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Trial registered on ANZCTR


Registration number
ACTRN12616000138482
Ethics application status
Approved
Date submitted
18/01/2016
Date registered
5/02/2016
Date last updated
18/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A study looking at the safety and effect of two kinds of Itolizumab in Normal Healthy Subjects.
Scientific title
A Randomized, Double Blind, Placebo Controlled, Single Ascending Dose, Phase I Study of Itolizumab (Bmab 600) Administered Subcutaneously and a Randomized, Partial Blind, Placebo-controlled, Comparative Pharmacokinetic and Safety Study of Two Formulations of Itolizumab Administered Intravenously and a Bioavailability Assessment of Subcutaneous Administration of Itolizumab (Bmab 600) in Normal Healthy Subjects
Secondary ID [1] 288046 0
Bm600-NHV-01-G-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Psoriasis 296909 0
Rheumatoid arthritis 296910 0
Multiple Sclerosis 297166 0
Condition category
Condition code
Inflammatory and Immune System 297146 297146 0 0
Rheumatoid arthritis
Skin 297384 297384 0 0
Dermatological conditions
Neurological 297385 297385 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Itolizumab (Bmab 600)
In Stage 1 -escalating single doses administered subcutaneously at 0.8, 1.6, 2.4 and 3.2 mg/kg dose levels.
In Stage 2 – single dose of 0.8mg/kg administered subcutaneously or intravenous infusion at 0.8 mg/kg dose level over 2 hours

Itolizumab (NS0)
Stage 2- single dose administered as intravenous infusion at 0.8 mg/kg dose level over 2 hours.

All doses will be administered in the clinic by study staff.
Intervention code [1] 293367 0
Treatment: Drugs
Comparator / control treatment
Stage 1- Itolizumab (Bmab 600) Placebo
Stage 2- Itolizumab NS0 is comparator and
Itolizumab (Bmab 600) Placebo

Placebo is the same formulation without the active substance (water, sucrose, histidine, polysorbate)


Stage 2 - Itolizumab (Bmab 600) Placebo
Control group
Placebo

Outcomes
Primary outcome [1] 296790 0
To evaluate the safety and tolerance of ascending, single doses of Itolizumab (Bmab 600) administered subcutaneously in normal healthy subjects.
This will be assessed by monitoring adverse events, physical examination findings including injection site reactions, vital signs, laboratory parameters and electrocardiogram.
Timepoint [1] 296790 0
For Stage 1, subjects will be assessed at Day 1-5, 8, 11, 15, 29, 43 and Day 57.
For Stage 2, Day 1-5, 6, 8, 11, 15, 29, 43, 57 and Day 75
Primary outcome [2] 296791 0
To compare the pharmacokinetics (PK) of Itolizumab NS0 and Bmab-600 administered intravenously.
This will be assessed by collecting and analysing blood samples for drug concentrations at various time points.
PK parameters include: Cmax, AUC, Tmax, T1/2
Timepoint [2] 296791 0
Collection of blood samples at various time points (pre-dose, 1, 1.5, 2, 2.5, 4, 6, 12, 24 hours and Days 3, 4, 5, 6, 8, 11, 15, 29, 43, 57 and 75)
Secondary outcome [1] 319365 0
To characterize the pharmacokinetic (PK) profile of single doses of Itolizumab (Bmab-600) administered subcutaneously.
This will be assessed by collecting and analysing blood samples for Bmab 600 drug concentrations at various time points.
PK parameters include: Cmax, AUC, Tmax, T1/2
Timepoint [1] 319365 0
Collection of blood samples at various time points (pre-dose, 2, 4, 8, 12, 24 hours and Days 3, 4, 5, 8, 11, 15, 29, 43, 57 and 75).
Secondary outcome [2] 319366 0
To evaluate immunogenicity of single doses of Itolizumab (Bmab 600) administered subcutaneously.
This will be assessed by analysing blood samples for anti-drug antibodies.
Timepoint [2] 319366 0
Collection of blood samples at various time points (Days 1, 8, 29, 57 and 75)
Secondary outcome [3] 319367 0
To determine the absolute bioavailability of Itolizumab (Bmab 600) administered subcutaneously.
This will be assessed by analysing blood samples for drug levels and comparing exposure (AUC) after subcutaneous and intravenous administration.
Timepoint [3] 319367 0
Collection of blood samples at various time points (pre-dose, 1, 1.5, 2, 2.5, 4, 6, 12, 24 hours and Days 3, 4, 5, 6, 8, 11, 15, 29, 43, 57 and 75)

Eligibility
Key inclusion criteria
1. Male or female between 18 and 50 years of age (inclusive).
2. Healthy with no clinically significant medical problems.
3. BMI between 18 to 30 kg/m2 with weight between 50 to 100 kg (both inclusive).
4. No history of alcohol or drug abuse (Paracetamol, Barbiturates, Benzodiazepines, Cocaine, Methadone, Amphetamines, Methamphetamines, Opiates, Phencyclidine, Tetrahydrocannabinol (cannabis), Tricyclic Antidepressants). Subjects should be enrolled only after passing the urine drug screen (positive test for paracetamol will be allowed).
5. Non smokers or light smokers (Less than 5 cigarettes per day) by history and planned during study.
6. No history of significant allergic diathesis such as urticaria, angioedema or anaphylaxis.
7. No prior exposure to Itolizumab or other biologicals including monoclonal antibodies, fusion proteins etc.
8. Willing and able to sign written, informed consent.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Any significant past or current cardiac, pulmonary, hepatic, renal or other medical condition which in the opinion of the investigator would make participation of the subject in this study medically unsafe or compromise the accuracy of assessment of safety, pharmacokinetic and pharmacodynamic data of the study.
2. Subjects who have abnormal safety labs outside the local lab ranges will be excluded as per PI's discretion based on his/her assessment of clinical significance.
3. Subjects with past medical history of malignancy except basal cell or squamous cell carcinoma of the skin who have had curative surgical treatment and at least 6 months has elapsed since the procedure.
4. A value outside the specified range of 90 mm Hg – 140 mm Hg for systolic blood pressure and 50 mm Hg – 90 mm Hg for diastolic blood pressure (both inclusive) at screening.
5. Subjects who show a positive Quantiferon TB test for tuberculosis will be excluded. Subjects with history of tuberculosis will be excluded irrespective of prior successful treatment.
6. History of clinically significant acute bacterial, viral, or fungal systemic infections in the last 4 weeks prior to screening.
7. Clinical or laboratory evidence of an active infection at the time of screening.
8. Serological evidence of human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus (Anti-HCV) at screening.
9. Vaccination within 3 months of screening for the study or requiring vaccination during the study or within 3 months after completion of the study.
10. Females who are pregnant or nursing.
11. Females of childbearing potential (i.e., any woman who is not surgically sterile e.g., hysterectomy, bilateral oophorectomy or more than 2 years post menopause) and all men who, if participating in heterosexual sexual activity that could lead to pregnancy are unable or unwilling to practice medically effective contraception during the study. They should agree to use two reliable methods of contraception (e.g., double-barrier condom plus diaphragm, condom or diaphragm plus stable dose of hormonal contraception) throughout the study period and until 3 months after receiving study drug. Women of childbearing potential will require compulsory pregnancy testing. A negative pregnancy test (serum and urine) will be documented during screening and at Day -1 respectively.
12. Participation in any other drug study within 8 weeks or 5 half lives of the study drug whichever is longer.
13. Unable or unwilling to comply with the protocol requirements for study visits and procedures.
14. Subjects who do not have good venous access for infusion of study drug or for blood sampling.
15. History of hypersensitivity to diphenhydramine or paracetamol.

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)
Allocation is concealed by having designated unblinded pharmacists at the study centre. Other members of the study team are unaware of the treatment allocation.

Stage 1: The randomisation list generated will be provided directly to the unblinded pharmacist at the study centre, Sealed envelopes will be available to be opened if unblinding a subject's treatment is required for safety concerns.

Stage 2: The randomisation list generated will be provided directly to the pharmacist at the study centre. Sealed envelopes will be available to be opened if unblinding a subject's treatment is required for safety concerns.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
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
The people analysing the results/data
Intervention assignment
Other
Other design features
Stage 1 of the study is a single ascending dose (SAD) study
Stage 2 of the study is parallel arm, partial-blind, placebo-controlled, single dose study
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
The Stage 1 portion of the study utilizes a 3:1 ratio assignment between active and placebo at each dose level in sequential cohorts . The Stage 2 portion of the study utilizes a sample of 42 normal subjects randomly assigned to 4 treatment groups (Itolizumab NS0 IV, Itolizumab (Bmab 600) IV, Itolizumab (Bmab 600) SC and placebo in a 2:2:2:1 ratio). Twelve subjects per active treatment group should be adequate to study comparative PK of the IV formulations. It is expected that the Bmab 600 SC will demonstrate between 50 and 70% absolute bioavailability with low CV based on historical data.

No statistical assumptions were used to support the sample size calculations. The sample size of 8 subjects per cohort in stage I of the study is based on the standard practice followed in first in human dose escalation studies. The sample size for stage II is empirically chosen to compare pharmacokinetics between two products. A sample size of 12 subjects per group is conventionally regarded as acceptable for pilot studies comparing pharmacokinetics between two formulations. The statement “It is expected that the Bmab 600 SC will demonstrate between 50 and 70% absolute bioavailability with low CV based on historical data” is referring to the PK data obtained from IV administration of Itolizumab NS0 to patients. This statement is included to explain that we don’t expect a very high CV hence the conventional sample size of 12 subjects should be enough to obtain meaningful data on comparative pharmacokinetics.

Adverse events will be summarized overall, by severity, and by relationship to study drug.
All evaluable subjects completing the study will be included in the pharmacokinetic analysis. Pharmacokinetic parameters for Itolizumab plasma concentration will be calculated using non-compartmental analysis.
Comparison of the log-transformed pharmacokinetic parameters for the two formulations be performed using an analysis of variance (ANOVA) model and the two one-sided t-tests procedure.
Bioavailability of Itolizumab (Bmab 600) SC will be determined by comparing exposure with that of Itolizumab (Bmab 600) administered intravenously.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Safety concerns
Date of first participant enrolment
Anticipated
15/02/2016
Actual
8/03/2016
Date of last participant enrolment
Anticipated
31/03/2017
Actual
23/08/2017
Date of last data collection
Anticipated
Actual
14/11/2017
Sample size
Target
74
Accrual to date
Final
39
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 292515 0
Commercial sector/Industry
Name [1] 292515 0
Biocon SA
Country [1] 292515 0
Switzerland
Primary sponsor type
Commercial sector/Industry
Name
Biocon Research Limited
Address
Biocon Park, Plot No: 2 and 3
Bommasandra Industrial Estate Phase IV
Bommasandra-Jigani Link Road
Bangalore-560 099, Karnataka
Country
India
Secondary sponsor category [1] 291215 0
Commercial sector/Industry
Name [1] 291215 0
Novotech (Australia) Pty Limited
Address [1] 291215 0
Level3, 235 Pyrmont Street
Pyrmont NSW 2009
Country [1] 291215 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293981 0
Queensland Institute of Medical Research Berghofer Human Research Ethics Committee
Ethics committee address [1] 293981 0
300 Herston Rd, Herston, QLD 4006
Ethics committee country [1] 293981 0
Australia
Date submitted for ethics approval [1] 293981 0
Approval date [1] 293981 0
18/11/2015
Ethics approval number [1] 293981 0

Summary
Brief summary
What is this study about? Biocon Research Limited (India) is developing itolizumab, a humanised monoclonal antibody which is aimed at modifying disease course of various auto-immune diseases. The aim of this study is to study the safety and pharmacokinetics of single ascending doses of Itolizumab (Bmab 600) given subcutaneously and also compare the PK of two formulations of itolizumab given intravenously and subcutaneously and determine the absolute bioavailability of Bmab 600 given subcutaneously..
Who is this study for? This study is for healthy volunteers aged between 18 and 50 years and Body Mass Index between 18-30 kg/m2.
What is involved? The study has 2 Stages. Stage 1 will investigate the safety and tolerability of Bmab-600, when administered to healthy volunteers as a subcutaneous injection. That is to find out how it makes people feel and whether there are any side effects or changes to laboratory results.
The pharmacokinetics (PK) of single, ascending doses of Bmab-600 will also be investigated. Pharmacokinetics is a science that looks at how the body absorbs, distributes, breaks down and then removes the study product from the body. This will be done by analysing the levels of Bmab-600 that are present in blood at various times following each dose. It will also evaluate whether there are any effects on immune system.
Stage two will compare the two formulations of itolizumab – It will investigate if these formulations are processed by the body in the same way, and if they have the same effect.
There will be a screening visit which could be up to 28 days before the dosing day and a 3 day confinement period at the study centre. After that, there will be approximately 9 out patient clinic visits. Individual participation in the study will be up to 16 weeks.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61906 0
Dr Paul Griffin
Address 61906 0
Clive Berghofer Cancer Research Centre (CBCRC)
Level 5, 300C Herston Road
Herston Qld 4006
Country 61906 0
Australia
Phone 61906 0
+617 3845 3636
Fax 61906 0
+617 3845 3630
Email 61906 0
[email protected]
Contact person for public queries
Name 61907 0
Claire Williams
Address 61907 0
Clive Berghofer Cancer Research Centre (CBCRC)
Level 5, 300C Herston Road
Herston Qld 4006
Country 61907 0
Australia
Phone 61907 0
+617 3845 3657
Fax 61907 0
+617 3845 3637
Email 61907 0
[email protected]
Contact person for scientific queries
Name 61908 0
Kanhei Charan Sahoo
Address 61908 0
Biocon Park, Plot No: 2 and 3
Bommasandra Industrial Estate Phase IV
Bommasandra-Jigani Link Road
Bangalore-560 099, Karnataka
Country 61908 0
India
Phone 61908 0
+91-80-6775 5331
Fax 61908 0
+91-80-6775 5000
Email 61908 0
[email protected]

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No Supporting Document Provided



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