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Trial registered on ANZCTR


Registration number
ACTRN12618001428257
Ethics application status
Approved
Date submitted
20/08/2018
Date registered
27/08/2018
Date last updated
27/02/2020
Date data sharing statement initially provided
24/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of NJA-730 in Healthy Volunteers
Scientific title
A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of NJA-730 in Healthy Volunteers
Secondary ID [1] 295491 0
73001-C111
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute graft-versus-host disease (aGvHD) 308763 0
Condition category
Condition code
Inflammatory and Immune System 307693 307693 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be conducted in 3 parts. Part 1 SAD will include approximately 56 healthy subjects divided into 7 cohorts of 8 subjects each. Subjects in each cohort will be randomized in a 3:1 ratio to receive a single blinded dose of study drug i.e. NJA 730 or placebo, respectively (6 subjects to receive NJA-730 and 2 subjects to receive placebo). Safety and tolerability for each cohort will be assessed by a SRC prior to dose escalation. Available PK data will also be assessed by the SRC prior to dose escalation.
Part 2 MAD of the study will include approximately 24 healthy subjects divided into 3 cohorts of 8 subjects each. This phase will commence after safety data for any dose in the SAD phase has been evaluated irrespective of the highest dose.
Each cohort in Part 1 and Part 2 of 8 subjects per cohort will be randomized in a 3:1 ratio to receive multiple blinded doses of NJA-730 or placebo, respectively, 3 times a week for a 1-week period (total 3 doses). Safety, tolerability, and available PK data will be assessed by the SRC in each dosing cohort prior to dose escalation.
Part 3: an Extension Study will include approximately 24 healthy subjects divided into 4 cohorts of 6 subjects each. Subjects in each cohort will be randomized in a 2:1 ratio to receive a single blinded dose of study drug i.e. NJA-730 or placebo, respectively (i.e. 4 subjects to receive NJA-730 and 2 subjects to receive placebo).
Safety and tolerability for each cohort will be assessed by the SRC prior to dose escalation. Available PK data will also be assessed by the SRC prior to dose escalation.
Mode of administration: Intravenous infusion
Dosing Schedule for SAD Phase:
Cohort 1, N=6 Dose NJA-730 5 µg, N=2 Placebo
Cohort 2, N=6 Dose NJA-730 25 µg, N=2 Placebo
Cohort 3, N=6 Dose NJA-730 75 µg, N=2 Placebo
Cohort 4, N=6 Dose NJA-730 150 µg, N=2 Placebo
Cohort 5, N=6 Dose NJA-730 300 µg, N=2 Placebo
Cohort 6, N=6 Dose NJA-730 450 µg, N=2 Placebo
Cohort 7, N=6 Dose NJA-730 600 µg, N=2 Placebo
The dose administered in the MAD is Dose dependent on results of SAD phase.
Dosing Schedule for Extension Study:
Cohort 8, N=4 Dose NJA-730 1,200 µg, N=2 Placebo
Cohort 9, N=4 Dose NJA-730 2,200 µg, N=2 Placebo
Cohort 10, N=4 Dose NJA-730 4,000 µg, N=2 Placebo
Cohort 11, N=4 Dose NJA-730 Higher dose based on safety, tolerability and available PK of Cohorts 8, 9 or
10, N=2 Placebo
Intervention code [1] 301814 0
Treatment: Drugs
Comparator / control treatment
Placebo will be phosphate-buffered saline solution. The study drugs will be given as 30 mins continuous IV infusion in 100 mL saline in 150 mL saline bags.
Control group
Placebo

Outcomes
Primary outcome [1] 306684 0
To assess safety and tolerability of NJA-730 following escalating single and multiple doses of NJA-730 in healthy volunteers.
Timepoint [1] 306684 0
Safety and tolerability of NJA-730 will be evaluated by clinical laboratory assessments, physical examinations, ECGs and adverse events (AEs) up to at least 45 days in SAD and 60 days in MAD and 32 days in Extension Study for follow-up, until resolution or stabilization.
Secondary outcome [1] 349244 0
To determine pharmacokinetics of NJA-730.
Timepoint [1] 349244 0
For Part 1 (SAD) and Part 2 (MAD), the following PK parameters will be assessed on Day 1: Cmax, Tmax, t1/2, AUC0-tlast, AUC0-inf, Vz/F, apparent terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration vs. time curve, CL/F as well as dose normalise parameters for Cmax, AUC0-inf and AUC0-tlast. Additionally, on Day 1, 3 and 5 for the MAD part of the study the following parameters will be assessed: AUC0-tau, AUC0-tlast, Cmin, Cmax, Tmax, apparent terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration vs. time curve, t1/2, CL/Fss, Vz/Fss as well as dose normalised parameters for Cmax, AUC0-tlast and AUC0-tau. SAD: Blood sampling for PK endpoints at pre-dose prior to IV drug infusion, at the end of infusion (within 2 hours prior to infusion), at the end of infusion (±2 min), at 10 (±2 min), 20 (±3 min), 45 (±5 min) minutes and 1 (±10 min), 1.5 (±10 min), 3 (±10 min), 4 (±15 min), and 8 (±15 min) hours from the end of IV infusion on Day 1. MAD: Blood sampling for PK endpoints at pre-dose prior to IV drug infusion (within 2 hours prior to infusion) on Days 1, 3 and 5, at the end of infusion (±2 min), at 10 (±2 min), 20 (±3 min), 45 (±5 min) minutes and 1 (±10 min), 1.5 (±10 min), 3 (±10 min), 4 (±15 min), and 8 (±15 min) hours from the end of IV infusion on dosing days.
For the Extension Study (Part 3): the following PK parameters will be assessed for the analyte NJA-730 on Day 1: Cmax, Tmax, t1/2, AUC0-tlast, AUC0-inf , Vz/F, apparent terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration vs. time curve, CL/F as well as dose normalize parameters for Cmax, AUC0-8 and AUC0-tlast. Blood sampling for PK endpoints at predose prior to study drug IV infusion (within 2 hours prior to infusion), at the end of infusion (±2 min), at 10 (±2 min), 20 (±3 min), 45 minutes (±5 min), and 1 (±10 min), 1.5 (±10 min), 3 (±10 min), 4 (±15 min), and 8 (±15 min) hours from the end of study drug IV infusion.
Secondary outcome [2] 351022 0
To determine pharmacodynamics of NJA-730.
For Part 1 (SAD) and Part 2 (MAD), CD40 mRNA cleavage and CD40 protein expression. 5’Ribonucleic acid ligase-mediated - rapid amplification of c deoxyribonucleic acid ends (5’RLM-RACE). The effect of NJA 730 will be confirmed by detecting cleavage of cluster of differentiation 40 (CD40) messenger ribonucleic acid (mRNA) using 5’ribonucleic acid ligase-mediated (RLM)-rapid amplification of c-deoxyribonucleic acid ends (RACE). The target RNA will be isolated from peripheral blood mononuclear cells and expanded using polymerase chain reaction (PCR). The PCR products will be identified as cleaved target mRNA. CD40 protein expression. As a result of the target mRNA, cleavage, CD40 protein expression in the target cells will be evaluated using flow cytometry.
For the Extension Study (Part 3), CD40 mRNA cleavage, and CD40 expression by mRNA and/or protein in PBMCs.
CD40 mRNA cleavage. The effect of NJA 730 will be investigated by evaluating cleavage of cluster of differentiation 40 (CD40) messenger ribonucleic acid (mRNA) using 5’ribonucleic acid ligase-mediated (RLM) -rapid amplification of complementary-deoxyribonucleic acid ends (RACE). The target RNA will be isolated from peripheral blood mononuclear cells and expanded using polymerase chain reaction (PCR). The PCR products will be identified as cleaved target mRNA. CD40 expression. The expression of CD40 mRNA will be evaluated by quantitative reverse transcription-PCR (RT-qPCR) and reverse transcriptase PCR (RT-PCR). Efforts will be made to select target cell population either by positive or negative selection. The expression of CD40 protein will be evaluated by flow cytometry using an anti CD40 antibody together with various cell surface markers.
Timepoint [2] 351022 0
SAD: Blood sampling for PD endpoints on Day -1 (pre-dose), Day 2 (24 hours), Day 4 (72 hours) and Day 7 (144 hours) from the end of IV infusion. MAD: Blood sampling for PD endpoints on Day –1 (pre-dose), Day 6 (24 hours), Day 8 (72 hours) and Day 16 (264 hours) from the end of IV infusion. For the Extension Study (Part 3): Blood sampling for PD endpoints at pre-dose., Day 2 (24 hours) and Day 4 (72 hours) from the end of study drug IV infusion.

Eligibility
Key inclusion criteria
A subject will be eligible for study participation if he meets all of the following criteria:
1. Healthy males aged between 18 and 55 years at time of informed consent
2. BMI of 18 kg/m2 to less than or equal to 30 kg/m2 (both inclusive)
3. A resting pulse greater than or equal to 40 bpm and less than or equal to 100 bpm at screening and on Day -1.
4. A resting systolic blood pressure of less than or equal to 140 mmHg and a resting diastolic blood pressure of less than or equal to 90 mmHg at screening and on Day -1.
5. Baseline laboratory test values within reference ranges based on the blood and urine samples taken at screening and on Day -1. Out of normal ranges values may be accepted by the Investigator, if not clinically significant.
6. Non-smoker and/or casual smoker who uses no more than 10 cigarettes (or equivalent quantity of any other nicotine containing products eg, cigars, chewing tobacco, snuff, etc.) per week. Subject must abstain from smoking 3 days prior to admission and throughout the confinement period, and test negative on Day -1 for urine cotinine test. Subject must also abstain from smoking 72 hours prior to each outpatient visit.
7. Male subjects with female partners of childbearing potential must agree to use barrier contraception (i.e. condom) and their female partners must use a highly effective method of contraception (i.e. hormonal contraceptives, or intrauterine contraception) from screening through 90 days after the last dose of study drug. Male subjects who are not sexually active (i.e. abstinent) will not be required to use a contraceptive method unless they become sexually active. Males must also refrain from donating sperm during the study and for 90 days post end of study.
8. Ability to understand and voluntarily give informed consent to communicate well with the Investigator, in the local language, to understand and comply with the requirements of the study and to have signed an informed
consent form in accordance with institutional and regulatory guidelines
9. Ability to remain in the study center for a 4-day period.
10. The subject is, in the opinion of the Investigator,
generally healthy based on assessment of medical history, physical examination, vital signs, electrocardiogram (ECG), and the results of the hematology, clinical chemistry, urinalysis, serology, and other laboratory tests.
Minimum age
18 Years
Maximum age
55 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
A subject will be ineligible for study participation if he meets any of the following criteria:
1. The subject has a history or presence of any clinically significant immunological disorder/disease (such as allergy, atopy, autoimmune diseases, etc.), cardiovascular, thromboembolic events, respiratory, metabolic, renal, hepatic, gastrointestinal, endocrinological (particularly diabetes or pre-diabetes), hematological, dermatological, venereal, neurological, chronic infectious or psychiatric disease or other major disorder. A history of childhood asthma, hay fever or mild eczema may be acceptable at the discretion of the investigator.
2. History of cancer, including any form of skin cancer, which has not been in remission for at least 5 years prior to the first dose of study product.
3. History of abdominal surgery (excluding laparoscopic cholecystectomy or uncomplicated appendectomy) or thoracic or non-peripheral vascular surgery within 6 months prior to the first dose of study product.
4. Current history of asthma and any skin disease. A history of childhood asthma or mild eczema may be acceptable at the discretion of the investigator.
5. The subject's corrected QT interval (QTcF) (Fridericia's correction) is >450 ms at screening and on Day -1. An out-of-range or abnormal ECG should be repeated. In total, 3 ECGs should be recorded consecutively, and the Investigator must evaluate the triplicate ECG. If the subject's QTcF is >450 ms on at least 2 ECGs, the subject must be excluded.
6. Prior exposure to NJA-730 or any other systemic immunosuppressive agent in the last 6 months or 5 half-lives (whichever is longer).
7. The subject has taken prescription or non-prescription medication, herbal remedies, vitamins or minerals within 2 weeks prior to the first dose of study product (or within 5 half-lives prior to the first dose of study product for any
medication ingested, whichever is longer) without approval of the Investigator, NapaJen representative and medical monitor.
8. The subject has taken any investigational products within 30 days prior to the first dose of study product or 5 halflives, whichever is longer. Unless the investigational product is an immunosuppressive agent in which case prior exposure considered is in the last 6 months according to exclusion criteria number 6.
9. The subject has a history of significant hypersensitivity or anaphylaxis involving any drug, food or other precipitating agent (e.g. bee sting).
10. The subject has any abnormal laboratory values that, in the opinion of the primary Investigator, are deemed clinically significant and would preclude participation in the study.
11. The subject has any concurrent illness that may affect the
particular target or absorption, distribution, and elimination of the study product.
12. The subject has had a clinically significant illness within 4 weeks prior to the first dose of study product.
13. Any major surgery or trauma with significant blood loss within the last 3 months prior to the first dose of study product.
14. Blood donation of 500 mL within 3 months prior to the first dose of study product.
15. Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV) at screening.
16. Any history of tuberculosis (TB), whether treated or untreated (and/or a positive QuantiFERON®-TB Gold blood test).
17. Chest x-ray undertaken 3 months prior to screen or at screening showing signs of inflammation, infection or malignancy.
18. A history of recurrent and/or severe infections, including any significant infection in the previous 6 months.
19. The subject has a substance abuse-related disorder or has
a history of drug, alcohol and/or substance abuse deemed significant by the Investigator.
20. Positive screen for drugs of abuse or alcohol at screening and on Day -1.
21. The subject is, in the opinion of the Investigator, unlikely to comply with the clinical study protocol or is unsuitable for any other reason.
22. Employees of the Investigator or study center, as well as first degree family members of the employees or the Investigator.

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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
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)
VIC

Funding & Sponsors
Funding source category [1] 300079 0
Commercial sector/Industry
Name [1] 300079 0
NapaJen Pharma Inc.
Address [1] 300079 0
533 Airport Blvd., #527 Burlingame
CA 94010 USA
PH: 650-685-2429
FAX: 650-401-2221.
Country [1] 300079 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
NapaJen Pharma Inc.
Address
533 Airport Blvd., #527 Burlingame
CA 94010 USA
PH: 650-685-2429
FAX: 650-401-2221.
Country
United States of America
Secondary sponsor category [1] 299483 0
Commercial sector/Industry
Name [1] 299483 0
NapaJen Pharma Co., Ltd.
Address [1] 299483 0
VP 302, 2-24-16 Nakacho, Koganei, Tokyo 184-0012, Japan
Telephone/Fax:+814-231-66773
Country [1] 299483 0
Japan
Other collaborator category [1] 280234 0
Commercial sector/Industry
Name [1] 280234 0
Novotech (Australia) Pty Limited
Address [1] 280234 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 280234 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300926 0
Alfred Health HREC
Ethics committee address [1] 300926 0
55 Commercial Road, Melbourne 3004 VIC
Ethics committee country [1] 300926 0
Australia
Date submitted for ethics approval [1] 300926 0
01/08/2018
Approval date [1] 300926 0
04/09/2018
Ethics approval number [1] 300926 0

Summary
Brief summary
This initial Phase 1 study will be conducted in normal healthy volunteers to gain an unconfounded understanding of the safety, tolerability, pharmacokinetics and pharmacodynamics of NJA-730. NJA-730 is being developed as an immunosuppressive drug for prevention and treatment of acute graft versus host disease associated with allogeneic hematopoietic stem cell transplant.
This first-in-human, randomized, double-blind study will evaluate single ascending doses (SAD) and subsequently multiple ascending doses (MAD) of NJA-730/placebo.
In the SAD part of the study, there will be 7 cohorts of 8 subjects each, with subjects in each cohort randomized in a 3:1 ratio to receive a single blinded dose of study drug i.e. NJA 730 or placebo, respectively (i.e. 6 subjects to receive NJA-730 and 2 subjects to receive placebo).
In the MAD part of the study, there will be 3 cohorts of 8 subjects each with subjects in each cohort randomized in a 3:1 ratio to receive multiple blinded doses of NJA-730 or placebo, respectively, 3 times a week for a 1-week period (total 3 doses).
A third part, an Extension Study (Part 3), will include approximately 24 healthy subjects divided into 4 cohorts of 6 subjects each. Subjects in each cohort will be randomized in a 2:1 ratio to receive a single blinded dose of study drug i.e. NJA-730 or placebo, respectively (i.e. 4 subjects to receive NJA-730 and 2 subjects to receive placebo).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85302 0
Dr Jason Lickliter
Address 85302 0
Nucleus Network Limited, Level 5 Burnet Institute, AMREP Precinct, 89 Commercial Road, Victoria 3004, Australia
Country 85302 0
Australia
Phone 85302 0
+61390768960
Fax 85302 0
Email 85302 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 85303 0
Ms Sofia Cendrawan
Address 85303 0
Project Manager Novotech P.O. Box 117 Carlton South, VIC 3053, Level 2, 15-31 Pelham Street, Carlton, VIC 3053, Australia
Country 85303 0
Australia
Phone 85303 0
+61 3 9341 1904
Fax 85303 0
Email 85303 0
sofia.cendrawan@novotech-cro.com
Contact person for scientific queries
Name 85304 0
Mr Kohji Shimasaki
Address 85304 0
Clinical Development NapaJen Pharma Co., Ltd. VP 302, 2-24-16 Nakacho, Koganei, Tokyo 184-0012
Country 85304 0
Japan
Phone 85304 0
+81423166773
Fax 85304 0
Email 85304 0
k.shimasaki@napajen.com

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