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Trial registered on ANZCTR


Registration number
ACTRN12616000428460
Ethics application status
Approved
Date submitted
28/03/2016
Date registered
4/04/2016
Date last updated
14/09/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized, double-blind, single-dose, 3-way, parallel group, comparator-controlled, adaptive design, pharmacokinetic, safety, and tolerability study in healthy male volunteers to evaluate bioequivalence of CBT124 to Avastin(Registered Trademark) (EU and US)
Scientific title
A randomized, double-blind, single-dose, 3-way, parallel group, comparator-controlled, adaptive design, pharmacokinetic, safety, and tolerability study in healthy male volunteers to evaluate bioequivalence of CBT124 to Avastin(Registered Trademark) (EU and US)
Secondary ID [1] 288847 0
Protocol No. CBT124/NHV/001
Secondary ID [2] 289081 0
NCT02747823
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
non-squamous non-small cell lung cancer 298140 0
metastatic colorectal cancer 298158 0
Condition category
Condition code
Cancer 298323 298323 0 0
Lung - Non small cell
Cancer 298324 298324 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Investigational Medicinal Product: CBT124 (Cipla BioTech bevacizumab) drug product is presented as a sterile solution containing 100 mg bevacizumab. Prior to administration, bevacizumab will be diluted to the required volume using 0.9% sodium chloride solution.
CBT124 will be supplied as 100 mg per 4 mL; a single dose of 1 mg per kg will be administered over-a-period of 90 minute intravenous infusion.
Reference products: EU-Avastin(Registered Trademark) will be supplied as 100 mg per 4 mL; a single dose of 1 mg per kg will be administered over-a-period of 90 minute intravenous infusion. US-Avastin(Registered Trademark) will be supplied as 100 mg per 4 mL; a single dose of 1 mg per kg will be administered over-a-period of 90 minute intravenous infusion.
Additional information, including the formulation, appearance, batch numbers,
reconstitution and administration details will be included in a separate Pharmacy Manual
Intervention code [1] 294311 0
Treatment: Drugs
Comparator / control treatment
EU-Avastin(Registered Trademark) and US-Avastin(Registered Trademark), both are available as 100mg/4ml - intravenous infusion; Reference Therapy, Dose and Route of Administration:
EU sourced Avastin(Registered Trademark) (bevacizumab): 1 mg per kg administered as a 90 minute IV infusion; US sourced Avastin(Registered Trademark) (bevacizumab): 1 mg per kg administered as a 90 minute IV infusion
Control group
Active

Outcomes
Primary outcome [1] 297786 0
Pharmacokinetic similarity between CBT124, EU Avastin(Registered Trademark) and US-Avastin(Registered Trademark) after a single IV infusion of 1 mg/kg in healthy male subjects detected using serum samples.
The PK parameters will be derived using noncompartmental methods. The actual
sampling times (mentioned in the timepoints below) will be used in the PK parameter calculations. The primary PK parameter - Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf)
Timepoint [1] 297786 0
PK blood samples will be collected at pre-infusion (or 0 hour, collected within 1 hour prior to the start of the infusion), 0.75 hours from the start of infusion (plus or minus 2 min), the end of infusion (0 hours post end of the infusion plus or minus less than or equal to 2 min [which is approximately 1.5 hours post start of infusion]) at 3 hours (plus or minus 5 min), 6 hours (plus or minus 15 min) and 12 hours (plus or minus 15 min) from the end of infusion, and at 24 hours (Day 2) (plus or minus 1 hour), 48 hours (Day 3) (plus or minus 2 hours), 72 hours (Day 4) (plus or minus 3 hours), 168 hours (Day 8) (plus or minus 8 hours), 336 hours (Day 15) (plus or minus 8 hours), 504 hours (Day 22) (plus or minus 1 day), 672 hours (Day 29) (plus or minus 1 day), 840 hours (Day 36) (plus or minus 1 day), 1008 hours (Day 43) (plus or minus 2 days), 1176 hours (Day 50) (plus or minus 2 days), 1512 hours (Day 64) (plus or minus 3 days), 1848 hours (Day 78) (plus or minus 3 days), and 2280 hours (Day 95) (plus or minus 4 days) post start of infusion.
Secondary outcome [1] 322224 0
The tools to test secondary PK parameters (these are different from the primary PK parameters) are as below:
*Area under the concentration-time curve from time 0 to the last quantifiable data point (AUC0-t)
*Maximum observed concentration (Cmax)
*Time to maximum observed concentration (tmax)
*Terminal half-life
*Terminal rate constant
*Volume of distribution at steady state
*Systemic clearance
The parameters AUC0-inf and AUC0-t will be calculated using the linear-up/log-down
methodology. Additional PK parameters may be determined if deemed appropriate..
Timepoint [1] 322224 0
Throughout the study, till end of the study including follow up period. PK blood samples will be collected at pre-infusion (or 0 hour, collected within 1 hour prior to the start of the infusion), 0.75 hours from the start of infusion (plus or minus 2 min), the end of infusion (0 hours post end of the infusion plus or minus less than or equal to 2 min [which is approximately 1.5 hours post start of infusion]) at 3 hours (plus or minus 5 min), 6 hours (plus or minus 15 min) and 12 hours (plus or minus 15 min) from the end of infusion, and at 24 hours (Day 2) (plus or minus 1 hour), 48 hours (Day 3) (plus or minus 2 hours), 72 hours (Day 4) (plus or minus 3 hours), 168 hours (Day 8) (plus or minus 8 hours), 336 hours (Day 15) (plus or minus 8 hours), 504 hours (Day 22) (plus or minus 1 day), 672 hours (Day 29) (plus or minus 1 day), 840 hours (Day 36) (plus or minus 1 day), 1008 hours (Day 43) (plus or minus 2 days), 1176 hours (Day 50) (plus or minus 2 days), 1512 hours (Day 64) (plus or minus 3 days), 1848 hours (Day 78) (plus or minus 3 days), and 2280 hours (Day 95) (plus or minus 4 days) post start of infusion.
Secondary outcome [2] 322280 0
Tools/tests which will be used to evaluate tolerability and safety of CBT124, EU-Avastin(Registered Trademark) and US-Avastin(Registered Trademark) after a single IV infusion of 1 mg per kg in healthy male subjects. will assess the safety through vital signs like pulse, breathing, ECG parameters, clinical safety laboratory tests (hematology, clinical biochemistry, coagulation, urinalysis (including proteinuria), and urine microscopy where clinically indicated), AEs and immunogenicity (ADA, ADA, titer, and nAb), physical examination, concomitant medication and injection site evaluations.
Timepoint [2] 322280 0
Till end of study including follow up period:
Vital signs (all in-house & visit days)
ECG parameters (screening, day -1, 1 (thrice - predose, 0.75, 3 & 12), 2, 4, 15, 43, 95)
Clinical safety laboratory tests:
Hematology (Screening, day -1, day 3, 4, 15, 43, 64, 95)
Clinical biochemistry (Screening, day -1, day 3, 4, 15, 43, 64, 95)
Coagulation (Screening, day -1, day 3, 4, 15, 43, 64, 95)
Urinalysis (including proteinuria) - (Screening, day -1, day 3, 4, 15, 43, 64, 95)
Immunogenicity (ADA, ADA, titer, and nAb): (screening, day 1, 15, 22, 29, 36, 43, 50, 64, 78, 95, FU at 6, 9, 12 months after study completion)
Physical examination: (screening, day -1, 1, 3, 15, 29, 43, 50, 64, 95)
concomitant medication: (all days, including ADA FU)
Injection site evaluations & AEs: : (all days, including ADA FU)
Secondary outcome [3] 322281 0
To evaluate the immunogenicity of CBT124, EU-Avastin(Registered Trademark) and US-Avastin(Registered Trademark) after a single IV infusion of 1 mg per kg in healthy male subjects: Immunogenicity (ADA, ADA, titer, and nAb): (screening, day 1, 15, 22, 29, 36, 43, 50, 64, 78, 95, FU at 6, 9, 12 months after study completion)
Timepoint [3] 322281 0
At screening, Within 1 hour prior to the start of infusion, during follow up visits 15th day plus or minus 1 day, 22nd day plus or minus 1 day, 29th day plus or minus 1 day, 36th day plus or minus 1 day, 43rd day plus or minus 2 days, 50th day plus or minus 2 days, 64th day plus or minus 3 days, 78th day plus or minus 3 days, 95th day plus or minus 4 days and if required at 6th/9th/12th month.
Secondary outcome [4] 322282 0
To evaluate the pharmacodynamics (PD) of CBT124, EU-Avastin(Registered Trademark) and US-Avastin(Registered Trademark) after a single IV infusion of 1 mg/kg in healthy male subjects - serum analysis for VEGF estimation
Timepoint [4] 322282 0
At screening, Within 1 hour prior to the start of the infusion, 29th day plus or minus 1 day, 95th day plus or minus 4 days

Eligibility
Key inclusion criteria
*Adult healthy male subjects aged 18 to 50 years (inclusive) and between 18.0 and 30.0 kg per sq mtr body mass index (inclusive) and body weight between 60 kg and 100 kg, both inclusive.
*Subjects who are healthy as determined by pre-study medical history, physical examination, vital signs and 12 lead electrocardiogram (ECG) at screening and admission.
Subjects whose clinical laboratory test results are normal, or where outside the reference range is judged as not clinically relevant by the Investigator.
*Have systolic blood pressure between 140 and 90 mmHg both inclusive, diastolic blood pressure 90 and 50 mmHg both inclusive and heart rate 40 and 90 bpm both inclusive at screening and admission. For single measurements in the 141 to 160 mmHg range (systolic) or in the 91 to 100 mmHg range (diastolic), a single repetition on a the same day is allowed and, in this case, the mean of both measurements will guide eligibility. The mean of both the measurements should be 140 mmHg (systolic) and 90 mmHg (diastolic) both inclusive.
*Have physical examination results without clinically relevant findings at screening and admission.
*Have 12-lead ECG results without clinically relevant findings at screening and admission.
*Subjects who are non-smokers and have not regularly used tobacco or nicotine containing products for at least 3 months preceding screening and have a less than 10 pack year smoking history.
*Males must be willing to use a medically acceptable method of contraception from the time of the administration of investigational product (IP), throughout the study and for a period of 6 months after the administration of the IP. Medically acceptable methods of contraception include the following: abstinence; or willing to use a condom in addition to having their female partner use another form of contraception such as an intra-uterine device, oral contraceptive, injectable progesterone, sub-dermal implant, or a tubal ligation. This requirement may be waived if the Principal Investigator or delegate is satisfied that the subject or subject’s female partner is sterile i.e. if female has undergone hysterectomy or tubal ligation at least 3 months prior to screening or is post-menopausal (no period for at least 12 months prior to screening) or if the subject has undergone vasectomy at least 6 months prior to screening.
*Must agree not to donate sperm for at least 6 months after the administration of IP.
*Must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures including standardized meal.
*Must be able to provide informed consent which must be obtained prior to any study related procedures.
*Subjects who have a negative fecal occult blood test and a negative Helicobacter pylori stool antigen test.
*Subjects who are willing to comply with the study restrictions, and comply with the scheduled visits from screening and throughout the study.
Minimum age
15 Years
Maximum age
50 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
*Have a history of hypersensitivity or allergic reactions (either spontaneous or following drug administration) to bevacizumab or vascular endothelial growth factor (VEGF) targeted
treatment or to any of the excipients.
*Have a history of or presence of current clinically significant gastrointestinal (including diverticulitis, stomach ulcers, inflammatory intestinal disease, gastrointestinal perforations/fistulae/intra-abdominal abscess), any other internal, non gastrointestinal fistulae that is at an increased risk of bleeding), renal, hepatic, cardiovascular, hematological (including pancytopenia, aplastic anaemia or blood dyscrasia), pulmonary, neurologic, metabolic (including known diabetes mellitus), psychiatric or allergic disease excluding mild asymptomatic seasonal allergies.
*Have a history of and/or current cardiac disease defined as one of the following:
*History of congestive heart failure;
*Angina pectoris requiring anti-anginal medication;
*Evidence of transmural infarction on ECG;
*History of sustained hypertension (systolic greater than 180 mmHg and/or diastolic greater than 100 mmHg) or hypertensive crisis or hypertension encephalopathy;
*Clinically significant valvular heart disease; or
*Severe arterial thromboembolic events.
*Have a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus, or human immunodeficiency virus (HIV) I and II at screening.
*Have a history of cancer including lymphoma, leukaemia and skin cancer (including any history of malignancy, even resected basal cell carcinoma or squamous cell carcinoma).
*Have an illness within 30 days prior to screening, or prior to dosing, that is classed as clinically significant by the Investigator.
*Prior exposure to any investigational monoclonal antibody within 12 months of study drug administration.
*Any clinically significant infection, in the opinion of the Investigator, ongoing at screening or admission to the clinical unit.
*Have had major surgery within 30 days prior to screening, or will have an operation between screening and the end of study visit, or still has an unhealed wound, including wound dehiscence and wound healing complications requiring medical intervention.
*Have received live vaccine(s) within 30 days prior to screening or will require a live vaccine(s) between screening and the end of study visit.
*Have an intake of alcoholic beverages of more than 28 units per week (1 unit = 250 mL of beer, 25 mL of spirits or one glass [125 mL] of wine).
*Have reasonable evidence (in the opinion of the Investigator) of drug abuse as indicated by a positive urinary drug test at screening or admission.
*Have taken medication with a half-life of more than 24 hours within 30 days or less than 10 half-lives of the medication prior to the administration of the study drug as determined by the Investigator.
*Have donated more than 100 mL blood within 4 weeks prior to the administration of the study drug. Blood donation and blood products is not permitted throughout study.
*Have participated in another clinical study of an investigational drug within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to the administration of the study drug, 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.
*Subjects who, in the opinion of the Investigator, are not likely to complete the study for whatever reason.
*The Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff directly involved in the conduct of the clinical study or any of their relatives.
*Abnormal or irregular bowel movements e.g., less than 1 bowel movement every 3 days.
*Any history of non-traumatic hemorrhage (i.e. any hemorrhage requiring medical intervention) or any condition which may increase bleeding risk including clotting disorders, thrombocytopenia (platelet count less than 150, 000 per micro L) or an international normalized ratio higher than 1.5 at screening.
*Impaired liver function as determined by:
*Serum alanine aminotransferase and/or aspartate aminotransferase more than 1.5 times upper limit of normal (ULN) at screening or admission. Subjects with values between ULN and 1.5 times ULN may be included in the study if considered not clinically significant by the Investigator.
*Any intake of a non-steroidal anti-inflammatory drug (NSAID) including any dose of aspirin in the 30 days before administration of the study drug (NSAIDs are not allowed for the duration of the study).
*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 30 days prior to study drug administration, unless agreed as not clinically relevant by the Investigator and Sponsor.
*Consumption of any foods containing poppy seeds within 48 hours prior to screening and admission to the clinical center.
*Strenuous exercise or activity within 96 hours prior to admission to the clinical center and has a creatinine kinase value is more than 2.5 times upper limit of normal.
*Subjects with unsuitable veins for infusion or venipuncture.
*Subjects with a non-healing wound or hematoma of a clinically relevant size as assessed by the Investigator, or a clinically significant current fracture.
*Presence of proteinuria (other than trace amounts) at screening or admission.
*Personal history of venous thromboembolic events or idiopathic venous thromboembolic events in first degree relatives.
*Inability to refrain from contact or collision sport until Day 30.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2016
Actual
14/07/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
150
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment outside Australia
Country [1] 7752 0
New Zealand
State/province [1] 7752 0
Auckland

Funding & Sponsors
Funding source category [1] 293207 0
Commercial sector/Industry
Name [1] 293207 0
Cipla BioTec
Country [1] 293207 0
India
Primary sponsor type
Commercial sector/Industry
Name
Cipla BioTec Pvt. Ltd.
Address
Cipla BioTec, Plot number L-147/B, Verna Industrial Estate, Verna, Goa 403721, India
Country
India
Secondary sponsor category [1] 292009 0
None
Name [1] 292009 0
Address [1] 292009 0
Country [1] 292009 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294691 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 294691 0
Ethics committee country [1] 294691 0
Australia
Date submitted for ethics approval [1] 294691 0
31/03/2016
Approval date [1] 294691 0
05/07/2016
Ethics approval number [1] 294691 0
2016-03-258
Ethics committee name [2] 294739 0
Northern A Health and Disability Ethics Committee
Ethics committee address [2] 294739 0
Ethics committee country [2] 294739 0
New Zealand
Date submitted for ethics approval [2] 294739 0
31/03/2016
Approval date [2] 294739 0
17/05/2016
Ethics approval number [2] 294739 0
16/NTA/42

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1033 1033 0 0
/AnzctrAttachments/370387-EC Approval_17May2016.pdf
Attachments [2] 1034 1034 0 0
/AnzctrAttachments/370387-ApprovalLetter-HREC2016-03-258.pdf
Attachments [3] 1035 1035 0 0
/AnzctrAttachments/370387-MedsafeApproval_04Apr16.pdf
Attachments [4] 1036 1036 0 0
/AnzctrAttachments/370387-12_CTN_AcknowledgementLetter_07July16.pdf

Contacts
Principal investigator
Name 64606 0
Prof Dr Christian Schwabe
Address 64606 0
Auckland Clinical Studies Ltd., 3 Ferncroft Street, Grafton, Auckland
Country 64606 0
New Zealand
Phone 64606 0
+6493733474
Fax 64606 0
Email 64606 0
[email protected]
Contact person for public queries
Name 64607 0
Renuka Joshi
Address 64607 0
Cipla BioTec Private Limited, Plot No: L-147/B, Verna Industrial Estate, Verna, Salcette, Goa, India 403 722
Country 64607 0
India
Phone 64607 0
+918698082266
Fax 64607 0
Email 64607 0
[email protected]
Contact person for scientific queries
Name 64608 0
Renuka Joshi
Address 64608 0
Cipla BioTec Private Limited, Plot No: L-147/B, Verna Industrial Estate, Verna, Salcette, Goa, India 403 722
Country 64608 0
India
Phone 64608 0
+918698082266
Fax 64608 0
Email 64608 0
[email protected]

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No Supporting Document Provided



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