Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615001204538
Ethics application status
Approved
Date submitted
7/10/2015
Date registered
5/11/2015
Date last updated
23/05/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A study assessing the similarity of Avastin (Registered Trademark) and the trial drug DRL_BZ.
Scientific title
A Single Dose, Double-Blind, Parallel Arm, Comparative Pharmacokinetic Study of Three Bevacizumab Preparations, Administered by the Intravenous Route to Male Normal Healthy Volunteers
Secondary ID [1] 287558 0
Nil
Universal Trial Number (UTN)
U1111-1175-3054
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Healthy Human Volunteers 296335 0
Metastatic colorectal cancer 296591 0
Metastatic breast cancer 296592 0
Non-squamous non-small cell lung cancer 296593 0
Condition category
Condition code
Cancer 296610 296610 0 0
Breast
Cancer 296611 296611 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 296612 296612 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Three Bevacizumab Preperations

Arm 1: DRL_BZ
100 mg in 4 mL - 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.

Arm 2: Avastin (Registered Trademark) United States-licenced (bevacizumab)
100 mg in 4 mL- 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.

Arm 3: Avastin (Registered Trademark) European Approved (bevacizumab)
100 mg in 4 mL- 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.

As the Infusion will be administered while the participants are inpatients of the facility, no strategy for adherence is required.
Intervention code [1] 293026 0
Treatment: Drugs
Comparator / control treatment
Avastin (Registered Trademark) United States-licenced (bevacizumab)
100 mg in 4 mL- 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.

Avastin (Registered Trademark) European Approved (bevacizumab)
100 mg in 4 mL- 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion
Control group
Active

Outcomes
Primary outcome [1] 296310 0
To demonstrate pharmacokinetic (PK) similarity of DRL_BZ versus the Reference Medicinal Product (RMP; Avastin (Registered Trademark) [EU-approved]) and the Reference Product (RP; Avastin (Registered Trademark) [US-licensed]) after administration of a single 1 mg/kg intravenous (IV) dose in healthy male subjects.
Timepoint [1] 296310 0
Blood samples for analysis of serum concentrations of the study drugs will be collected at the following specified times to perform a comparison of PK similarity.
All PK sampling time points are relative to end of infusion (i.e., after fixed infusion of 90 minutes, or up to 93 minutes, considering the maximum of 3 minutes infusion
interruption allowed). Sampling time points relative to end of infusion will have a designated nominal time point: End of infusion, 1 hour, 2 hours, 5 hours, 8 hours, 12 hours, and 24 hours post end of infusion and so on up to Day 85.
Mid infusion (at 45 minutes) and end of infusion (at 90 minutes +/- 3 minutes) are relative to the start of infusion.
The primary PK parameters will consist of:
- Cmax, AUC(08) and AUC(0t).
Secondary outcome [1] 318138 0
To assess the safety of the administered dose of DRL_BZ, RMP, and RP in healthy male
subjects.
Timepoint [1] 318138 0
The following assessments will be reviewed:
Vital Signs: Pre Dose, 30 mins, 60 mins, Post dose 15 mins, 30 mins, 6 hour, 12 hour, Day 2, Day 3, Day 5, Day 8, Day 15, Day 22, Day 29, Day 43, Day 57, Day 71, Day 85
Physical Examination: An abbreviated physical examination will be performed on every alternate day during the residential period and Day 85
ECG: Pre Dose 30 mins, 90mins, Post dose 4 hour, Day 2, Day 5, Day 15, Day 85
Adverse Events will be collected at each and every visit throughout the trial
Clinical Laboratory Tests: Screening, Day 8, Day 15 and Day 85
Secondary outcome [2] 318469 0
To assess the immunogenicity of the administered dose of DRL_BZ, RMP, and RP in healthy
male subjects.
Timepoint [2] 318469 0
Immunogenicity will be assessed by means of the occurrence of ADA, ADA titres, and the occurrence of neutralising antibodies.
Blood Samples taken at Predose, Day 15, Day 29, Day 57, Day 85 will be assessed
After the End-of-Study visit, subjects who are confirmed positive for anti-bevacizumab antibodies will be followed for 12 months after study drug administration.
Blood Sampling will be collected at 6, 9, and 12 months after study drug administration or until 2 consecutive samples have been negative for ADA, whichever comes first. (All
subjects who have an early discontinuation from the study following study drug administration, and are confirmed positive for anti-bevacizumab antibodies will have an
additional visit at 3 months following study drug administration for a follow-up assessment of their ADA status.)

Eligibility
Key inclusion criteria
1. Healthy adult male subjects, 20 to 45 years of age (inclusive) 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, and vital signs.
3. Have all Screening results (vital signs, physical examination, clinical laboratory tests, 12-lead electrocardiogram [ECG], and thyroid function) within the normal range or outside the normal range but assessed as clinically non-significant by the Investigator.
4. Body mass index between 18.0 and 28.5 kg/m2 (inclusive) and body weight of 50 to 100 kg (inclusive).
5. Subjects should be willing to abstain from sexual intercourse or be willing to use a condom in addition to having their female partner use another form of contraception (such as an intra-uterine device, barrier method with spermicide, oral contraceptive, injectable
progesterone, sub-dermal implant) unless their partners are infertile or surgically sterile from the time of the first administration of the study drug until completion of study procedures and for a period of 7 months after administration of the study drug.
6. Capable and amenable to providing signed and dated informed consent to the study
requirements.
7. Willing to stay on study restrictions for 4 months (7 months for contraception) from Screening.
Minimum age
20 Years
Maximum age
45 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Positive test results for hepatitis B, hepatitis C, or human immunodeficiency virus-1 or -2.
2. Live virus vaccination within 3 months prior to Screening or intention to receive live virus
vaccination during the study or up to 3 months after the administration of the study drug.
3. History of immunodeficiency or other clinically significant immunological disorders,
auto-immune disorders, ongoing or frequent/recurring clinically significant infection defined as more than 3 events per year requiring treatment.
4. Any prior exposure to bevacizumab or vascular endothelial growth factor (VEGF) targeted treatment.
5. Prior exposure to any investigational monoclonal antibody within 12 months before enrolment.
6. Known allergy or hypersensitivity to Chinese hamster ovary cell products or to any recombinant human or humanised antibodies, other therapeutic proteins, or any excipients in the study formulations.
7. Abnormal and clinically relevant (in the opinion of the Investigator) ECG or corrected QT value (Fridericia correction) longer than 450 msec.
8. Blood donation in the 2 months before Screening.
9. Screening or admission to the study centre (Day -1) blood pressure higher than 160 mmHg (systolic) or higher than 100 mmHg (diastolic). For single measurements in the 140 to 160 mmHg range (systolic) or in the 90 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 less than or equal to 140 mmHg (systolic) and 90 mmHg (diastolic).
10. History of symptomatic orthostatic hypotension, fainting spells, syncope, or blackouts.
11. Fasting low density lipoprotein cholesterol higher than 160 mg/dL (or equivalent in mmol/L, 4.14 mmol/L) at Screening, or fasting triglycerides higher than 200 mg/dL (or equivalent in mmol/L, 2.26 mmol/L) at Screening or fasting glucose higher than 110 mg/dL (or equivalent in mmol/L, 6.11 mmol/L) at Screening.
12. Presence of any haemodynamically relevant abnormality or of any valvulopathy including mitral valve prolapse in the Screening echocardiography.
13. History of hypertension, angina, exertional dyspnoea, orthopnoea, congestive heart failure or myocardial infarction.
14. A history or current presence of clinically significant (in the opinion of the Investigator) atopic allergy (e.g., asthma including childhood asthma, urticaria, angioedema, eczematous
dermatitis), hypersensitivity or allergic reactions (either spontaneous or following drug
administration), including known or suspected clinically relevant drug hypersensitivity to any components of the study drug formulations, comparable drugs, or to latex.
15. Any history of thrombotic or embolic episodes or requirement for anticoagulation.
16. Any history of non-traumatic relevant haemorrhage, defined as any haemorrhage requiring medical intervention or any condition which may increase bleeding risk including
coagulopathies or an international normalised ratio higher than 1.5.
17. History or presence of any clinically relevant (in the opinion of the Investigator) nervous system disease including, but not restricted to any stroke/transient ischaemic attack, migraine headaches or migrainous aura (scotoma with zig-zag lines or blinking lights) or of seizures (other than febrile seizures before the age of 5 years).
18. Significant family or personal history of intestinal inflammatory disease as well as personal history or current presence of gastrointestinal ulceration, bleeding or perforation, acute or chronic pancreatitis, and/or current gallbladder or bile duct disease.
19. Any intake of a non-steroidal anti-inflammatory drug including antiaggregant doses of aspirin in the last 2 weeks before administration of the study drug (non-steroidal anti-inflammatory drugs are forbidden until the last study visit) or marked constipation (less than 1 bowel movement every 3 days).
20. Any history of kidney disease, including, but not restricted to glomerulonephritis, minimum change nephropathy, and other renal diseases producing proteinuria, renal Fanconi syndrome, polycystic kidney disease, pyelonephritis or nephrolithiasis as well as history of nephrectomy.
21. History of and/or current gastrointestinal, endocrine, pulmonary, hepatic,
psychiatric/neurological, cardiovascular, haematological (including pancytopenia, aplastic
anaemia or blood dyscrasia), metabolic (including known diabetes mellitus), central nervous system disease, considered as significant by the Investigator.
22. Impaired liver function as determined by one of the following:
a. Serum alanine aminotransferase and/or aspartate aminotransferase >1.5 x upper limit
of normal (ULN) at Screening or admission to the study centre. Subjects with values
between ULN and 1.5 x ULN may be included in the study if considered not clinically
significant by the Investigator. b. Hepatic disease (e.g., cirrhosis) considered clinically significant by the Investigator.
23. Any clinically significant active infection, even if minor, ongoing at the time of Screening or study drug administration.
24. Presence of any non-healed wound or haematoma of a clinically relevant size (in the
Investigator’s opinion), presence of any non-healed bone fracture at the time of Screening or administration of the study drug or increased accident risk due to professional or leisure time activities (e.g., motorcycle riding, martial arts) throughout the study participation. Subjects are expected to abstain from indulging in strenuous physical activity, outdoor contact sporting activities, which can possibly lead to any physical injury or trauma from 96 hours prior to the study drug administration until 8 weeks after the administration of the study drug. Early withdrawal subjects should also abstain from activities that carry an increased risk of injury until at least 8 weeks after the study drug administration.
25. Heparin sensitivity.
26. Any disorder 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, such as history of chronic alcohol or drug abuse, significant endocrinological, respiratory, mental, or nervous disorder or other illness.
27. Participation in an interventional or Phase 1 study in the last 3 months, currently is on a
follow-up visit schedule for any study, participation in more than 3 studies of experimental drug products in the past 12 months, or intake of an investigational drug in another study within 3 months or 5 half-lives (whichever is longer) prior to administration of the study drug in this study or planned intake of an investigational drug during the course of this study.
28. Any prior exposure (either due to treatment or to a research study) to bisphosphonates.
29. History of any cancer, including carcinoma in situ, lymphoma or leukaemia.
30. 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.
31. Current or former smoker or tested positive in the urine cotinine test at Screening or admission to the study centre.
32. History of alcohol abuse and/or inability to refrain from intake of alcoholic beverages from 48 hours prior to study drug administration and until Day 15 postdose or a positive alcohol breath test on Screening or admission to the study centre prior to study drug administration.
33. History of illegal drug abuse or abuse of medications or positive drug screen at Screening or admission to the study centre including urine tests for cotinine, amphetamines, barbiturates, cocaine, methadone, phencyclidine, 3, 4 methylenedioxymethamphetamine (ecstasy), tetrahydrocannabinol, and opiates.
34. Intake of prescribed or over-the-counter drugs (including acetaminophen) within less than 6 half-lives of the respective drug or herbal drugs within 28 days prior to study drug
administration.
35. Legal incapacity or limited legal capacity.
36. Any person who is an employee of the Principal Investigator or study centre(s) with direct involvement in this proposed study or any other study under the direction of the Principal Investigator or the study centre or who is directly involved in the planning and/or conduct of the study, as well as close relatives of the employee, the Investigators, or the Sponsor.

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 involved contacting the holder of the allocation schedule who was "off-site" or at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised 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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
The diagnostic parameter %AUCex will be reported, as a measure of the percentage of AUC(0-00) obtained by extrapolation.
The few published values of the inter-subject CV of the PK parameters determined over
sufficient subjects are
- 27.5% (ponderated mean by the number of subjects treated at each dose level for
AUC after multiple dose; AUC was considered because its CV is higher than
those of Cmax, only arithmetic CV available),
- 30.2% (ponderated mean by the number of subjects treated at each dose level for
AUC after multiple doses; AUC was considered because its CV is higher than
those of Cmax, only arithmetic CV available) and
- 31.0% (highest CV% recalculated from bioequivalence comparison confidence
intervals [CIs] after the first dose).
Under the above conditions, a total of 165 evaluable subjects (55 per arm) would provide
90% power for each pairwise comparison assuming geometric mean ratios of 95.00%, a
CV of 31%, using 90% CIs to assess equivalence and the usual pre-defined 80.00% to
125.00% equivalence margins for the geometric mean ratio test/reference on the original
scale. This sample size would provide a power of approximately 80% to show equivalence
for all 3 pairwise comparisons based on simulations under the above assumptions.

Due to the uncertainty in the actual PK variability of bevacizumab and trying to limit the
study size to that strictly needed, a BSSR will be performed after approximately 40
evaluable subjects per arm (150 subjects total assuming 20% dropouts provision) have
completed the study, as little precision is gained in the estimation of the pooled variability
beyond this number. This number of subjects is expected to provide a sufficiently precise
calculation of the variability in the actual study population.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
23/11/2015
Actual
Date of last participant enrolment
Anticipated
1/06/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
300
Accrual to date
Final
Recruitment outside Australia
Country [1] 7214 0
New Zealand
State/province [1] 7214 0

Funding & Sponsors
Funding source category [1] 292185 0
Commercial sector/Industry
Name [1] 292185 0
Dr Reddy’s Laboratories, Ltd (Biologics)
Country [1] 292185 0
India
Primary sponsor type
Commercial sector/Industry
Name
Dr Reddy’s Laboratories, Ltd (Biologics)
Address
Survey Number 47, Bachupally Village, Qutbullapur Mandal, Ranga Reddy District –
500 090, Telangana, India
Country
India
Secondary sponsor category [1] 290862 0
Commercial sector/Industry
Name [1] 290862 0
Quintiles Pty Ltd
Address [1] 290862 0
Level 9, 67 Albert Avenue, Chatswood New South Wales 2067, Australia
Country [1] 290862 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293658 0
Norther A Health and Disability Ethics Committee
Ethics committee address [1] 293658 0
Ethics committee country [1] 293658 0
Australia
Date submitted for ethics approval [1] 293658 0
01/10/2015
Approval date [1] 293658 0
02/11/2015
Ethics approval number [1] 293658 0

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

Contacts
Principal investigator
Name 60658 0
Dr Chris Wynne
Address 60658 0
Christchurch Clinical Studies Trust
PO Box 2856
Christchurch
8140
Country 60658 0
New Zealand
Phone 60658 0
+64 3 372 9477
Fax 60658 0
+64 3 372 9478
Email 60658 0
[email protected]
Contact person for public queries
Name 60659 0
Chris Taylor
Address 60659 0
Christchurch Clinical Studies Trust
PO Box 2856
Christchurch
8140
Country 60659 0
New Zealand
Phone 60659 0
+64 3 372 9477
Fax 60659 0
+64 3 372 9478
Email 60659 0
[email protected]
Contact person for scientific queries
Name 60660 0
Chris Wynne
Address 60660 0
Christchurch Clinical Studies Trust
PO Box 2856
Christchurch
8140
Country 60660 0
New Zealand
Phone 60660 0
+64 3 372 9477
Fax 60660 0
+64 3 372 9478
Email 60660 0
[email protected]

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
EmbaseA comparative pharmacokinetic study of DRL_BZ, a candidate biosimilar of bevacizumab, with Avastin (EU and US) in healthy male subjects.2018https://dx.doi.org/10.1111/bcp.13691
N.B. These documents automatically identified may not have been verified by the study sponsor.