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Trial registered on ANZCTR


Registration number
ACTRN12620000657921
Ethics application status
Approved
Date submitted
3/04/2020
Date registered
9/06/2020
Date last updated
9/06/2020
Date data sharing statement initially provided
9/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I biosimilar study to compare the pharmacokinetics, Pharmacodynamics, safety and tolerability of BP14 (Pegfilgrastim) with EU-approved Neulasta® in healthy male adult volunteers following a subcutaneous (SC- under the skin) injection.
Scientific title
A Randomized, Single-Dose, Double-Blind, Two-Sequence, Two-Period Crossover Study to compare Pharmacokinetics, Pharmacodynamics, Immunogenicity and Safety of BP14 (Pegfilgrastim) with EU-approved Neulasta® in Healthy Male Adult Subjects.
Secondary ID [1] 299633 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chemotherapy-induced-neutropenia 314951 0
Condition category
Condition code
Cancer 313298 313298 0 0
Any cancer
Blood 315288 315288 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Test Product
Treatment A: Single subcutaneous (SC) dose of BP14 (pegfilgrastim)
(Manufactured by CURATEQ BIOLOGICS PRIVATE LIMITED
PLOT NO.2, MAITRIVIHAR, AMEERPET,
HYDERABAD, Telangana, India, 500038

Reference Product
Treatment B: Single subcutaneous (SC) dose of Neulasta®.
(Manufactured by Amgen Technology (Ireland) Unlimited Company)

The treatments will be BP14 (Treatment A) and Neulasta® (Treatment B) the total dose will be a single 6mg subcutaneous injection per treatment over 2 separate treatment periods. It will be conducted as a cross over study design, which means that participants will receive a sequence of two different treatments. Each treatment will be administered in a separate inpatient period separated by a washout period which is at least 42 days between two treatment periods.
When participants are dosed at the site, they will receive investigational product (IP) directly from the Investigator or designee, under medical supervision. The date and time of each dose administered in the clinic will be recorded in the source documents and recorded in the eCRF. The dose of IP and study participant identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study intervention.
Intervention code [1] 315892 0
Treatment: Drugs
Comparator / control treatment
Reference Product
Treatment B: Single subcutaneous (SC) dose of EU-approved Neulasta®.
(Manufactured by Amgen Technology (Ireland) Unlimited Company)
Control group
Active

Outcomes
Primary outcome [1] 321777 0
To compare the Pharmacokinetics of BP14 (pegfilgrastim) with EU-approved Neulasta®

Assessed by pre dose, during dose and post dose blood sample collection and analysis.
Endpoints:
PK:
AUC(0-t): Area under the concentration time-curve of the drug from time zero up to the last measurable concentration
Cmax: Maximum concentration of the drug in the serum
Timepoint [1] 321777 0
Day -1 to 21 (Period 1) and day 62 to day 84 (Period 2) of the study

1. PK samples: pre-dose (i.e., between 5 and 45 minutes prior to dosing), 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 (Day 1), 24, 28, 32, 36, 40 (Day 2), 48 (Day 3), 60, 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 168 (Day 8), 192 (Day 9), 216 (Day 10), 240 (Day 11), 264 (Day 12), 312 (Day 14) and 480 (Day 21) hours post-dose of both treatment periods.

Primary outcome [2] 323820 0
To compare the Pharmacodynamics of BP14 (pegfilgrastim) with EU-approved Neulasta®

PD:
AUC(0-t): Area under the concentration-time curve of the absolute neutrophil count up to the last measurable
concentration
Emax: Maximum change from base line for ANC
Timepoint [2] 323820 0
Day -1 to 21 (Period 1) and day 62 to day 84 (Period 2) of the study

PD sample for CD34+ cells: Pre-dose, and post dose following hour: 6 hr (Day 1), 24 hr(Day 2), 48 hr (Day 3), 72 hr (Day 4), 96 hr (Day 5), 120 hr (Day 6) 144 (Day 7), 168 (Day 8), 192 hr (Day 9), 216 hr (Day 10), 240 hr (Day 11), 264 hr (Day 12), 312 hr (Day 14) and 480 hr (Day 21) for both treatment periods
Secondary outcome [1] 376176 0
To compare the Pharmacokinetics of BP14 (pegfilgrastim) with EU- approved Neulasta®

Endpoints:
t1/2: Terminal elimination half-life of the drug AUC0-inf: AUC of the drug extrapolated to infinite time

The method of assessment is blood sample collection and analysis.
Timepoint [1] 376176 0
Day -1 to 21 (Period 1) and day 62 to day 84 (Period 2) of the study

1. PK samples: pre-dose (i.e., between 5 and 45 minutes prior to dosing), 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 (Day 1), 24, 28, 32, 36, 40 (Day 2), 48 (Day 3), 60, 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 168 (Day 8), 192 (Day 9), 216 (Day 10), 240 (Day 11), 264 (Day 12), 312 (Day 14) and 480 (Day 21) hours post-dose of both treatment periods.



Secondary outcome [2] 376268 0
To compare CD34+ cell response between BP14, and EU-approved Neulasta®

Endpoints:
AUC0-t: AUC of the absolute CD34+ cell count up to the last measurable concentration
Emax: Maximum change from baseline for absolute CD34+ cell count

The method of assessment is blood sample collection and analysis.
Timepoint [2] 376268 0
Day -1 to 21 (Period 1) and day 62 to day 84 (Period 2) of the study

PD sample for CD34+ cells: Pre-dose, and post dose following hour: 6 hr (Day 1), 24 hr(Day 2), 48 hr (Day 3), 72 hr (Day 4), 96 hr (Day 5), 120 hr (Day 6) 144 (Day 7), 168 (Day 8), 192 hr (Day 9), 216 hr (Day 10), 240 hr (Day 11), 264 hr (Day 12), 312 hr (Day 14) and 480 hr (Day 21) for both treatment periods

Secondary outcome [3] 376269 0
To explore the potential immunogenicity of BP14 and EU-approved Neulasta®.

Endpoints:Incidence of anti-pegfilgrastim antibodies

The method of assessment is blood sample collection and analysis.
Timepoint [3] 376269 0
Day -1 to 21 (Period 1) and day 62 to day 84 (Period 2) of the study

Anti-drug antibodies will be assessed during the pre-dose (between 5 and 45 minutes prior to dosing) on Day 1, and on Days 14 and 21 for both treatment periods.
Secondary outcome [4] 376270 0
To assess and compare the safety and tolerability of BP14 and EU-approved Neulasta®.

Endpoints:Adverse events, clinical laboratory values, vital signs, physical examinations, and ECG
Timepoint [4] 376270 0
Day -1 to 21 (Period 1) and day 62 to day 84 (Period 2) of the study

Eligibility
Key inclusion criteria
1. Subject is 18 to 55 years of age inclusive, at the time of signing the informed consent.
2. Subject is healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (12-lead electrocardiogram [ECG]).
3. Subject has body mass index (BMI) within the range 18 – 32 kg/m2 (inclusive).
4. Subject is male.
5. The subject must agree to use a highly effective contraception during the study and for at least 90 days after the last dose of IMP and refrain from donating sperm during this period.
6. Subject is capable of and willing to give signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
7. Non-smokers or casual smokers who smoke no more than 5 cigarettes (or equivalent quantity of any other nicotine containing substance) per week. Subject must abstain from smoking 48 hours prior to admission and throughout both the treatment periods.
8. Subject should have a negative breathalyzer result at screening, Day -1, and Day 62.
9. Screening laboratory results (hematology, biochemistry, coagulation, iron profile, and urinalysis) should be within normal limits, or any abnormalities should not be clinically significant, as determined by the Investigator. Repeat laboratory tests are permitted at Investigator’s discretion.
10. Must be general good health as determined by the Investigator based on comprehensive medical history, physical examination findings, vital sign measurements, and clinical laboratory tests (including iron status transferrin saturation greater than or equal to 15%), unless considered not clinically significant by the PI.
At the screening visit, supine vital signs must be within the following ranges:
• Systolic blood pressure between 90 and 139 mmHg,
• Diastolic blood pressure between 60 and 89 mmHg,
• Pulse between 50 and 90 beats per minute (bpm),
• Oral body temperature between 35.0 and 37.5°C.
Normal hematological function at screening as follows:
• ANC 1.5 to 7.0 x 109/L,
• Red blood cells 4.7 to 6.1 million cells per microliter (mcL),
• Platelet count 150 to 400 x 109/L,
• Hemoglobin 14 to 17 g/dL.
11. To rule out symptoms of glandular fever, subjects must test negative for antibodies to the Epstien-Barr virus at screening.
12. Must have normal organ function as per the Investigator judgment.
13. Must have normal liver function as determined by serum bilirubin, alkaline phosphatase (ALP), and transaminases (alanine aminotransaminase [ALT] and aspartate. aminotransaminase [AST]) the upper limit of normal (ULN) unless deemed not clinically significant by the Investigator.
14. Must have adequate renal function defined as serum creatinine less than or equal 1.5 x ULN.
Minimum age
18 Years
Maximum age
55 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Current or previous cancer, diabetes, or any clinically significant cardiovascular, metabolic, renal, hepatic, gastrointestinal, hematologic, respiratory, dermatological, neurological, psychiatric, or any other disorder clinically relevant as judged by the Investigator.
2. History of chronic cough, fever or acute respiratory illness within 4 weeks prior to the day of IMP administration.
3. Known or suspected allergic reaction to latex.
4. Any past or concurrent medical conditions that potentially increase the subject's risks or affect the evaluation of any study results. The Investigator shall take a final call on any medical condition that can interfere in the study results or potentially increase the subject’s risk.
5. Hypersensitivity to the constituents of Neulasta®, pegfilgrastim (sorbitol E420, polysorbate 20 and acetate or acetic acid) or hypersensitivity to E. coli derived proteins.
6. Any history of major surgery that in the opinion of the Investigator would interfere with the study or place the subject at risk.
7. Hereditary fructose and/or sorbitol intolerance.
8. Any history of previous exposure to pegfilgrastim or filgrastim or known allergy to PEG or any similar analogue.
9. Treatment with non-topical medications within 5 days prior to first admission to the study center, with the exception of over the counter medications (such as paracetamol, acetaminophen, vitamins, minerals, or health supplements) which in the Investigator’s judgment do not interfere with IMP administration or the subject’s ability to participate in the study.
10. Participation in a drug study involving hematopoetic growth factors, monoclonal antibodies, or immunoglobulins in the last 6 months prior to first administration of IMP or currently is on a follow-up visit for any other drug studies.
11. Unable to follow protocol instructions in the opinion of the Investigator.
12. Donation or loss of more than 500 mL of blood over a period of 90 days prior to first IMP administration.
13. Positive drug screen for alcohol and drugs of abuse (opiates, methadone, methamphetamines, phencyclidine, tetrahydrocannabinol, cocaine, amphetamines [including ecstasy], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, cotinine and alcohol) at screening and admission (Day-1), unless a positive result is attributable to a documented use of a concomitant medication and is approved by the Investigator. (In case of positive urine drug screen at screening or on Day -1 of Period 1. At the Investigator’s discretion, the drug screen test may be repeated in the possible instance of a false positive due to i.e., poppy seed consumption.)
14. History of alcohol abuse or excessive intake of alcohol in the past 2 years as judged by the Investigator.
15. Positive screen on hepatitis B surface antigen (HBsAg), hepatitis B core antibody, anti hepatitis C virus (HCV) antibodies, or anti-human immunodeficiency virus (HIV) 1/2 antibodies at screening.
16. Family history of acute myeloid leukemia or subjects with splenomegaly (spleen size greater than 13 cm in the craniocaudal dimension by ultrasound) at baseline, or with sickle cell disease.
17. Involvement of any Aurobindo Pharma Ltd., CuraTeQ Biologics GmbH, Contract Research Organization (CRO) or study center employee or their close relatives.

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)
Sealed opaque randomization envelopes
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
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, minimum, maximum and number of observations, unless otherwise stated. Categorical data will be summarized in terms of the number of subjects providing data at the relevant time point (n), frequency counts and percentages. Any planned collapsing of categories will be detailed in the SAP text and the data displays.
Data of subjects prematurely terminating the study will be used to the maximum possible extent. If a baseline value is missing or not reliable, the latest value before application of study medication will serve as baseline. Missing or incomplete dates of onset of adverse events and start of medications other than the study drug will be estimated in a conservative manner. Adverse events will be assumed to be treatment emergent and medications will be considered concomitant if it is not clear from the recorded onset and start dates, respectively.

Primary Endpoint(s)
Pharmacokinetic analysis:
Summary statistics will be used to describe the PK profiles of BP14 and Neulasta®-EU. Individual and mean serum concentration versus time curves will be presented for both linear and semi-log scales. Descriptive statistics (arithmetic and geometric mean, SD, coefficient of variation (CV%), minimum (min.), maximum (max.), and median of the serum concentrations by nominal time will be presented. Similarly descriptive statistics will be presented for the PK parameters.

A linear mixed effects model will be fitted separately on natural log transformed area under the time curve concentration (AUC(0-t)) and Cmax. The model will contain terms for sequence, period and treatment as fixed effects, and term for subject nested within sequence as random effect. Within the framework of this model, the difference between least squares means of BP14 and Neulasta®-EU will be exponentiated to obtain ratio of adjusted geometric means. Similarly, the 90% CI for the difference in least squares means obtained in natural logarithm scale will be exponentiated to obtain 90% CI for ratio of geometric means. A comparability range of 80 - 125% will be considered for assessment of clinical biosimilarity using above 90% CI for ratio of geometric means.

Pharmacodynamics analysis
The primary PD endpoints ANC AUC(0-t) and ANC Emax will be analyzed using analysis of covariance (ANCOVA). The ANCOVA model will contain terms for sequence, period and treatment as fixed effects, the term for subject nested within sequence as random effect and baseline ANC (pre-dose ANC in each period) as a covariate. Within the framework of this model, 95% CI for ratio of adjusted least squares means of BP14 and Neulasta®-EU will be obtained. A comparability range of 90 - 110% will be considered for assessment of clinical biosimilarity using above 95% CI for ratio of means.

Immunogenicity analysis:
Incidence of ADAs to PEG, PEG-GCSF, and GCSF PEG and their neutralizing potential will be summarized using frequency of ADA-positive and neutralizing antibody (NAb)-positive (if available) samples for each time point and overall for each treatment separately. The summarization will be based on all subjects who received at least one dose of the study drug.

Other Safety Analyses
Clinical safety will be evaluated by assessing treatment emergent AEs (TEAEs), physical examination, laboratory assessments, ECG and vital signs results in a descriptive manner. Original results and changes from baseline will be summarized for the laboratory data, vital signs, and ECG values. Values will be categorized as low/normal/high according to normal
ranges, and shift tables versus baseline will be created to determine treatment emergent abnormalities.
Adverse events will be collected and classified according NCI-CTCAE v5.0.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 15039 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 28323 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 304108 0
Commercial sector/Industry
Name [1] 304108 0
CURATEQ BIOLOGICS PRIVATE LIMITED
Address [1] 304108 0
PLOT NO.2, MAITRIVIHAR, AMEERPET,
HYDERABAD, Telangana,
India, 500038

Country [1] 304108 0
India
Primary sponsor type
Commercial sector/Industry
Name
CURATEQ BIOLOGICS PRIVATE LIMITED
Address
PLOT NO.2, MAITRIVIHAR, AMEERPET,
HYDERABAD, Telangana,
India, 500038
Country
India
Secondary sponsor category [1] 304324 0
Commercial sector/Industry
Name [1] 304324 0
Parexel International Pvt Ltd
Address [1] 304324 0
Suite B, Level 6
15 Talavera Road
North Ryde, NSW 2113, Australia
Country [1] 304324 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304598 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 304598 0
123 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 304598 0
Australia
Date submitted for ethics approval [1] 304598 0
30/10/2019
Approval date [1] 304598 0
24/02/2020
Ethics approval number [1] 304598 0

Summary
Brief summary
The purpose of this study is to compare the pharmacokinetics (what the body does to a drug), pharmacodynamics (effect of drugs on the body), immunogenicity (ability to provoke an immune response) and safety of BP14 with Neulasta in healthy males.

Who is it for?
You may be eligible to join this study if you are a healthy male aged 18 to 55 years.

Study details
All participants in this study will undergo two separate treatments in random order separated by a period of 42 days. One treatment involves administration of the ‘test product’, a drug called BP14 (pegfilgrastim). A single 6mg dose will be administered by injection under the skin (subcutaneous). The other treatment is a 6 mg injection of the European Union-approved drug, Neulasta. This drug is recommended for use in cancer patients undergoing chemotherapy, to reduce the incidence of infection.

All participants will undergo regular blood tests and safety assessments throughout the study, in order to evaluate how the body responds to the drug. We hope that BP14 (pegfilgrastim) will be comparable to Neulasta, warranting further investigational trials to evaluate its efficacy in cancer patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97526 0
Dr Kristi McLendon
Address 97526 0
Q-Pharm
300c Herston Road
Herston QLD 4006
Country 97526 0
Australia
Phone 97526 0
+61 7 3845 3637
Fax 97526 0
Email 97526 0
k.mclendon@nucleusnetwork.com.au
Contact person for public queries
Name 97527 0
Ms Vicki Rossi
Address 97527 0
Q-Pharm
300c Herston Road
Herston QLD 4006
Australia
Country 97527 0
Australia
Phone 97527 0
+61 7 3845 3637
Fax 97527 0
Email 97527 0
v.rossi@nucleusnetwork.com.au
Contact person for scientific queries
Name 97528 0
Dr Kristi Mclendon
Address 97528 0
Q-Pharm
300c Herston Road
Herston QLD 4006
Australia
Country 97528 0
Australia
Phone 97528 0
+61 7 3845 3637
Fax 97528 0
Email 97528 0
k.mclendon@nucleusnetwork.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be shared publicly as this is a phase 1 study and only aggregate data may be posted/published.
What supporting documents are/will be available?
No other documents available
Summary results
No Results