Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000859280
Ethics application status
Approved
Date submitted
16/05/2018
Date registered
22/05/2018
Date last updated
5/11/2018
Date data sharing statement initially provided
5/11/2018
Date results information initially provided
5/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Phase I, Pharmacokinetic, Safety and Tolerability Study in Healthy Volunteers to Evaluate Bioequivalence of LusiNEX and Tocilizumab (EU and US)
Scientific title
Phase I, Double-Blind, Randomized, Three-Arm, Parallel-Group, Pharmacokinetic, Safety and Tolerability Study in Healthy Volunteers to Evaluate Bioequivalence of LusiNEX and Tocilizumab (EU and US)
Secondary ID [1] 294889 0
NCT03522012
Secondary ID [2] 294890 0
LusiNEX-HV-PK-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Elevated liver enzymes 307844 0
neutropenia 307923 0
thrombocytopenia 307924 0
Condition category
Condition code
Inflammatory and Immune System 306886 306886 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tocilizumab

Experimental: LusiNex - 4 mg/kg, single-dose intravenously infusion (Mycenax tocilizumab)

Treatment: Drugs: Tocilizumab
Tocilizumab is a recombinant human monoclonal antibody of the immunoglobulin G1 subclass, directed against the Interleukin-6 ligand specific receptor. By preventing the binding of Interleukin-6 to its receptor, tocilizumab inhibits the biological activity of Interleukin-6. Tocilizumab was approved by the US Food and Drug Administration (4 mg/kg with an increase to 8 mg/kg based upon clinical response) for the treatment of adult patients with moderate to severe active rheumatoid arthritis, who have had inadequate response to one or more tissue necrotizing factor (TNF) antagonist therapies. Tocilizumab is currently approved in 95 countries for the treatment of adult onset moderate to severe rheumatoid arthritis.
Intervention code [1] 301202 0
Treatment: Drugs
Comparator / control treatment
Active Comparator: RoActemra - 4 mg/kg, single-dose IV infusion (RoActemra; tocilizumab marketed in EU )

Active Comparator: Actemra - 4 mg/kg, single-dose IV infusion (Actemra; tocilizumab marketed in US)
Control group
Active

Outcomes
Primary outcome [1] 305883 0
Pharmacokinetics- serum assay for area under concentration-time curve from time 0 (predose) extrapolated to infinity AUC(0-8)).
Timepoint [1] 305883 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.
Secondary outcome [1] 346877 0
serum assay for maximum concentration (Cmax)
Timepoint [1] 346877 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.
Secondary outcome [2] 346878 0
serum assay for time to reach maximum concentration (tmax)
Timepoint [2] 346878 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.
Secondary outcome [3] 346879 0
serum assay for area under concentration-time curve from time 0 (predose) to the last quantifiable data point (AUC(0-t))
Timepoint [3] 346879 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.
Secondary outcome [4] 346880 0
serum assay for terminal half-life (t1/2)
Timepoint [4] 346880 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.
Secondary outcome [5] 346881 0
serum assay for volume of distribution at steady-state
Timepoint [5] 346881 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.
Secondary outcome [6] 346882 0
serum assay for volume of distribution (Vd)
Timepoint [6] 346882 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.
Secondary outcome [7] 346883 0
serum assay for systemic clearance (CL)
Timepoint [7] 346883 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.
Secondary outcome [8] 346884 0
serum assay for elimination rate constant (Kel)
Timepoint [8] 346884 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.
Secondary outcome [9] 346885 0
As tocilizumab have been reported to cause neutropenia, thrombocytopenia and raised transaminases in patients. Laboratory parameters via blood and urine assay will monitored throughout the study.
Safety- The safety evaluation will include vital signs, ECG parameters, clinical safety laboratory tests (hematology, clinical biochemistry, coagulation, urinalysis, and urine microscopy where clinically indicated), Adverse events, physical examination, concomitant medication and injection site evaluations.
Timepoint [9] 346885 0
Day1, 2, 3, 5, 8, 11, 14, 17, 21, 25, 29, 36, 55 after drug infusion
Secondary outcome [10] 346886 0
Blood samples will be collected for antidrug antibodies(means of the occurrence of antidrug antibodies (ADA))
Timepoint [10] 346886 0
pre-infusion (or predose or 0 hour, collected within 1 hour prior to the start of the infusion), at the end of infusion , at 1 , 2 , 6 , 12 hours from the end of infusion, and at 24 hours (Day 2), 48 hours (Day 3), 96 hours (Day 5), 168 hours (Day 8), 240 hours (Day 11), 312 hours (Day 14), 384 hours (Day 17). 480 hours (Day 21), 576 hours (Day 25), 672 hours (Day 29), and 840 hours (Day 36), and at 1296 hours (Day 55, follow-up) from the start of infusion.

Eligibility
Key inclusion criteria
1. Willing to provide written informed consent prior to performing study-related
procedures.

2. Healthy male or female aged between 18 to 55 years, inclusive.

3. A body mass index between 18 to 30 kg/m2, inclusive.

4. Medically healthy with clinically insignificant results (e.g., medical history,
electrocardiograms [ECGs], and physical examination) as judged by the Principal
Investigator at Screening/Day 1 (admission to study center).

5. All laboratory results including, but not restricted to, complete blood counts, liver
function, and lipid profile should be within the normal range or clinically
insignificant as judged by the Investigator at Screening/Day 1 (admission to study
center). An abnormal laboratory result considered to be erroneous, may be repeated
once during Screening at the discretion of the Investigator.

6. Have systolic blood pressure less than or equal to 140 and greater than or equal to 90 mmHg, diastolic blood pressure less than or equal to 90 and greater than or equal to 50 mmHg, and a heart rate greater than or equal to 40 and less than or equal to 100 beats per minute at Screening/Day 1 (admission to study center).

7. Has to agree to abstain from alcohol intake 48 hours before administration of the
study drug and during the inpatient period of the study.

8. Negative urine drug screen/alcohol breathylzer test at Screening/Day 1 (admission to
study center).

9. Non-smokers or social smokers (defined as less than 10 cigarettes per week). No
current use of any nicotine containing product. Cotinine levels =5 ng/mL.

10. Willing to abstain from sexual intercourse or use 2 methods of contraception (both
male and female partners) as defined in the protocol for 3 months after study drug
administration.

Female subjects who are using oral hormonal contraceptives must be willing to use,
with their partner, 2 methods of contraception as defined as defined in the protocol.

11. Has to agree to not donate sperm or ova for at least 3 months after study drug
administration.

12. Subjects who are negative for hepatitis B surface antigen, hepatitis B core antibody,
hepatitis C antibodies, human immunodeficiency virus I and II, as well as tuberculosis
(TB) tests at Screening.

13. Did not receive a blood transfusion within 4 weeks prior to study drug administration,
donate 400 mL or more blood within 8 weeks prior to study drug administration or
donate plasma within 4 weeks prior to study drug administration and agrees to not make blood donations, including red blood cells, plasma, platelets, or whole blood for the duration of the study and for 3 months after study drug administration.

14. Able to be compliant with the protocol and attend all scheduled visits.

15. Has to agree to not consume any caffeine and/or xanthine products from 24 hours before admission to the study center until 48 hours after study drug administration.

16. Not have consumed grapefruit and/or grapefruit containing products, Seville oranges or quinine (tonic water) from 24 hours before admission to the study center until after the last sample has been collected for the study.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Volunteers with any known active current or history of recurrent bacterial, viral,
fungal, mycobacterial or other infections.

2. Have been treated with IV antibiotics for an infection within 8 weeks or oral
antibiotics within 2 weeks prior to Screening.

3. History of TB infection, active TB or latent TB infection, or recent exposure to a
person with active TB.

4. Previous exposure to therapeutic monoclonal antibodies in the past 6 months prior to
Screening.

5. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
antibodies.

6. A history of clinically significant gastrointestinal, renal, hepatic, cardiovascular,
or allergic disease.

7. Evidence of active malignant disease, malignancies diagnosed within the previous 2
years (except basal cell carcinoma of the skin that has been excised and cured), or
breast cancer diagnosed within the previous 2 years.

8. Impaired liver function as determined by:

• Serum alanine aminotransferase and/or aspartate aminotransferase >1.5 x upper limit
of normal (ULN) at Screening or admission to the study center. Subjects with values
between ULN and 1.5 x ULN may be included in the study if considered not clinically
significant by the Investigator.

9. Current or past history of diverticulitis or biliary obstruction.

10. Presence of proteinuria (other than trace amounts i.e., +, ++/+++) at Screening or
admission to the study center.

11. Administration of an investigational product in another study within 30 days or 5
half-lives of the investigational drug (whichever is longer) prior to screening, or
are currently participating in another clinical study of an investigational drug, or
intending to participate in another clinical study of an investigational drug before
completion of all scheduled evaluations in this clinical study.

12. Use of any prescription or over-the-counter medication (with the exception of
contraceptive medication in females and paracetamol) within 7 days of Screening and
for the duration of participation in the study. This includes the use of any NSAIDs
(including aspirin) within 28 days before study drug administration and for the
duration of participation in the study.

13. Intake of herbal drugs or dietary supplements excluding routine vitamins but including
megadose (intake of 20 to 600 times the recommended daily dose) vitamin therapy within
28 days prior to study drug administration, unless agreed as not clinically relevant
by the Investigator and Sponsor.

14. Regular alcohol consumption of >14 (female subjects) or >21 (male subjects) units of
alcohol per week at the time of Screening (1 unit = 150 mL of wine or 360 mL of beer
or 45 mL of 40% alcohol).

15. Failure to satisfy the Principal Investigator of fitness to participate for any other
reason.

16. Female subjects who are pregnant, trying to become pregnant, or lactating.

17. Subjects who have a history of relevant drug hypersensitivity or hypersensitivity to
the active substance or to any of the excipients.

18. Inability to undergo venipuncture and/or tolerate venous access.

19. Subjects who do not agree to use medically acceptable methods of contraception (as
defined in the protocol).

20. Involvement in the planning and/or conduct of the study (applies to the Sponsor,
Contract Research Organizations, and study center staff, etc.).

21. Subjects who are unlikely to co-operate with the requirements of the study.

22. Any live virus vaccination or planned vaccination within 28 days before Screening and
for the duration of 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)
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
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
17/10/2017
Date of last participant enrolment
Anticipated
31/08/2018
Actual
2/08/2018
Date of last data collection
Anticipated
31/12/2018
Actual
Sample size
Target
190
Accrual to date
Final
190
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 10407 0
New Zealand
State/province [1] 10407 0

Funding & Sponsors
Funding source category [1] 299473 0
Commercial sector/Industry
Name [1] 299473 0
Mycenax Biotech Inc.
Country [1] 299473 0
Taiwan, Province Of China
Primary sponsor type
Commercial sector/Industry
Name
Mycenax Biotech Inc.
Address
4F., No.50-7, Keyan Rd., Zhunan Township, Miaoli County 350, Taiwan 35053
Country
Taiwan, Province Of China
Secondary sponsor category [1] 298786 0
None
Name [1] 298786 0
None
Address [1] 298786 0
None
Country [1] 298786 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300379 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 300379 0
Ethics committee country [1] 300379 0
Australia
Date submitted for ethics approval [1] 300379 0
Approval date [1] 300379 0
18/09/2017
Ethics approval number [1] 300379 0
375/17
Ethics committee name [2] 300390 0
Health and Disability Ethics Committees
Ethics committee address [2] 300390 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [2] 300390 0
New Zealand
Date submitted for ethics approval [2] 300390 0
Approval date [2] 300390 0
05/05/2018
Ethics approval number [2] 300390 0
18/CEN/71

Summary
Brief summary
This is a randomized, double-blind, 3-arm, parallel-group single-dose study to compare the
PK, PD, safety, tolerability, and immunogenicity of LusiNEX (Mycenax tocilizumab) versus
RoActemra (EU tocilizumab) and Actemra (US tocilizumab) after a single IV infusion of 4 mg/kg
in healthy volunteers (hereafter referred to as subjects). The therapeutic dose of
tocilizumab starts with 4 mg/kg and ranges to 12 mg/kg, considering 4 mg/kg is the lowest
dose, the same has been selected for the study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83470 0
Dr Oscar Walsh,
Address 83470 0
Nucleus Network Ltd
Level 5, 89 Commercial Road
Melbourne, 3004
Australia
Country 83470 0
Australia
Phone 83470 0
+ 613 9076 8900
Fax 83470 0
Email 83470 0
[email protected]
Contact person for public queries
Name 83471 0
Miss Ruby Lin
Address 83471 0
4F., No.50-7, Keyan Rd., Zhunan Township, Miaoli County 350, Taiwan 35053
Country 83471 0
Taiwan, Province Of China
Phone 83471 0
+886-(0)26558517
Fax 83471 0
Email 83471 0
[email protected]
Contact person for scientific queries
Name 83472 0
Dr Miles Yeh
Address 83472 0
4F., No.50-7, Keyan Rd., Zhunan Township, Miaoli County 350, Taiwan 35053
Country 83472 0
Taiwan, Province Of China
Phone 83472 0
+886-(0)37586988#1829
Fax 83472 0
Email 83472 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
Individual participant data will not publish only statistic and summary data will.


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.