ANZCTR - Registration

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

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]

NCT03522012

Secondary ID [2]

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

neutropenia

thrombocytopenia

Condition category

Condition code

Inflammatory and Immune System

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]

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]

Pharmacokinetics- serum assay for area under concentration-time curve from time 0 (predose) extrapolated to infinity AUC(0-8)).

Timepoint [1]

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]

serum assay for maximum concentration (Cmax)

Timepoint [1]

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]

serum assay for time to reach maximum concentration (tmax)

Timepoint [2]

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]

serum assay for area under concentration-time curve from time 0 (predose) to the last quantifiable data point (AUC(0-t))

Timepoint [3]

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]

serum assay for terminal half-life (t1/2)

Timepoint [4]

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]

serum assay for volume of distribution at steady-state

Timepoint [5]

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]

serum assay for volume of distribution (Vd)

Timepoint [6]

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]

serum assay for systemic clearance (CL)

Timepoint [7]

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]

serum assay for elimination rate constant (Kel)

Timepoint [8]

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]

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]

Day1, 2, 3, 5, 8, 11, 14, 17, 21, 25, 29, 36, 55 after drug infusion

Secondary outcome [10]

Blood samples will be collected for antidrug antibodies(means of the occurrence of antidrug antibodies (ADA))

Timepoint [10]

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

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]

New Zealand

State/province [1]

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Mycenax Biotech Inc.

Country [1]

Taiwan, Province Of China

Primary sponsor type

Commercial sector/Industry

Name

Mycenax Biotech Inc.

Country

Taiwan, Province Of China

Secondary sponsor category [1]

None

Name [1]

None

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Alfred Hospital Ethics Committee

Ethics committee address [1]

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

18/09/2017

Ethics approval number [1]

375/17

Ethics committee name [2]

Health and Disability Ethics Committees

Ethics committee address [2]

Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011

Ethics committee country [2]

New Zealand

Date submitted for ethics approval [2]

Approval date [2]

05/05/2018

Ethics approval number [2]

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

Public notes

Contacts

Principal investigator

Name

Dr Oscar Walsh,

Address

Nucleus Network Ltd
Level 5, 89 Commercial Road
Melbourne, 3004
Australia

Country

Australia

Phone

+ 613 9076 8900

Email

[email protected]

Contact person for public queries

Name

Ruby Lin

Address

4F., No.50-7, Keyan Rd., Zhunan Township, Miaoli County 350, Taiwan 35053

Country

Taiwan, Province Of China

Phone

+886-(0)26558517

Email

[email protected]

Contact person for scientific queries

Name

Miles Yeh

Address

4F., No.50-7, Keyan Rd., Zhunan Township, Miaoli County 350, Taiwan 35053

Country

Taiwan, Province Of China

Phone

+886-(0)37586988#1829

Email

[email protected]

Trial Review

Documents added manually

Documents added automatically