Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001341910
Ethics application status
Approved
Date submitted
9/10/2020
Date registered
14/12/2020
Date last updated
22/12/2021
Date data sharing statement initially provided
14/12/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Double-Blind, Randomized, Parallel, Controlled, Study to Compare Pharmacokinetics and Pharmacodynamics of BP13 (filgrastim) with EU-approved Neupogen® in Healthy Male Adult Subjects
Scientific title
A Double-Blind, Randomized, Parallel, Controlled, Study to Compare Pharmacokinetics and Pharmacodynamics of BP13 (filgrastim) with EU-approved Neupogen® in Healthy Male Adult Subjects
Secondary ID [1] 301974 0
Nil known
Universal Trial Number (UTN)
Trial acronym
BP13-101
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chemotherapy induced febrile neutropenia 318539 0
Condition category
Condition code
Blood 316545 316545 0 0
Other blood disorders
Cancer 316570 316570 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The treatments will be BP13 (Treatment A) and Neupogen (Treatment B), subjects will receive daily 5 mcg/kg/day subcutaneous (SC) injection of either BP13 or Neupogen from Day 1 to Day 5.
When participants are dosed at the site, they will receive investigational product (IP) directly from the Investigator or designee, under medical supervision.
Intervention code [1] 318285 0
Treatment: Drugs
Comparator / control treatment
Treatment B: One subcutaneous (SC) injection per day of Neupogen.
® for 5 days (Day 1 to Day 5).
Control group
Active

Outcomes
Primary outcome [1] 324703 0
To compare the PK of BP13 (filgrastim) with EU-approved Neupogen®
Timepoint [1] 324703 0
Assessed by pre dose, during dose and post dose blood sample collection and analysis.
Endpoints
PK:
AUC(0-t): AUC of the drug up to the last quantifiable concentration (Day 5)
Cmax: Maximum observed concentration of the drug in the serum (Day 5)
Blood samples for PK will be collected on Day 1: Pre-dose (between 5 and 45 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24h (Day 2); Days 2 to 4: Pre-dose, and Day 5: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24h (Day 6), 36, 48h (Day 7), 60, and 72h (Day 8). Time window for PK samples: between 30 to 0 hours pre dose, ±5 minutes for the first 2 hours post-dose, ±10 minutes for 2-24h, and ±30 minutes for >24h sample.
Primary outcome [2] 324704 0
To compare the PK and PD of BP13 (filgrastim) with EU approved Neupogen®
Timepoint [2] 324704 0
PD:
AUEC(0-t): AUEC from time 0 up to the last scheduled ANC sample (Day 5)
ANC Emax: Maximum observed ANC (Day 5) Pharmacodynamics of BP13 (filgrastim) with EU-approved Neupogen®

Blood samples for the determination of Pharmacodynamic ie CD34+ cells: 0 (i.e., between 5 and 45 minutes prior to dosing): Days 1 to 5 pre-dose samples, post Day 5 dose at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24h (Day 6), 36, 48h (Day 7), 60, 72h (Day 8), 84, 96h (Day 9), 108, 120h (Day 10), 144h (Day 11), 168h (Day 12), 216h (Day 14) and 240h (Day 15). Venous blood samples for the determination of ANC: Days 1 to 5 pre-dose samples, post Day 5 dose at 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24h (Day 6), 36, 48h (Day 7), 60, 72h (Day 8), 84, 96h (Day 9), 108 and 120h (Day 10). Time window for PD (CD34+) samples: between -30 to 0 hours pre dose, ±5 minutes for the first 2 hours post-dose, ±10 minutes for 2-24h, ±30 minutes >24h sample, and ±120 minutes for ambulatory visits. Time window for PD (ANC) samples: between -30 to 0 hours pre dose, ±5 minutes for the first 2 hours post-dose, ±10 minutes for 2-24h, and ±30 minutes >24h sample.
Secondary outcome [1] 385431 0
To compare the PK of BP13 (filgrastim) with EU-approved Neupogen®
Timepoint [1] 385431 0
AUC0-24: AUC of the drug from time 0 to 24 hours (Day 1)
Cmax: Maximum observed concentration of the drug in the serum (Day 1)
Tmax: Time of Maximum concentration observed (Day 1 and Day 5)
t1/2: Terminal elimination half-life of the drug (Day 5)
AUC0-inf: AUC of the drug extrapolated to infinite time (Day 5)
Ctrough: pre-dose concentration on (Days 2 to 5)

Blood samples for PK will be collected on Day 1: Pre-dose (between 5 and 45 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24h (Day 2); Days 2 to 4: Pre-dose, and Day 5: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24h (Day 6), 36, 48h (Day 7), 60, and 72h (Day 8). Time window for PK samples: between 30 to 0 hours pre dose, ±5 minutes for the first 2 hours post-dose, ±10 minutes for 2-24h, and ±30 minutes for >24h sample
Secondary outcome [2] 385432 0
To compare the PD of BP13 (filgrastim) with EU-approved Neupogen®
Timepoint [2] 385432 0
Measurement of ANC, CD34+ cell count and Tmax (Day 5)
Blood samples for the determination of Pharmacodynamic ie CD34+ cells: 0 (i.e., between 5 and 45 minutes prior to dosing): Days 1 to 5 pre-dose samples, post Day 5 dose at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24h (Day 6), 36, 48h (Day 7), 60, 72h (Day 8), 84, 96h (Day 9), 108, 120h (Day 10), 144h (Day 11), 168h (Day 12), 216h (Day 14) and 240h (Day 15). Venous blood samples for the determination of ANC: Days 1 to 5 pre-dose samples, post Day 5 dose at 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24h (Day 6), 36, 48h (Day 7), 60, 72h (Day 8), 84, 96h (Day 9), 108 and 120h (Day 10). Time window for PD (CD34+) samples: between -30 to 0 hours pre dose, ±5 minutes for the first 2 hours post-dose, ±10 minutes for 2-24h, ±30 minutes >24h sample, and ±120 minutes for ambulatory visits. Time window for PD (ANC) samples: between -30 to 0 hours pre dose, ±5 minutes for the first 2 hours post-dose, ±10 minutes for 2-24h, and ±30 minutes >24h sample
Secondary outcome [3] 385433 0
To compare CD34+ cell response between BP13, and EU-approved Neupogen®
assessed by blood samples collection
Timepoint [3] 385433 0
AUEC: AUEC of CD34+ cell count from Day 2 through 240 h post-dose on Day 5
CD34+max: Maximum observed CD34+ cell count on Day 5

Blood samples for the determination of Pharmacodynamic ie CD34+ cells: 0 (i.e., between 5 and 45 minutes prior to dosing): Days 1 to 5 pre-dose samples, post Day 5 dose at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24h (Day 6), 36, 48h (Day 7), 60, 72h (Day 8), 84, 96h (Day 9), 108, 120h (Day 10), 144h (Day 11), 168h (Day 12), 216h (Day 14) and 240h (Day 15).
Secondary outcome [4] 385434 0
To explore the potential immunogenicity of BP13 and EU-approved Neupogen®
These will be assessed with blood samples to measure ADAs
Timepoint [4] 385434 0
Presence of anti-GCSF antibodies
Anti-drug antibodies will be assessed during the pre-dose (0 hour) on Days 1 (baseline) to Day 5. Any ADA-positive (ADA+ve) subject should be followed up every 3 months until 12 months or until the subject is ADA-negative (ADA-ve), whichever comes first
Secondary outcome [5] 385435 0
To assess and compare the safety and tolerability of BP13 with EU-approved Neupogen®
They will be assessed by:
AEs, as defined by TEAEs, SAEs, related TEAEs and related SAEs
Laboratory parameters (hematology, clinical chemistry, urinalysis, vital signs, etc.)
Local Injection site reaction.
Safety analyses like calculation of risk ratios for bone pain events and myalgia events.
Monitoring of ADEs like alopecia, granulocytopenia, fever, nausea, vomiting, fatigue, and diarrhea
Secondary timepoint: AEs, as defined by TEAEs, SAEs, related TEAEs and related SAEs
Laboratory parameters (hematology, clinical chemistry, urinalysis, vital signs, etc.)
Biochemistry at screening, Day-1, Day 2, 6, 10 and 15
Hematology at screening, Day-1, Day 2,4, 6, 8,10, 12 and 15
Iron profile and Virology at screening visit
Urine analysis at screening,, Day -1, Day 6 and Day 15
Urine drug screen and alcohol breath tesy screening and Day -1
Local ISRs at all visits from Day 1 to Day 15
Safety analyses like calculation of risk ratios for bone pain events, myalgia events.
Monitoring of ADE’s like alopecia, granulocytopenia, fever, nausea, vomiting, fatigue, and diarrhea
Timepoint [5] 385435 0
AEs, as defined by TEAEs, SAEs, related TEAEs and related SAEs,
Safety analyses like calculation of risk ratios for bone pain events, myalgia events.
Monitoring of ADE’s like alopecia, granulocytopenia, fever, nausea, vomiting, fatigue, and diarrhea, will be measured at all study visits.
Laboratory parameters measured at the following time points:
Biochemistry at screening, Day-1, Day 2, 6, 10 and 15
Hematology at screening, Day-1, Day 2,4, 6, 8,10, 12 and 15
Iron profile and Virology at screening visit
Urine analysis at screening,, Day -1, Day 6 and Day 15
Urine drug screen and alcohol breath test screening and Day -1
Local ISRs at all visits from Day 1 to Day 15

Eligibility
Key inclusion criteria
1. Subject is 18 to 55 years of age inclusive, at the time of signing the informed consent form (ICF).
2. Subject is healthy as determined by medical evaluation including comprehensive medical history, physical examination, vital sign measurements, cardiac monitoring (12-lead electrocardiogram [ECG]), and clinical laboratory tests (including iron status transferrin saturation greater than or equal to 15%), unless considered not clinically significant by the Investigator. At Screening, a subject with a supine/semi supine systolic BP > 145 mmHG and/or a supine/semi supine diastolic BP > 90 mmHg. Two repetitions on the same day are allowed and, in this case, the mean of the 3 measurements will guide eligibility.
3. Subject has body mass index (BMI) within the range 18 – 35 kg/m2 (inclusive). Body weight should be less than or equal to 95 kg.
4. Subject is a male.
5. The subject must agree to use a highly effective double form of 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 ICF and in this protocol.
7. Non-smokers or casual smokers who smoke no more than 10 cigarettes (or equivalent quantity of any other nicotine containing substance) per week. Subject must abstain from smoking during the inpatient stay of the study.
8. Ability and willingness to abstain from alcohol during the study.
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 the Investigator’s discretion.
10. To rule out symptoms of glandular fever, subjects must test negative for antibodies to the Epstein-Barr virus at screening for study participation.
11. Must have normal organ function as per the Investigator’s judgment.
12. 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. The ULN is left to the discretion of the Investigator.
13. Must have adequate renal function defined as serum creatinine less than or equal to 1.5 x ULN.
Minimum age
18 Years
Maximum age
55 Years
Sex
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. As judged by the Investigator, any past or concurrent medical conditions, which in the opinion of the Investigator would potentially increase the subject’s risks or affect the evaluation of study results.
4. Any history of major surgery that in the opinion of the Investigator would interfere with the study or place the subject at risk.
5. Hereditary fructose and/or sorbitol intolerance.
6. Any history of previous exposure to pegfilgrastim or filgrastim, GCSF, or any analogue of these.
7. Hypersensitivity to the constituents of Neupogen®, filgrastim (acetate, polysorbate 20, sodium and sorbitol) or hypersensitivity to Escherichia. Coli derived proteins.
8. Treatment with non-topical medications within 5 days prior to admission to the study center (Day -1), with the exception of hormonal contraceptives, multivitamins, vitamin C, food supplements and a limited amount of paracetamol (acetaminophen), which may be used throughout the study.
9. Participation in a drug study involving hemopoietic growth factors, monoclonal antibodies, or immunoglobulins in the last 3 months prior to first administration of IMP or currently is on a follow-up visit for any other drug studies.
10. Unable to follow protocol instructions in the opinion of the Investigator.
11. Donation or loss of 470 mL or more of blood over a period of 90 days prior to first IMP administration.
12. Positive screen for alcohol breath test and/or positive screen for drugs of abuse (opiates, methadone, methamphetamines, phencyclidine, tetrahydrocannabinol, cocaine, amphetamines [including ecstasy], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants,) 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, 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).
13. History of alcohol abuse or excessive intake of alcohol in the past 2 years as judged by the Investigator.
14. Positive screen on hepatitis B surface antigen (HbsAg), hepatitis B core antibody, anti hepatitis C virus (HCV) antibodies, or anti-human immunodeficiency virus (HIV) ½ antibodies at screening.
15. Family history of acute myeloid leukemia or subjects with splenomegaly (spleen size >13 cm in the craniocaudal dimension by ultrasound) at baseline, or with sickle cell disease.
16. Involvement with any CURATEQ BIOLOGICS PRIVATE LIMITED, 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
Parallel
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 AEs and start of medications other than the IMP 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.
rimary Endpoints
Pharmacokinetic analysis:
Summary statistics will be used to describe the PK profiles of BP13 and EU-approved Neupogen®. 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, 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.
An analysis of variance (ANOVA) will be performed on In-transformed Day 5 AUC(o-t) and Cmax at the alpha level of 0.05. The ratio of geometric means (BP13/Neupogen®) and go% confidence interval for the ratio of geometric means, based on least-squares means from the ANOVA of the In-transformed data, will be calculated for Day 5 AUC(o-t) and Cmax, respectively. A comparability range of 80-125% will be considered for assessment of bio equivalence. Further details of aLL analyses will be described in the Statistical Analysis Plan.
Pharmacodynamics analysis
The primary PD endpoints: AUC(o-t) and Emax of ANC will be analyzed using ANOVA. A comparability

range of go% to 110% will be considered for assessment of bio equivalence.
Further details of aLL analyses will be described in the SAP.
Immunogenicity analysis:
The incidence of ADAs to filgrastim and their neutralizing potential and titer of positive 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 summary will be based on the safety population.
Safety analysis:
Safety will be assessed based on observed AEs, clinical laboratory tests, physical examinations and results from vital sign assessments and ECGs.
Safety analysis includes:
• AEs, as defined by TEAEs, SAEs, related TEAEs and related SAEs
o AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA v23.0) and will be tabulated by System Organ Class and Preferred Term.
• Laboratory parameters (hematology, clinical chemistry, urinalysis, vital signs, etc.)
• Monitoring of ADEs like alopecia, granulocytopenia, fever, nausea, vomiting, fatigue, and diarrhea.
• Calculation of risk ratios for bone pain events and myalgia events.
• Local injection site reactions (ISRs).
Other Safety Analyses
Clinical safety will be evaluated by assessing physical examination, ECG and vital sign results in a descriptive manner. Original results and changes from baseline will be summarized for the 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 to NCI-CTCAE v5.0.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
9/11/2020
Date of last participant enrolment
Anticipated
15/06/2021
Actual
13/05/2021
Date of last data collection
Anticipated
15/08/2021
Actual
27/05/2021
Sample size
Target
144
Accrual to date
Final
146
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 30935 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 306397 0
Commercial sector/Industry
Name [1] 306397 0
CURATEQ BIOLOGICS PRIVATE LIMITED
Country [1] 306397 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] 306903 0
Commercial sector/Industry
Name [1] 306903 0
Parexel International Pty Ltd
Address [1] 306903 0
Suite B, Level 6
15 Talavera Road
North Ryde, NSW 2113, Australia
Country [1] 306903 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306599 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 306599 0
Ethics committee country [1] 306599 0
Australia
Date submitted for ethics approval [1] 306599 0
13/05/2020
Approval date [1] 306599 0
17/06/2020
Ethics approval number [1] 306599 0
2020-03-242

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

Contacts
Principal investigator
Name 104414 0
Dr Kristi McLendon
Address 104414 0
Q-Pharm
300c Herston Road
Herston QLD 4006
Country 104414 0
Australia
Phone 104414 0
+61 7 3845 3637
Fax 104414 0
Email 104414 0
[email protected]
Contact person for public queries
Name 104415 0
Vicki Rossi
Address 104415 0
Q-Pharm
300c Herston Road
Herston QLD 4006
Country 104415 0
Australia
Phone 104415 0
+61 7 3845 3637
Fax 104415 0
Email 104415 0
[email protected]
Contact person for scientific queries
Name 104416 0
Kristi McLendon
Address 104416 0
Q-Pharm
300c Herston Road
Herston QLD 4006
Country 104416 0
Australia
Phone 104416 0
+61 7 3845 3637
Fax 104416 0
Email 104416 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
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 Supporting Document Provided



Results publications and other study-related documents

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