cytokines/biomarkers

Visit 18: D105, Safety FU: Physical examination, Concomitant medications, Vital signs
Weight, Biochemistry, Hematology, Cyclosporine trough levels, GVHD evaluation
AE/SAE assessment

Visits 19-21: Days 130, 155 and 180, Safety FU:

Concomitant medications, Vital signs, Biochemistry, Hematology, Cyclosporine trough levels, GVHD evaluation, Karnofsky scale assessment, AE/SAE assessment
Intervention code [1] 301895 0
Treatment: Drugs
Intervention code [2] 301894 0
Prevention
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 306818 0
To evaluate the safety and tolerability of repeat doses of CBD for the prevention of aGVHD until Day 98 post HSCT as assessed according to the consensus grading system (Andrew C. Harris et. Al, 2016).
Timepoint [1] 306818 0
180 days post HSCT
Primary outcome [2] 306817 0
To describe the Pharmacokinetic (PK) profile of repeat doses of CBD derived from an analysis of the plasma and urine concentrations of CBD.

The following PK parameters to be calculated:
Cmax Maximum plasma concentration
Tmax Time of maximum plasma concentration
Tlag Absorption lag-time defined as the time of the first concentration = Limit of Quantitation (LOQ)
AUC0-t The area under the plasma concentration-time curve up to the last quantifiable concentration (LOQ) from time of administration (t=0) up to the selected interval after dosing, calculated by the linear trapezoidal method
AUC0-8 The area under the plasma concentration-time curve extrapolated to infinity, calculated as: AUC0-8 = 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
T1/2 Terminal elimination half-life, defined as 0.693/lamdaz
fu Fraction excreted in urine unchanged

Additional PK parameters may be calculated as deemed necessary.

Timepoint [2] 306817 0
Plasma Sampling: Blood samples for PK evaluation will be obtained on Day 7 (±3) before HSCT (study visit 1) immediately prior to dosing of CBD (Time = 0) and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after the dose of CBD. On Study Day 7 (study visit 4), blood samples will be obtained at 15, 30, 45, 60, 120, 180, and 240 min, and 8, 12 and 24 hours after CBD administration. Sampling may commence at any time of the day as long as subjects have fasted for at least 10 hours prior to first PK sample. No food is allowed for the first 4 hours post-dose during the PK sampling. PK sampling should be completed within 24 hours of commencement. Blood samples will be centrifuged immediately at 4°C and then aliquoted and stored at -80°C until analysis.

Urine Sampling: On PK sampling days, two urine samples will be obtained: 1) prior to CBD dosing, and 2) as an aliquot derived from a total urine collection in the first 12 hours after CBD dosing.
Secondary outcome [1] 369505 0
Karnofsky functional status scale
Timepoint [1] 369505 0
Baseline and Day 21, 56, 98, 130, 155 and 180 post HSCT
Secondary outcome [2] 349796 0
To evaluate the effect of repeat oral dosing of CBD on the cumulative incidence of aGVHD between Day 98 and Day 168 as assessed according to the consensus grading system (Andrew C. Harris et. Al, 2016).
Timepoint [2] 349796 0
Day 98 and Day 168 post HSCT
Secondary outcome [3] 349787 0
To evaluate the effect of repeat oral dosing of CBD on the cumulative incidence rates of Grades 2-4 aGVHD by Day 98 after HSCT, as assessed according to the consensus grading system (Andrew C. Harris et. Al, 2016).
Timepoint [3] 349787 0
98 days post HSCT
Secondary outcome [4] 349789 0
To evaluate the effect of repeat oral dosing of CBD on the cumulative incidence rates of Grades 3-4 aGVHD by Day 98 after HSCT, as assessed according to the consensus grading system (Andrew C. Harris et. Al, 2016).
Timepoint [4] 349789 0
98 days post HSCT
Secondary outcome [5] 349794 0
To evaluate the effect of repeat oral dosing of CBD on the time to platelet engraftment after HSCT by assessing the platelet counts via the hematology blood panel
Timepoint [5] 349794 0
Day 98 post HSCT
Secondary outcome [6] 349790 0
To evaluate the effect of repeat oral dosing of CBD on the rate of Non-Relapse Mortality (NRM) by Day 98 after HSCT by assessing the time to deaths without relapse/recurrence as per assessment by the Investigator
Timepoint [6] 349790 0
98 days post HSCT
Secondary outcome [7] 349795 0
To evaluate the effect of repeat oral dosing of CBD on the extent of GVHD free/disease free survival at Day 98 after HSCT by assessing the time to death and/or time of onset of GVHD as assessed according to the consensus grading system (Andrew C. Harris et. Al, 2016).
Timepoint [7] 349795 0
Day 98 post HSCT
Secondary outcome [8] 349792 0
To evaluate the effect of repeat oral dosing of CBD on the time to onset of acute GVHD as assessed according to the consensus grading system (Andrew C. Harris et. Al, 2016).
Timepoint [8] 349792 0
Day 98 post HSCT
Secondary outcome [9] 349791 0
To evaluate the effect of repeat oral dosing of CBD on the rate of full (>95%) donor chimerism in bone marrow/peripheral blood by Days 35 and 105 after HSCT by evaluating the ratio of donor and recipient DNA in the recipients blood or bone marrow.
Timepoint [9] 349791 0
Day 35 and Day 105 post HSCT
Secondary outcome [10] 349793 0
To evaluate the effect of repeat oral dosing of CBD on the time to neutrophil engraftment after HSCT by assessing the neutrophil counts via the hematology blood panel
Timepoint [10] 349793 0
Day 98 post HSCT
Secondary outcome [11] 349797 0
To evaluate the effect of repeat oral dosing of CBD on biomarkers predictive and diagnostic for acute GVHD. This is an exploratory outcome to be assessed via collected serum samples.
Timepoint [11] 349797 0
Day 105 post HSCT

Eligibility
Key inclusion criteria
1. Any malignant hematological disease in CR or Myelodysplastic Syndrome (MDS)
2. Age greater than or equal to 18 years
3. Karnofsky Score (KS) greater than or equal to 60%
4. HSCT-Comorbidity Index (HSCT-CI) score less than or equal to 3
5. No major organ dysfunction
6. Myeloablative or reduced intensity conditioning regimen
7. matched (7/8 or 8/8) unrelated donor
8. Peripheral blood stem cell graft
9. Subject’s written informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Malignant hematological disease, other than MDS, not in CR
2. Myelofibrosis
3. Allogeneic transplantation from a matched or mismatched sibling donor
4. Cord blood transplantation
5. Positive serology for HIV
6. Serious psychiatric or psychological disorders
7. Any uncontrolled infection at time of registration
8. Study subjects must not be pregnant or breastfeeding or planning to become pregnant or breastfeed during the course of the trial, as well as within 30 days after the anticipated date the subjects would complete the study.
9. Active consumption of illicit drugs (such as: Crack cocaine, Heroin, Methamphetamines, Cocaine, Bath Salts, Amphetamines, Methadone, Benzodiazepine, Marijuana, Ecstasy)
10. Use of Cannabis and/or its derivatives fourteen days prior to HSCT and for the duration of study participation
11. QTc greater than 450ms per Friderica's correction and impaired cardiac function or clinically significant cardiac disease
12. Inadequate renal function defined as measured creatinine clearance greater than 2.0 mg/dl
13. Liver enzymes: ALT and AST greater than 3 times the upper limit of normal
14. Pregnant or breastfeeding (positive serum beta-HCG 7 days before first dose)
15. Treatment with another investigational drug, biological agent, or device within 30 days of first dose, or investigational cell therapy within 6 months of first dose..

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Open-label
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
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
13/06/2018
Date of last participant enrolment
Anticipated
30/04/2019
Actual
Date of last data collection
Anticipated
30/10/2019
Actual
Sample size
Target
36
Accrual to date
15
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 13635 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 26303 0
2010 - Darlinghurst
Recruitment outside Australia
Country [1] 10674 0
Israel
State/province [1] 10674 0

Funding & Sponsors
Funding source category [1] 300173 0
Commercial sector/Industry
Name [1] 300173 0
Kalytera Therapeutics Israel Ltd.
Country [1] 300173 0
Israel
Primary sponsor type
Commercial sector/Industry
Name
Kalytera Therapeutics Israel Ltd
Address
Technology Building, Road #4
Katzrin 1290005, Israel
Country
Israel
Secondary sponsor category [1] 299603 0
None
Name [1] 299603 0
Address [1] 299603 0
Country [1] 299603 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301024 0
St Vincent's Hospital HREC (Sydney)
Ethics committee address [1] 301024 0
Ethics committee country [1] 301024 0
Australia
Date submitted for ethics approval [1] 301024 0
09/08/2018
Approval date [1] 301024 0
05/03/2019
Ethics approval number [1] 301024 0
HREC/18/SVH/194

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

Contacts
Principal investigator
Name 85570 0
Dr Keith Fay
Address 85570 0
St Vincent's Hospital Sydney
370 Victoria Road
Darlinghurst NSW 2010
Australia
Country 85570 0
Australia
Phone 85570 0
+61 2 93555656
Fax 85570 0
Email 85570 0
keith.fay@svhs.org.au
Contact person for public queries
Name 85571 0
Toula Papadodimitrakis
Address 85571 0
Salzman Group CRO
270 Ferntree Gully Road
Notting Hill
Vic 3168
Country 85571 0
Australia
Phone 85571 0
+613 8375 7156 ext 2601
Fax 85571 0
Email 85571 0
toula@salzgrp.com
Contact person for scientific queries
Name 85572 0
Toula Papadodimitrakis
Address 85572 0
Salzman Group CRO
270 Ferntree Gully Road
Notting Hill
Vic 3168
Country 85572 0
Australia
Phone 85572 0
+613 8375 7156 ext 2601
Fax 85572 0
Email 85572 0
toula@salzgrp.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the participant data collected during the trial, after de-identification
When will data be available (start and end dates)?
Immediately following study publication and Clinical Study Report finalization and for 5 years post marketing application
Available to whom?
Anyone who wishes to access it
Available for what types of analyses?
Only to achieve the aims in the approved proposal, for CBD meta-analyses
How or where can data be obtained?
Web access via Sponsor's website:
https://kalytera.co


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.