Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000663853
Ethics application status
Approved
Date submitted
26/02/2021
Date registered
1/06/2021
Date last updated
14/07/2024
Date data sharing statement initially provided
1/06/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
A single dose phase 1 study to evaluate safety and Pharmacokinetics of three tocilizumab products in normal healthy volunteers
Scientific title
A Single Dose, Double-Blind, Two-Period, Crossover, Comparative Pharmacokinetic Study of Three Tocilizumab Products Administered by the Subcutaneous Route to Normal Healthy Volunteers
Secondary ID [1] 303351 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid arthritis (RA) 320614 0
Giant Cell Arteritis (GCA) 320616 0
Condition category
Condition code
Inflammatory and Immune System 318465 318465 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study consists of two intervention periods. Subjects will be randomised 1:1:1 to one of the three possible treatment pairs (DRL_TC & RP, DRL_TC & RMP or RMP & RP) and immediately thereafter to one of the two possible sequences for the pair (e.g. for the DRL_TC & RMP pair to receive DRL_TC on Day 1 (Period I) and RMP on Day 1 (Period II) or RMP on Day 1 (Period I) and DRL_TC on Day 1 (Period II). All the 3 (DRL_TC/RP/RMP) contain Tocilizumab.
Consequently, each subject will receive two of the following three treatment regimens: DRL_TC (162 mg/0.9 mL); RP (162 mg/0.9 mL); RMP (162 mg/0.9 mL) during the study.

DRL_TC /RP/RMP: will be given as single subcutaneos injection in the upper arm on day 1 during Period 1 and day 1 during period 2.
Participants will be randomized to either of the 3 IP's (DRL_TC/Actemra/RoActemra) on day 1 and then further randomized to one of the 2 sequences after this (eg if DRL_TC (out of the 3 options available) given during Period 1 then during period 2 on day 1-either participant will be dosed with RP or RMP.
Period I consist of 42 days and Period II consist of 42 days. But during washout period there is flexibility up to 9 weeks (63 days)
Site will be responsible for adherence to the intervention. 2-3 attempts will be made to contact the participants via phone if not booked for dosing during period 2.
Intervention code [1] 319664 0
Treatment: Drugs
Comparator / control treatment
Actemra (RP) and RoActemra (RMP)
Control group
Active

Outcomes
Primary outcome [1] 326430 0
To demonstrate pharmacokinetic (PK - AUC0-8, AUC0-t and Cmax) similarity of DRL_TC versus Actemra® (RP) after administration of a 162 mg single SC dose.
Timepoint [1] 326430 0
A total of 39 blood samples (3.5 ml each) will be collected in Period I and Period II to assess the pharmacokinetic parameters.
Pre-dose (0) samples will be collected within 1 hour prior to the study drug administration on Day 1.
Post dose samples will be collected at 2 h, 8 h and 24 h after the dosing, 36 h, 48 h, 60 h and 72 h, 84 h 96 h during housing period and ambulatory samples on Day 6 (120 h), Day 7 (144 h), Day 9 (192 h), Day 11 (240 h), Day 15 (336 h) and on Days 18, 22, 29, 36 during both periods and Day 43 of Period II.
Note: If check in time for Period II is different from Day 42, it would oblige to an additional PK sample at Day 43 (1008h) of Period I ± 4 hours for those subjects
Primary outcome [2] 327678 0
To demonstrate pharmacokinetic (PK - AUC0-8, AUC0-t and Cmax) similarity of DRL_TC versus RoActemra® (RMP) after administration of a 162 mg single SC dose.
Timepoint [2] 327678 0
A total of 39 blood samples (3.5 ml each) will be collected in Period I and Period II to assess the pharmacokinetic parameters.
Pre-dose (0) samples will be collected within 1 hour prior to the study drug administration on Day 1.
Post dose samples will be collected at 2h, 8h and 24h after the dosing, 36h, 48h, 60h and 72h, 84h 96h during housing period and ambulatory samples on Day 6 (120 h), Day 7 (144 h), Day 9 (192 h), Day 11 (240 h), Day 15 (336 h) and on Days 18, 22, 29, 36 during both periods and Day 43 of Period II.
If the check in time for Period II is different from Day 42, it would oblige to an additional PK sample at Day 43 (1008h) of Period I ± 4 hours for those subjects.
Primary outcome [3] 327679 0
To demonstrate pharmacokinetic (PK - AUC0-8, AUC0-t and Cmax) similarity of Actemra® (RP) versus RoActemra® (RMP) after administration of a 162 mg single SC dose.
Timepoint [3] 327679 0
A total of 39 blood samples (3.5 ml each) will be collected in Period I and Period II to assess the pharmacokinetic parameters.
Pre-dose (0) samples will be collected within 1 hour prior to the study drug administration on Day 1.
Post dose samples will be collected at 2h, 8h and 24h after the dosing, 36h, 48h, 60h and 72h, 84h 96h during housing period and ambulatory samples on Day 6 (120 h), Day 7 (144 h), Day 9 (192 h), Day 11 (240 h), Day 15 (336 h) and on Days 18, 22, 29, 36 during both periods and Day 43 of Period II.


If the check in time for Period II is different from Day 42, it would oblige to an additional PK sample at Day 43 (1008h) of Period I ± 4 hours for those subjects.
Secondary outcome [1] 391468 0
To assess the safety and tolerability of the administered dose of DRL_TC, Actemra, and RoActemra
Timepoint [1] 391468 0
Safety laboratory investigations:

12-lead ECG will be recorded at screening, on the day of check-in, with in 1 hour prior to dosing as well as 15 minutes after dosing with a window period of +/- 5 minutes
on Day 1 ,Day 5 of both periods and EOS (Day 43 of Period II). A 12-lead ECG is to be recorded at 72h after dosing in both the periods also.

Fasting (approximately 10 hours) blood samples will be collected for performing laboratory investigations, following laboratory parameters will be evaluated at respective evaluations:

Screening and EOS (after 10 h fasting) : Safety Laboratory Panel 1 assessment i.e. Total blood count including hemoglobin, hematocrit, mean corpuscular volume, leukocyte counts (total and differential), and platelet count; clinical chemistry including urea, creatinine, uric acid, glucose, ALT, AST, total bilirubin (and direct if increased), sodium, potassium, chloride, calcium, total proteins, albumin, and LDH; coagulation tests (aPTT and INR); thyroid hormones (T3, T4 and TSH); lipid profile (including total, LDL and HDL cholesterol as well as triglycerides) and urine evaluation with dipstick (confirmation with microscopic examination, if abnormalities are found)

On EOS, Quantiferon- TB Gold test will be performed for all subjects.

On the day of check-in Day-1 and on Days 2 , 5 , 15 (after 10 h fasting) for both the period : -Safety Laboratory Panel 2 assessment i.e. Total blood count; clinical chemistry including urea, creatinine, uric acid, glucose, ALT, AST, total bilirubin (and direct if increased), sodium, potassium, chloride, calcium and LDH; coagulation tests (aPTT and INR); lipid profile (as in Screening) and urine evaluation with dipstick (confirmation with microscopic examination if abnormalities are found).

On Days 9 , Day 29 for both the period : Safety Laboratory Panel 3 assessment i.e. Total blood count; clinical chemistry including urea, creatinine, uric acid, glucose,ALT, AST, total bilirubin (and direct if increased), sodium, potassium, chloride, calcium and LDH; coagulation tests (aPTT and INR); lipid profile (as in Screening) and urine evaluation with dipstick (confirmation with microscopic examination if abnormalities are found).

AEs will be monitored throughout the study duration. For all those subjects who will be followed up for anti-drug antibodies at 3 monthly intervals (starting from Day
90 post the second dose) until 2 consecutive negative results or one year post-dose, whichever is earlier), all ongoing AEs need to be monitored.
Adverse events can be reported or elicited during open-ended questioning, examination, or evaluation of a subject.

Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at Screening and significantly worsen following the study drug administration will be reported as AEs or SAEs.



The Investigator establish a diagnosis of the event based on signs, symptoms, and/or other clinical information.



The Investigator makes an assessment of intensity for each AE and SAE reported during the study. The assessment of intensity will be based on the CTCAE v-5.0 or the latest applicable version.



The Investigator assess the relationship between the study medication and the occurrence of each AE/SAE, and categorize the relationship to the study drug either as;

Related: There is a reasonable causal relationship between the study drug administered and the AE;

Not Related: There is no reasonable causal relationship between the study drug administered and the AE
Secondary outcome [2] 392059 0
To comparatively assess the immunogenicity of the administered dose of DRL_TC, RP, and RMP.
Timepoint [2] 392059 0
Blood samples for immunogenicity assessment will be collected at pre-dose (within 1 hours) prior to drug administration on Day 1, Days 15, 29 of period I and Period II and at the EOS .


Subjects positive at Day 29 and/or at EOS (Day 43) of Period II will be followed up for anti-drug antibodies at 3 monthly intervals (starting from Day 90 post the second dose) until 2 consecutive negative results or one year post-second dose, whichever is earlier.
Secondary outcome [3] 392060 0
To evaluate pharmacodynamics in terms of the changes from baseline to selected time-points of IL-6
Timepoint [3] 392060 0
Blood samples for PD assessments (IL-6) will be collected at the day before each dose (i.e., on Day -1) in both the periods. Post dose samples will be collected on Days 2 (24 h), 5 (96 h) 15 (336 h) for both the period.
Secondary outcome [4] 392061 0
To evaluate pharmacodynamics in terms of the changes from baseline to selected time-points of hsCRP: change from pre-dose to selected time-points post-dose;
Timepoint [4] 392061 0
Analysis for hsCRP will be done from safety blood samples will be collected at the day before each dose (i.e., on Day -1) in both the periods. Post dose samples will be collected on Days 2 (24 h), 5 (96 h) 15 (336 h) for both the period.
Secondary outcome [5] 392062 0
To evaluate changes in neutrophil count from pre-dose to the different evaluations (with special emphasis on the Day 5 and Day 48 samples) expressed as a percent of the individual subject baseline count
Timepoint [5] 392062 0
Analysis for neutrophil count will be done from safety blood samples will be collected at the day before each dose (i.e., on Day -1) in both the periods. Post dose samples will be collected on Days 2 (24 h), 5 (96 h) 15 (336 h)for both the period.
Secondary outcome [6] 392063 0
To evaluate changes in lipid parameters from baseline to the different time-points post-dose will also be evaluated as a PD endpoint;
Timepoint [6] 392063 0
Analysis for lipid profile will be done from safety blood samples will be collected at the day before each dose (i.e., on Day -1) in both the periods. Post dose samples will be collected on Days 2 (24 h), 5 (96 h) 15 (336 h) for both the period.
Secondary outcome [7] 392064 0
Comparative incidence, (and if present, titer and neutralizing capacity) of anti-tocilizumab antibodies towards immunogenicity assessment.
Timepoint [7] 392064 0
Blood samples for immunogenicity assessment will be collected at pre-dose (within 1 hour ) prior to drug administration on Day 1, Day 15, 29 of both the periods and at the EOS visit post dose. Subjects positive at Day 29 and/or at EOS (Day 43) of Period II will be followed up for anti-drug antibodies at 3 monthly intervals (starting from Day 90 post the second dose) until 2 consecutive negative results or one year post-second dose, whichever is earlier.

Eligibility
Key inclusion criteria
1. Healthy male and female volunteers, 18 to 50 years of age at the time of signing informed consent.
2. In general good health as determined by a qualified physician based on a comprehensive medical history, physical examination including vital signs, laboratory haematology, clinical chemistry, urinalysis and 12-lead ECG during screening.
3. Body mass index (BMI) between 18.5 and 30.0 kg/m2 and body weight between 50 and 100 kg (both inclusive).
4. Screening parameters (vital signs, physical examination, clinical laboratory tests, 12-lead ECG, chest x-ray, thyroid function etc.) are within the normal range or if outside the normal range, assessed as clinically non-significant by the Investigator (unless the value constitutes an explicit exclusion criterion).
5. Male volunteers must be willing to abstain from sexual intercourse, sperm donation or willing to use in all relationships with a partner from the opposite sex a condom for the male partner and another effective method of contraception (such as an intra-uterine device, vaginal ring, oral contraceptive, injectable progesterone, or sub-dermal implant) for the female partner from the time of dosing until 3 months after the last dosing date, unless one of the partners is medically confirmed to be either infertile or surgically sterile.
6. Female volunteers should be either post-menopausal or surgically sterile
Note: (“Postmenopausal” is defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone levels >40 mIU/ml, or 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy)
7. Capable, and amenable, to provide written informed consent to the study requirements.
8. Willing to abide by study restrictions for the entire study duration.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Positive test result for Quantiferon-TB Gold test, syphilis, hepatitis B, hepatitis C, or HIV-1 or 2.
2. Any prior exposure to tocilizumab or to any other agent directly acting on interleukin-6 or on its receptors including investigational products (e.g. siltuximab, sarilumab etc.).
3. Live virus vaccination within 3 months prior to screening or intention to receive live virus vaccination during the trial or up to 3 months after the administration of the study drug.
4. Administration of immunoglobulins for anti-tetanus and antirabies post-exposure prophylaxis within 3 weeks prior to administration of study drug.
5. History of immunodeficiency or other clinically significant immunological disorders, or auto-immune disorders, ongoing or frequent/ recurring infection defined as more than 3 per year requiring treatment or prior herpes zoster not fully healed (including the post-herpetic neuralgia period if occurring) within one year prior to randomization or history of systemic fungal infection at any time.
6. Allergy, or hypersensitivity to any recombinant human, or humanized antibodies, other therapeutic proteins, or any excipients in the study formulations.
7. Current manifestation of clinically significant (in the opinion of the Investigator) atopic allergy (e.g., asthma including childhood asthma currently showing clinical manifestations, urticaria, angioedema, eczematous dermatitis), hypersensitivity, or allergic reactions.
8. Non-suitable skin for dosing or post-dosing evaluations of upper arm (same arm to be used as the injection site in the both periods) for any reasons (including presence of tattoos, skin pigmentation disorders, scarring etc., which may obscure the injection site).
9. Blood donation, participation in any study requiring repeated blood sampling or haemorrhage requiring treatment or any transfusion in the past 3 months.
10. Screening blood pressure higher than 140 mm Hg (systolic) or higher than 90 mm Hg (diastolic) or volunteers currently on anti-hypertensive drugs. Up to two repeats on different days are allowed and, in this case, the mean of the measurements will be used to decide on eligibility. Screening blood pressure is to be measured in the sitting position after 5 minutes rest.
11. History of relevant orthostatic hypotension, fainting spells, or blackouts deemed in the opinion of the Investigator to pose clinical risk to the subjects.
12. QTc (Fridericia correction) longer than 450 milliseconds or other clinically relevant ECG abnormalities such as atrial fibrillation, atrial flutter, Wolf-Parkinson-White syndrome, or presence of a cardiac pacemaker.
13. History or presence of any clinically relevant nervous system disease including, but not restricted to any stroke/TIA (Transient Ischemic Attack), or of seizures other than febrile seizures before the age of 5 years.
14. History of and/or current gastrointestinal, renal endocrine, pulmonary, hepatic, cardiovascular (including history of or presence of angina, exertional dyspnoea, orthopnoea, congestive heart failure or myocardial infarction and thrombotic or embolic episode requiring treatment), hematological (including pancytopenia, aplastic anemia or blood dyscrasia and coagulopathies, or an INR higher than 1.5), metabolic (including known diabetes mellitus) considered as significant by the Investigator. This criterion includes any disorder or condition that, in the Investigator’s opinion, may interfere with the safety of the subject, the study evaluations or the subject compliance to the study procedures and limitations.
15. ALT or AST higher than 1.25 times the ULN at screening.
16. Neutrophil count below 2 x 109/liter (2,000 per mm3) or platelet count below 100 x 109/liter (100,000 per mm3) at screening.
17. Clinically relevant hyperlipidemia (fasting serum LDL-cholesterol higher than 190 mg/dL or fasting serum triglycerides higher than 200 mg/dL or subject currently on antihyperlipidemic drugs).
18. Any active infection, even if minor, ongoing at the time of screening or dosing.
19. Presence of any non-healed wound or bone fracture of a clinically relevant size (in the Investigator’s opinion).
20. Participation in an interventional or Phase I study in the last three months, or on, or participation in more than 3 studies of experimental drug products in the past 12 months, or intake of an investigational drug in another trial within 3 months or 5 half-lives (whichever is longer) prior to intake of study drug in this trial or planned intake of an investigational drug (any drug administered in a clinical trial setting is considered an investigational drug) or follow up visit scheduled from any study during the course of this trial or intake for any reason in the last 6 months of some specific long body residence drugs such as any immunoglobulin or antibody drug (except for post-exposure prophylaxis of tetanus or rabies given more than 3 weeks before the date of the first study drug dose) pirimethamine, teicoplanin, systemic retinoids, mefloquine and hydroxychloroquine.
21. History of any cancer, including carcinoma in situ, lymphoma or leukemia.
22. History of, or current intestinal ulceration or diverticulitis.
23. Major surgery within the past 12 months, major surgery planned within 12 months of study enrolment or any surgery including dental interventions planned within 3 months of study enrolment.
24. Intake of any medication including herbal products within 3 weeks prior to dosing other than for the exceptions detailed in Section 10.2-Prior and Concomitant Medications.
25. Current smokers or those who gave up smoking less than 3 months prior to screening, (thus 3 months cessation required at screening time), including alternative tobacco products such as chewing tobacco and vaping, or positive urine cotinine test at screening.
26. Positive test for alcohol in breath or drugs of abuse (including benzodiazepines, amphetamines, barbiturates, cocaine, methadone, phencyclidine 3,4-methylenedioxymethamphetamine [MDMA/ecstasy], tetrahydrocannabinol, and opiates) in urine.
27. Any history of difficulty in blood sampling or any vasovagal attack during blood sampling which in the opinion of the Investigator may relevantly interfere with the study sampling.

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)
Central randomisation by Computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects eligible for study will be randomized to receive (DRL_TC & RP; DRL_TC& RMP or RMP & RP) in 1:1:1 proportion and there after 1:1 proportion to one of the two possible sequence for the pair by IRTS (Interactive Response Technology System).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
Subjects eligible for study will be randomized to receive (DRL_TC & RP; DRL_TC & RMP or RMP & RP). Study subjects will be randomly assigned in a 1:1:1 ratio to one of the comparisons and within each comparison subjects will be randomized in a 1:1 ratio to one of the two possible product sequences. IRTS(Interactive Response Technology System) will be used to randomize subjects.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
31/05/2021
Date of last participant enrolment
Anticipated
Actual
21/03/2022
Date of last data collection
Anticipated
14/06/2022
Actual
4/05/2023
Sample size
Target
300
Accrual to date
Final
300
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment outside Australia
Country [1] 23476 0
New Zealand
State/province [1] 23476 0
Auckland, Christchurch
Country [2] 24826 0
India
State/province [2] 24826 0
Karnataka

Funding & Sponsors
Funding source category [1] 307767 0
Commercial sector/Industry
Name [1] 307767 0
Dr. Reddy’s Laboratories Ltd., Biologics
Country [1] 307767 0
India
Primary sponsor type
Commercial sector/Industry
Name
Dr. Reddy’s Laboratories Ltd., Biologics
Address
Survey No. 47, Bachupally Village,
Bachupally Mandal,
Medchal Malkajgiri District,
Telangana, India - 500 090
Country
India
Secondary sponsor category [1] 308470 0
Commercial sector/Industry
Name [1] 308470 0
INCResearch Australia Pty Ltd
Address [1] 308470 0
159 Port Road, Hindmarsh SA 5007
Country [1] 308470 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307790 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 307790 0
Ethics committee country [1] 307790 0
Australia
Date submitted for ethics approval [1] 307790 0
22/02/2021
Approval date [1] 307790 0
22/04/2021
Ethics approval number [1] 307790 0
Ethics committee name [2] 307925 0
Northern B Health and Disability Ethics Committee
Ethics committee address [2] 307925 0
Ethics committee country [2] 307925 0
New Zealand
Date submitted for ethics approval [2] 307925 0
18/02/2021
Approval date [2] 307925 0
22/03/2021
Ethics approval number [2] 307925 0

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

Contacts
Principal investigator
Name 108502 0
Dr Kristi Mclendon
Address 108502 0
Q-Pharm
300c Herston Road
Herston QLD 4006
Country 108502 0
Australia
Phone 108502 0
+61 7 3707 2700
Fax 108502 0
+61 7 3845 3637
Email 108502 0
[email protected]
Contact person for public queries
Name 108503 0
Rajesh CN
Address 108503 0
Dr. Reddy's Laboratories, Sy No - 47, Bachupally Village, Bachupally Mandal, Medchal-Malkajgiri District, Hyderabad, Telangana - 500090, India
Country 108503 0
India
Phone 108503 0
+917995015140
Fax 108503 0
Email 108503 0
[email protected]
Contact person for scientific queries
Name 108504 0
Dr. Shalu Kasliwal,
Address 108504 0
Dr. Reddy's Laboratories, Sy No - 47, Bachupally Village, Bachupally Mandal, Medchal-Malkajgiri District, Hyderabad, Telangana - 500090, India
Country 108504 0
India
Phone 108504 0
+917993355300
Fax 108504 0
Email 108504 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
As this is a Phase 1 study, only aggregate data may be posted/published


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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