Comparative Immunogenicity Study of Multiple Doses of Proposed Pegfilgrastim Biosimilar, INTP5 of Intas Pharmaceuticals Ltd., India Against Neulasta of Amgen Inc., USA in Healthy, Adult Human Subjects.

Study Overview
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Brief Summary
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The study was an assessor-blind, balanced, parallel, randomized, two-treatment, comparative immunogenicity study of multiple doses of subcutaneous (SC) Pegfilgrastim injection (6 mg/0.6 mL; Intas Pharmaceuticals Ltd. proposed biosimilar INTP5 compared to innovator product, US-Neulasta) in healthy, adult, human subjects under fed conditions.

Official Title
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An Assessor-blind, Balanced, Parallel, Randomized, Two-treatment, Comparative Immunogenicity Study of Multiple Doses of INTP5 of Intas Pharmaceuticals Limited, India Against Neulasta® of Amgen Inc., USA Administered Subcutaneously in Healthy, Adult, Human Subjects Under Fed Condition.

Conditions
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Immunogenicity, Healthy Volunteers

Intervention / Treatment
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* Combination Product: INTP5
* Combination Product: US Neulasta


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Normal, healthy adult human volunteers between 18 to 45 years of age (both inclusive) living in and around Ahmedabad city or western part of India. Having body weight ≥50 kg and body mass index (BMI) between 18.5 and 29.9 (both inclusive), calculated as weight in kg/height in meter^2. Not having any significant disease in medical history or clinically significant abnormal findings during screening, abdominal ultrasonography, medical history, clinical examination, laboratory evaluations, 12-lead echocardiogram (ECG) and chest X-ray (posterior-anterior view; within the last 6 months) recordings. Able to understand and comply with the study procedures, in the opinion of the investigator. Able to give voluntary written informed consent for participation in the trial. In case of female subjects: Surgically sterilized at least 6 months prior to study participation; Or If a woman of child bearing potential is willing to use a suitable and effective double barrier contraceptive method or intra uterine device during the study. Serum pregnancy test (for female subjects) must be negative. Exclusion criteria: Known hypersensitivity to the study drug or its constituents and/or hypersensitivity to E. coli derived proteins, and/or previous exposure to the study drug. History or presence of any disease or condition which might compromise the haemopoietic, renal, hepatic, endocrine, pulmonary, central nervous, cardiovascular, immunological, dermatological, gastrointestinal or any other body system. Known case of hereditary fructose intolerance. Subjects with latex allergies will be excluded as the needle cover on the single-use prefilled syringe contains dry natural rubber (latex). Any clinically significant laboratory finding including absolute neutrophil count (ANC), platelet, red blood cells (RBC) count, and hemoglobin level at the time of screening. Prior exposure to any peptide colony stimulating or growth factor, including erythropoietin, filgrastim or Pegfilgrastim; Prior exposure to any vaccines, immunoglobulin preparations or immunomodulators within the past 6 months prior to receiving first dose; evidence of E. coli diarrhea or diseases within 3 months. Any history or presence of asthma (including aspirin-induced asthma) or nasal polyp or NSAIDs induced urticaria. Subjects with a history of pulmonary infiltrate or pneumonia in the last 6 months. History of any hematologic disease including sickle cell disorders. Ingestion or use of any prescribed medication at any time within 1 month prior to receiving first dose. Receipt of over-the-counter medicines which have not yet cleared from the body (5 half-lives must have passed for the medicine to be considered to have cleared from the body). A recent history of harmful use of alcohol, i.e. alcohol consumption of more than 14 standard drinks per week for men and more than 7 standard drinks per week for women (A standard drink is defined as 360 mL of beer or 150 mL of wine or 45 mL of 40% distilled spirits, such as rum, whisky, brandy etc.) or consumption of alcohol or alcoholic products within 72 hours prior to receiving study medicine. Smokers, who smoke 10 or more than 10 cigarettes/day or inability to abstain from smoking during the study. Use of any recreational drugs or history of drug addiction or testing positive in pre-study drug scans. Donation of blood (1 unit or 350 mL) or equivalent amount of blood substitute. Receipt of an investigational medicinal product or participation in a drug research study within a period of 90 days prior to the first dose of study medication. Elimination half-life of the study drug should be taken into consideration for inclusion of the subject in the study. Positive result for human immunodeficiency virus (HIV I &/or II) and/or hepatitis B and C tests. History or presence of cancer because of which anticipated life span is less than 5 years as per the investigator's assessment. History or presence of psychiatric disorders. Presence of tattoo or scars or any type of skin lesions due to infection, burning, wound or inflammation at the proposed site of injection. An unusual diet, for whatever reason (e.g. low-sodium), for 4 weeks prior to receiving the study medicine. In any such case, subject selection will be at the discretion of the Principal Investigator. Consumption of grape fruit or grape fruit products within 72 hours prior to receiving study drug. A history of difficulty in donating blood. Females, pregnant or lactating, or planning to become pregnant during the time the subject is on study or found positive in pregnancy test at screening. Any infections in the last 4 weeks before receiving study medication.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INTP5 biosimilar product<br>INTP5 subcutaneously at a dose of 6 mg/0.6 mL. | Combination Product: INTP5<br>* INTP5, a pegfilgrastim biosimilar to US Neulasta.<br>|
| Active Comparator: US Neulasta reference product<br>US Neulasta subcutaneously at a dose of 6 mg/0.6 mL. | Combination Product: US Neulasta<br>* US Neulasta: FDA approved pegfilgrastim innovator product.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity Screening Incidence to Detect the Presence of Anti-PegG-CSF Antibodies. | Immunogenicity (anti-drug antibody; ADA) data is presented for all subjects' samples collected and a descriptive analysis is provided for immunogenicity (ADA) data. Percentage incidence within + 10% of the expected ADA positivity incidence of Test (6% ADA in Test is anticipated from literature) is not considered clinically significant. Evaluation of immunogenicity is carried out in a tiered fashion: Screening assay to assess if samples were positive or negative for anti-PegG-CSF. Confirmatory assays for samples that were positive in the screening assay. The confirmatory assays assessed if antibodies were specific for INTP5, Neulasta, PEG and/or filgrastim. Titer assay was performed to determine titer of the anti-PEG-GCSF antibody samples. Neutralizing antibody (NAb) assay for those samples that were positive in the confirmatory assays to assess the neutralizing capability of the antibody to inhibit pegfilgrastim activity. | Samples (8 mL each) were withdrawn at screening, at pre-dose and at 336 (D-15, Week 2), 504 (D-22, Week 3, within 60 minutes before 2nd dose), 840 (D-36, Week 5), 1176 (D-50, Week 7), 1680 (D-71, Week 10) and 2016 (D-85, Week 12) hours after first dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Endpoints: Pegfilgrastim C[Max] | Pharmacokinetic (PK) properties of the test and reference formulations were assessed by measuring serum Pegfilgrastim concentration. Maximum measured serum concentration, calculated from the serum concentration vs. time profile of the individual subjects. | Venous blood samples (4 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) hours following 1st and 2nd dose, administration. | 
| PK Endpoints: Pegfilgrastim AUC[0-t] | Area under the serum concentration vs. time curve, calculated by linear trapezoidal rule from measured data points from the time zero to the time of last quantified concentration. | Venous blood samples (4 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) hours following 1st and 2nd dose, administration. | 
| PK Endpoints: Pegfilgrastim AUC[0-∞] | Area under the serum concentration versus time curve from time zero to infinity. Where AUC[0-infinity]= AUC[0-t] + Ct/lambda-z, Ct is the last measurable concentration and lamda-z is the terminal rate constant. AUC[0-infinity] is the sum of measurable and extrapolated parts. | Venous blood samples (4 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) hours following 1st and 2nd dose, administration. | 
| PK Endpoints: Pegfilgrastim T[Max] | The time of observing the peak concentration, calculated from the serum concentration vs. time profile of the individual subjects. | Venous blood samples (4 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) hours following 1st and 2nd dose, administration. | 
| PK Endpoints: Pegfilgrastim λz (Lambda-z) | Terminal rate constant: First order rate constant associated with the terminal (log-linear) portion of the curve. This was estimated via linear regression of time vs. log concentration. This parameter was calculated by linear least squares regression analysis using last three or more nonzero plasma concentration values. | Venous blood samples (4 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) hours following 1st and 2nd dose, administration. | 
| PK Endpoints: Pegfilgrastim R^2 Adjusted | Goodness of fit statistic for the terminal phase, adjusted for the number of points used in the estimation of λz (lambda-z). R^2 is the coefficient of determination and can range from 0 to 1, with higher values indicating greater predictability. | Venous blood samples (4 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) hours following 1st and 2nd dose, administration. | 
| PK Endpoints: Pegfilgrastim AUC[_%Extrap_Obs] | The residual area in percentage determined by the formula, [(AUC[0-infinity]-AUC[0-t])/AUC[0-infinity]] x 100. | Venous blood samples (4 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) hours following 1st and 2nd dose, administration. | 
| PK Endpoints: Pegfilgrastim t[1/2] | The terminal half-life calculated using the formula 0.693/(lambda-z) | Venous blood samples (4 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) hours following 1st and 2nd dose, administration. | 
| PD Endpoints for Baseline Non-adjusted ANC: E[Max] | Maximum measured absolute neutrophil count (ANC). | Venous blood samples (2 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) following 1st and 2nd dose administration. | 
| PD Endpoints for Baseline Non-adjusted ANC: T[Max] | Area under the ANC versus time curve from time zero to the last measurable concentration as calculated by linear trapezoidal method. | Venous blood samples (2 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) following 1st and 2nd dose administration. | 
| PD Endpoints for Baseline Non-adjusted ANC: AUEC[0-t] | Time to reach the maximum measured absolute neutrophil count (ANC) | Venous blood samples (2 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) following 1st and 2nd dose administration. | 
| PD Endpoints for Baseline Adjusted ANC: E[Max] | Maximum measured absolute neutrophil count (ANC). | Venous blood samples (2 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) following 1st and 2nd dose administration. | 
| PD Endpoints for Baseline Adjusted ANC: AUEC[0-t] | Area under the absolute neutrophil count (ANC) versus time curve from time zero to the last measurable concentration as calculated by linear trapezoidal method. | Venous blood samples (2 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) following 1st and 2nd dose administration. | 
| PD Endpoints for Baseline Adjusted ANC: T[Max] | Time to reach the maximum measured absolute neutrophil count (ANC) | Venous blood samples (2 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) following 1st and 2nd dose administration. | 
| PD Endpoints for Baseline Adjusted ANC: λz (Lambda-z) | First order rate constant associated with the terminal (log-linear) portion of the curve. This was estimated via linear regression of time vs. log concentration. This parameter was calculated by linear least squares regression analysis using last three or more non-zero plasma concentration values. | Venous blood samples (2 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) following 1st and 2nd dose administration. | 
| PD Endpoints for Baseline Adjusted ANC: t[1/2] | The terminal half-life will be calculated as 0.693/(lambda-z) | Venous blood samples (2 mL each) were withdrawn at pre-dose and at 8, 16, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 240 (Day 11), 336 (Day 15) and 504 (Day 22) following 1st and 2nd dose administration. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pegfilgrastim, Biosimilar, Immunogenicity, Pharmacokinetics, Pharmacodynamics, Safety, Healthy Volunteers