Conditions: Breast Cancer
Keywords: Breast Carcinoma Breast neoplasms Breast Tumors Cancer of Breast Anti-Drug Antibodies (ADA) Immunogenicity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 138
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the immunogenicity of Peg-filgrastim versus Neulasta® as an adjunct to chemotherapy in patients with breast cancer

Detailed description:
An open-label, randomized, comparative, parallel group study to assess the Immunogenicity of Lupin's Peg-filgrastim versus Neulasta® as an Adjunct to Chemotherapy in Patients with Breast Cancer

Primary Objective: To assess the immunogenicity of Lupin's Peg-filgrastim with Neulasta® in patients with breast cancer.

Secondary Objectives: To assess the safety of Lupin's Peg-filgrastim with Neulasta® in patients with breast cancer

Arms:
arm 1: 6 mg, subcutaneous injection on day 2/3 of each 21 ± 3 day cycle. Number of cycles: 4. arm 2: 6 mg, subcutaneous injection on day 2/3 of each 21 ± 3 day cycle. Number of cycles: 4.

Interventions: intervention 1: Lupin's Pegfilgrastim intervention 2: Neulasta®
Intervention descriptions: intervention 1: Administration of Pegfilgrastim intervention 2: Administration of Neulasta®

Protocol document:
Prot_SAP_000.pdf: 
16 APPENDICES 
 
16.1 
Study Information 
 
16.1.1 
Protocol and Protocol Amendments 
 
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Page 1 of 65
Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
CLINICAL STUDY PROTOCOL 
 
Title: 
An open-label, randomized, comparative, parallel group study 
to assess the Immunogenicity of Lupin’s Peg-filgrastim versus
Neulasta® as an Adjunct to Chemotherapy in Patients with 
Breast Cancer 
 
Protocol No. 
LRP/PegGCSF/2016/004 
Version No.: 2.2, Dated 02 Jul 2018;  
Supersedes: Version No.: 2.1, Dated 16 Oct 2017 
 
Name of Study Drug: 
Pegfilgrastim (PegGCSF) 
 
Development Phase: 
Phase 4 (In India) 
 
Sponsor: 
Lupin Limited (Biotechnology Division) 
Gat No: 1156, Village-Ghotawade, 
Taluka-Mulshi, Pune. Pin: 412115 
Maharashtra, India 
 
 
 
 
Sponsor Signatory: 
Dr. Dhananjay Bakhle/ Dr. Akshaya Odak 
 
 
 
 
 
This study will be conducted according to the protocol and in compliance with the International 
Conference on Harmonization - Good Clinical Practice (ICH - GCP) and applicable regulatory 
requirements. 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information of Lupin Limited. Do not copy or 
distribute without written permission from Lupin Limited. The confidential information 
in this document is provided to you as an Investigator, potential Investigator or 
consultant for review by you, your staff and applicable Ethics Committee. It is 
understood that the information will not be disclosed to others without written 
authorization from Lupin Limited except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 
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Page 2 of 65
Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 J ul 20 18 
SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE: An open-label, randomized, comparative, parallel group study to assess 
the Immunogenicity of Lupin's Peg-filgrastim versus Neulasta® as an Adjunct to 
Chemotherapy in Patients with Breast Cancer 
PROTOCOL NUMBER: LRP/PegGCSF/2016/004 
Dr. Akshaya Odak 
Head Regulatory Affairs, 
Lupin Limited (Biotechnology Division), 
Gat No.: 1156, Ghotawade, 
Tal-Mulshi, Pune-412115, 
Maharashtra, India 
Dr. Dhananjay Bakhle 
Executive Vice-President, 
Medical Research, 
Lupin Limited (Research Park), 
46A/47A, Nande, 
Tal-Mulshi, Pune-412115, 
Maharashtra, India 
CONFIDENTIAL 
/ r 
Voz=-~-\< 
Signature & Date 
~
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~~ ::r~~\g-
signature & Date 
Page 2 of60 
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Page 3 of 65
Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                        Page 3 of 60 
 
 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Lupin Limited 
Protocol No. 
LRP/PegGCSF/2016/004 
 
Name of Active Ingredient: 
Pegfilgrastim 
Title of Study: 
An open-label, randomized, comparative, parallel group study to assess the Immunogenicity of 
Lupin’s Peg-filgrastim versus Neulasta® as an Adjunct to Chemotherapy in Patients with Breast 
Cancer 
Study Site(s): 
Approximately 30 sites, in India, having qualified Investigators (Oncologists or other qualified 
clinicians). 
Planned Study Period: 
Q4 2017 to Q4 2018 
Development Phase: 
Phase 4 (In India) 
Objectives: 
Primary Objective: 
To assess the immunogenicity of Lupin’s Peg-filgrastim with Neulasta® in patients with breast cancer. 
Secondary Objectives: 
To assess the safety of Lupin’s Peg-filgrastim with Neulasta® in patients with breast cancer 
Study Design: 
Randomized, Open-Label, Two-Arm, Parallel, Multi-Center study 
Methodology: 
This study will be conducted in India. Patients with breast cancer who are eligible to receive 
Pegfilgrastim and willing to give informed consent will be randomized to receive either Lupin’s 
Pegfilgrastim or Neulasta® in 1:1 ratio.  
Pegfilgrastim will be administered subcutaneously once per chemotherapy cycle (of 21± 3 days) for 
up to 4 cycles. The myelosuppressive chemotherapy (like docetaxel/ paclitaxel/doxorubicin/ 
cyclophosphamide/ epirubicin) will be given on Day 1 of each cycle and Pegfilgrastim will be 
administered on Day 2/ Day 3 of each cycle (at least 24 hrs after chemotherapy administration). Blood 
samples for detection of anti-pegfilgrastim-antibodies against Pegfilgrastim, anti-peg antibodies, 
safety laboratory assessments, pharmacokinetic assessment (serum drug concentrations at baseline 
and trough [pre-dose]) and pharmacodynamic assessments (absolute neutrophil count [ANC]) will be 
collected at randomization (pre-dose) and on Day 10, Day 21 of cycle 1 and at the end of cycle 2 (Day 
42), cycle 3 (Day 63) and cycle 4 (Day 84). Adverse events will be monitored at all cycles during the 
study. Day 84 will be the End of Study (EOS) visit. 
Number of Patients: 
Approximately 150 patients will be randomized in this study. However, sample size will be re-
estimated based on interim analysis of ADA rate in first 75 patients. 
Diagnosis and Main Criteria for Inclusion: 
Ambulatory female patients aged ≥ 18 years with histologically or cytologically proven breast cancer 
receiving myelosuppressive chemotherapy that contains at least one chemotherapeutic agent from 
docetaxel/ paclitaxel / doxorubicin/ cyclophosphamide/ epirubicin and who are naïve to 
hematopoietic growth factors (e.g. G-CSF, PegGCSF) will be randomized in the study.  
Investigational Product (IP): 
The investigational products will be supplied as:  
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                        Page 4 of 60 
 
 
Name of Sponsor/Company: 
Lupin Limited 
Protocol No. 
LRP/PegGCSF/2016/004 
 
Name of Active Ingredient: 
Pegfilgrastim 
Test Product: Lupin’s Pegfilgrastim supplied as single-use, pre-filled syringe containing 6 mg of 
pegfilgrastim designed to deliver 6 mg pegfilgrastim  
Reference Product: Neulasta® supplied as single-use, pre-filled syringe containing 6 mg of 
pegfilgrastim  designed to deliver 6 mg pegfilgrastim 
Dose and Administration: 
Pegfilgrastim 6 mg (Neulasta® or Lupin’s Pegfilgrastim) will be administered once every 
chemotherapy cycle of 21 days for 4 cycles, as a subcutaneous injection to each patient. 
Study Duration: 91 days 
 
Screening Period: Maximum 7 full days 
 
Treatment and Subsequent Assessments: up to 4 chemotherapy cycles (84 days) 
Study Endpoints: 
Primary Endpoint: 
Comparison of cumulative incidence of anti-pegfilgrastim antibodies (binding & neutralizing) to 
Pegfilgrastim between treatment groups at the end of cycle 4 (Day 84).  
Secondary Endpoint: 
Secondary Immunogenicity Endpoints: 
 
Comparison of cumulative incidence of anti-peg antibodies (binding & neutralizing) between 
treatment groups at the end of cycle 4 (Day 84). 
 
Comparison of incidence of anti-pegfilgrastim antibodies (binding & neutralizing) to 
Pegfilgrastim between treatment groups on Day 10, Day 21, Day 42, Day 63 and Day 84. 
 
Comparison of incidence of anti-peg antibodies (binding & neutralizing) between treatment 
groups on Day 10, Day 21, Day 42, Day 63 and Day 84. 
Secondary Safety Endpoint: 
Safety during the study based on following assessment: 
 
Adverse Events (AE) assessment  
 
Vital signs  
 
Physical & systemic examination  
 
Laboratory parameters: Blood (hematology & biochemistry) and urinalysis 
Statistical Methods: 
Statistical analyses will be performed using SAS version 9.1.3 or higher. Immunogenicity will be 
assessed in the intent to treat (ITT) and per protocol (PP) populations. The ITT will be the primary 
immunogenicity analysis population. 
Primary analysis 
The difference in the proportion of patients with cumulative incidence of anti-pegfilgrastim 
antibodies (binding & neutralizing) to Pegfilgrastim between study groups at the end of cycle 4 (Day 
84) will be calculated, along with the one-sided 95% confidence interval for the difference in 
proportions.  Noninferiority will be assessed using a noninferiority margin of 10 percentage points. 
Sample size justification 
Noninferiority of Lupin’s Pegfilgrastim versus Neulasta® will be assessed based on the one-sided 
95% confidence interval for the difference between proportions using a noninferiority margin of 10 
percentage points.  For a two-arm, parallel-group trial with 1:1 randomization, and assuming true 
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Page 5 of 65
Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                        Page 5 of 60 
 
 
Name of Sponsor/Company: 
Lupin Limited 
Protocol No. 
LRP/PegGCSF/2016/004 
 
Name of Active Ingredient: 
Pegfilgrastim 
rates of 2% in each of the two arms, the required total sample size for 90% power is 128 patients 
(Farrington and Manning, 1990). The expected rate for incidence of anti-pegfilgrastim antibodies is 
based on the various studies with Neulasta® conducted across the globe. In order to allow for a 15% 
dropout rate, the planned total sample size is 150 patients.   
Interim analysis 
An interim analysis will be conducted when primary endpoint data are available for approximately 
50% of the planned total sample size (approximately 75 patients).  The overall proportion of patients 
with anti-pegfilgrastim antibodies (binding & neutralizing) to Pegfilgrastim and anti-peg antibodies 
at the end of cycle 4 (Day 84) will be estimated at interim analysis.  Based on the overall proportion, 
the sample size required for 90% power will be re-estimated using the approach of Farrington and 
Manning (1990). Safety of the drug will be also evaluated, in above set of patients, before the sample 
size re-estimation to rule out any drug related safety concerns. Descriptive statistics will be provided 
for safety analysis. 
During interim analysis, if any neutralizing anti-pegfilgrastim antibody activity is observed in the 
“Lupin Pegfilgrastim” arm or if the results from interim analysis clearly suggest that “Lupin 
Pegfilgrastim” has increased anti-pegfilgrastim antibody responses (greater than pre-specified 
amount 
of 
2%) 
compared 
to 
Neulasta® 
then 
appropriate 
decision 
about 
the 
continuation/discontinuation of the study will be taken by sponsor. 
 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                                                                      Page 6 of 60 
 
 
Table 1 
Schedule of Assessment 
D = Days, 
V = Visit 
C = Cycle 
EOS = End of Study 
Early 
Disc= 
Early
Discontinuation 
Screening 
period  
(Max 7 days) 
Treatment Phase 
Cycle 1 
(Study Days 1-21±3) 
Cycle 2 
(Study Days 22-42±3) 
Cycle 3 
(Study Days 43-63±3) 
Cycle 4 
(Study Days 64-84±3) 
D1 
(V1) 
D2 
Day 10 
±3 (V2) 
C1-D21 or  
C2-D1 (V3) * 
D2 
C2-D21 or  
C3-D1 (V4) * 
D2 
C3-D21or 
C4-D1 (V5) * 
D2 
D21/ EOS/ 
Early Disc. 
(V6) 12 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical and systemic 
examination 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Vital signs1  
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Weight 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Blood sampling for lab 
investigations 2  
X 
X 3, 9, 10 
 
 
X10 
 
X10 
 
X10 
 
X 
Urine sample for urine 
analysis 2 
X 
X10 
 
 
X10 
 
X10 
 
X10 
 
X 
Urine pregnancy test 4 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Serum Pregnancy test4 
X 
 
 
 
 
 
 
 
 
 
 
HIV, HBV and HCV 
X 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                                                                      Page 7 of 60 
 
 
D = Days, 
V = Visit 
C = Cycle 
EOS = End of Study 
Early 
Disc= 
Early
Discontinuation 
Screening 
period  
(Max 7 days) 
Treatment Phase 
Cycle 1 
(Study Days 1-21±3) 
Cycle 2 
(Study Days 22-42±3) 
Cycle 3 
(Study Days 43-63±3) 
Cycle 4 
(Study Days 64-84±3) 
D1 
(V1) 
D2 
Day 10 
±3 (V2) 
C1-D21 or  
C2-D1 (V3) * 
D2 
C2-D21 or  
C3-D1 (V4) * 
D2 
C3-D21or 
C4-D1 (V5) * 
D2 
D21/ EOS/ 
Early Disc. 
(V6) 12 
ECG 
X 
 
 
 
X9 
 
X9 
 
X9 
 
X 
Abdominal 
Ultrasonography 
(USG) 5 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent illnesses 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication/treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 6  
 
X 
 
 
 
 
 
 
 
 
 
Chemotherapy 
Administration 7 
 
X 
 
 
X 
 
X 
 
X 
 
 
Study 
Drug 
Administration 8 
 
 
X 
 
 
X 
 
X 
 
X 
 
Adverse 
event 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for 
immunogenicity 
assessments 
 
X11 
 
X 
X11 
 
X11 
 
X11 
 
X 
Blood sampling for 
PK assessments 
 
X11 
 
X 
X11 
 
X11 
 
X11 
 
X 
Blood sampling for 
 
X11 
 
X 
X11 
 
X11 
 
X11 
 
X 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                                                                      Page 8 of 60 
 
 
D = Days, 
V = Visit 
C = Cycle 
EOS = End of Study 
Early 
Disc= 
Early
Discontinuation 
Screening 
period  
(Max 7 days) 
Treatment Phase 
Cycle 1 
(Study Days 1-21±3) 
Cycle 2 
(Study Days 22-42±3) 
Cycle 3 
(Study Days 43-63±3) 
Cycle 4 
(Study Days 64-84±3) 
D1 
(V1) 
D2 
Day 10 
±3 (V2) 
C1-D21 or  
C2-D1 (V3) * 
D2 
C2-D21 or  
C3-D1 (V4) * 
D2 
C3-D21or 
C4-D1 (V5) * 
D2 
D21/ EOS/ 
Early Disc. 
(V6) 12 
ANC assessments 
 
Explanation of symbols used: 
* 
Day 21 assessments of previous cycle can be done on Day 1 (Pre chemotherapy) of next cycle. 
1             Includes body temperature, pulse rate, blood pressure, and respiratory rate.   
2 
Hematology: Complete blood count (CBC) [hemoglobin, hematocrit, red blood cells (RBCs), white blood cells (WBCs), platelets and differential blood cell counts 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils)], Absolute Neutrophil count  
Blood chemistry: Bilirubin (total, direct, indirect), alkaline phosphatase, ALT, AST, BUN, total protein, albumin, globulin, uric acid, urea, creatinine, random glucose, 
LDH. 
Urinalysis: Appearance, color, specific gravity, pH, protein, glucose, ketones, urobilinogen, occult blood (and microscopic examination, if abnormality is suspected). 
In case of premature termination of the study, these investigations should be repeated on the day of termination as far as possible 
3  
Hematology tests to be repeated if the gap between screening laboratory investigations and Cycle 1-Day 1 is more than 7 days.  
4 
In female patients of child-bearing potential. UPT should be repeated anytime during the study, if pregnancy is suspected. 
5 
Only in cases with clinically suspected splenomegaly. Abdominal USG should be repeated anytime during study if splenomegaly is suspected. 
6  
Randomization to be performed on the Day 1/2 of chemotherapy Cycle 1.  
7  
The chemotherapy to be started on Day 1. Chemotherapy may be given for 2 days as per site practice.  
8 
To be administered not less than 24 h after chemotherapy in each cycle (on day 2/3). In addition Pegfilgrastim treatment will not be given within 14 days period before 
the next chemotherapy.  
9 
Assessments to be done pre chemotherapy 
10  
Sampling for laboratory tests to be done on Day 1 (predose) and Day 21(of previous cycle) or Day 1(predose) of subsequent cycle. 
11  
Blood sampling for immunogenicity, PK and PD assessments will be done on Day 1 before the start of each chemotherapy cycle. 
12 
In case of early discontinuations/ premature termination of the study all EOS investigations should be done on the day of termination as far as possible 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                          Page 9 of 60 
 
 
Figure 1 
Study Flow Chart 
 
 
 
 
Visits & Assessments 
Screening: Eligibility 
Rand. V1– Randomization (Visit 1/ Day 1 of cycle 1): Immunogenicity at baseline  
Visit 2 (V2) – Day 10±3 of chemotherapy cycle 1: Immunogenicity, safety & PK-PD 
Visit 3 (V3) - end of chemotherapy cycle 1 (C1D21± 3)/ C2D1: Immunogenicity, safety & PK-PD 
Visit 4 (V4) - end of chemotherapy cycle 2 (C2D42± 3)/ C3D1: Immunogenicity, safety & PK-PD 
Visit 5 (V5) - end of chemotherapy cycle 3 (C3D63± 3)/ C4D1: Immunogenicity, safety & PK-PD 
Visit 6 (V6 EOS)* - end of chemotherapy cycle 4 (C4D84± 3)/End of Study visit or Early discontinuation visit: 
Immunogenicity, safety & PK-PD 
 
 C=Cycle, D=Day, EOS=End of Study, Early Disc=Early Discontinuation, PK= Pharmacokinetics, 
PD=Pharmacodynamics 
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Page 10 of 65
Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                          Page 10 of 60 
 
 
1 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................... 2 
STUDY SYNOPSIS ........................................................................................................... 3 
1 
TABLE OF CONTENTS .................................................................................... 10 
1.1 
List of Tables .......................................................................................... 14 
1.2 
List of Figures......................................................................................... 14 
2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................ 15 
3 
INTRODUCTION ............................................................................................... 17 
3.1 
Background............................................................................................. 17 
3.2 
Scientific Findings .................................................................................. 18 
3.3 
Rationale ................................................................................................. 19 
4 
STUDY OBJECTIVES ....................................................................................... 21 
4.1 
Primary Objective ................................................................................... 21 
4.2 
Secondary Objectives ............................................................................. 21 
5 
STUDY ENDPOINTS ......................................................................................... 22 
5.1 
Primary Endpoints .................................................................................. 22 
5.2 
Secondary Endpoints .............................................................................. 22 
5.2.1 
Secondary Immunogenicity Endpoint ............................................... 22 
5.2.2 
Secondary Safety Endpoint: ............................................................... 22 
6 
INVESTIGATIONAL PLAN .............................................................................. 23 
6.1 
Overall Study Design and Plan............................................................... 23 
6.2 
Discussion of Study Design.................................................................... 24 
6.2.1 
Choice of Study Population ............................................................... 24 
6.2.2 
Appropriateness of Measurements ..................................................... 24 
6.2.3 
Control Group .................................................................................... 25 
6.2.4 
Duration of Study .............................................................................. 25 
6.2.5 
Risk/ Benefit Ratio ............................................................................ 25 
6.3 
Schedule of Assessments ........................................................................ 26 
6.3.1 
Detailed Study Assessments .............................................................. 26 
6.4 
Selection of Study Population ................................................................ 30 
6.4.1 
Inclusion Criteria ............................................................................... 30 
6.4.2 
Exclusion Criteria .............................................................................. 31 
6.4.3 
Withdrawal of Patients....................................................................... 32 
6.4.4 
Rescreening of Patients ...................................................................... 32 
6.4.5 
Other Patient Restrictions .................................................................. 32 
6.4.6 
Early Termination of Study/ Site ....................................................... 33 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                          Page 11 of 60 
 
 
7 
TREATMENT OF PATIENTS AND INVESTIGATIONAL PRODUCT 
MANAGEMENT ................................................................................................ 34 
7.1 
Treatment of Patients .............................................................................. 34 
7.1.1 
Dosages & Treatment Regimen ......................................................... 34 
7.1.2 
Precautions while Administering Investigational Product (IP).......... 34 
7.1.3 
Randomization of Study Treatment(s) ............................................... 35 
7.1.4 
Blinding of Study Treatment ............................................................. 35 
7.1.5 
Patient Compliance ............................................................................ 35 
7.1.6 
Concomitant Therapy ........................................................................ 35 
7.2 
IP MANAGEMENT ............................................................................... 36 
7.2.1 
IP Dosage Form and Strength ............................................................ 36 
7.2.2 
IP Packaging and Labeling ................................................................ 36 
7.2.3 
Storage ............................................................................................... 36 
7.3 
IP Supply, Handling and Accountability ................................................ 37 
8 
ASSESSMENT OF IMMUNOGENICITY ......................................................... 38 
8.1 
Immunogenicity Endpoints .................................................................... 38 
8.2 
Immunogenicity Variables ..................................................................... 38 
8.3 
Anti-Pegfilgrastim and Anti-Peg Antibodies Detection ......................... 38 
8.3.1 
Collection, Handling and Analysis of Immunogenicity Samples ...... 38 
9 
ASSESSMENT OF SAFETY.............................................................................. 40 
9.1 
Adverse Events ....................................................................................... 40 
9.1.1 
Definitions ......................................................................................... 40 
9.1.2 
Recording and Collection of Adverse Events .................................... 41 
9.1.3 
Evaluation of Adverse Events ............................................................ 42 
9.2 
Physical and Systemic Examination ....................................................... 44 
9.3 
Vital Signs .............................................................................................. 44 
9.4 
Electrocardiogram Assessments (ECGs) ................................................ 45 
9.5 
Clinical Laboratory Examinations .......................................................... 45 
9.5.1 
Central Laboratory Samples .............................................................. 45 
9.6 
Pregnancy ............................................................................................... 46 
10 
ASSESSMENT OF PHARMACOKINETICS .................................................... 47 
10.1 
PK Parameters ........................................................................................ 47 
10.2 
Blood Sampling ...................................................................................... 47 
10.3 
Bioanalysis ............................................................................................. 47 
11 
ASESSMENT OF PHARMACODYNAMICS ................................................... 48 
11.1 
PD Parameters ........................................................................................ 48 
11.2 
Blood Sampling ...................................................................................... 48 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                          Page 12 of 60 
 
 
12 
STATISTICAL EVALUATION ......................................................................... 49 
12.1 
Sample Size and Power .......................................................................... 49 
12.2 
Statistical Methods ................................................................................. 49 
12.3 
Handling of Missing Data ...................................................................... 49 
12.4 
Patient Disposition.................................................................................. 49 
12.5 
Analysis Population ................................................................................ 49 
12.5.1 
Intention to Treat (ITT)...................................................................... 50 
12.5.2 
Per Protocol (PP) ............................................................................... 50 
12.5.3 
Immunogenicity Population ............................................................... 50 
12.5.4 
Safety Population ............................................................................... 50 
12.5.5 
Pharmacokinetic Population .............................................................. 50 
12.5.6 
Pharmacodynamic Population ........................................................... 50 
12.6 
Immunogenicity Analysis ....................................................................... 50 
12.6.1 
Primary Endpoint ............................................................................... 50 
12.6.2 
Secondary Immunogenicity Endpoint ............................................... 50 
12.7 
Safety Analysis ....................................................................................... 51 
12.7.1 
Parameters for Assessment of Safety ................................................. 51 
12.8 
Exploratory Analysis .............................................................................. 52 
12.9 
Interim Analysis for sample size adaptation .......................................... 52 
13 
DATA MANAGEMENT .................................................................................... 53 
13.1 
Data Handling ......................................................................................... 53 
14 
CLINICAL STUDY MANAGEMENT .............................................................. 54 
14.1 
Conduct of the Study .............................................................................. 54 
14.2 
Direct Access to Source Data ................................................................. 54 
14.3 
Amendments to the Protocol .................................................................. 54 
14.4 
Guidance and Supervision of Sub-Investigators .................................... 54 
14.5 
Archiving Study Records ....................................................................... 54 
15 
QUALITY ASSURANCE AND QUALITY CONTROL .................................. 55 
15.1 
Monitoring .............................................................................................. 55 
15.2 
Agreement and Compliance with the Protocol ....................................... 55 
15.3 
Audits and Inspections ........................................................................... 55 
16 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS .............................. 56 
16.1 
IEC/ IRB Approval ................................................................................. 56 
16.2 
Written Informed Consent ...................................................................... 56 
16.3 
Confidentiality ........................................................................................ 56 
16.4 
Liability and Insurance ........................................................................... 56 
16.5 
Publication Policy ................................................................................... 57 
17 
APPENDICES ..................................................................................................... 58 
17.1 
Appendix 1: Study Management Details ................................................ 58 
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17.2 
Appendix 2: Investigator’s Signature Page ............................................ 59 
18 
REFERENCE LIST ............................................................................................. 60 
 
 
 
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1.1 
List of Tables 
Table 1 
 Schedule of Assessment .............................................................................. 6 
Table 2 
 Doses and Treatment Regimen ................................................................. 34 
Table 3 
 IP Details ................................................................................................... 36 
Table 4 
 Clinical Laboratory Parameters ................................................................. 45 
Table 5 
Projected sample size adaptations for different proportions of anti-
pegfilgrastim antibodies (actual data) at interim analysis .......................... 52 
 
1.2 
List of Figures 
 
Figure 1 
Study Flow Chart ......................................................................................... 9 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Full form 
AC 
Doxorubicin and Cyclophosphamide 
ADA 
Anti-Drug Antibodies 
ADR 
Adverse Drug Reaction 
AE 
Adverse Events 
ALT 
Alanine Transaminase 
ANC 
Absolute neutrophil count  
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CIN 
Chemotherapy-induced neutropenia 
CMF 
Cyclophosphamide, Methotrexate, and Fluorouracil  
CRA 
Clinical Research Associate 
CRF/ eCRF 
Case Report Form/ electronic Case Report Form 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DNA 
Deoxyribose Nucleic Acid 
ECG 
Electrocardiogram 
EOS 
End of Study 
FN 
Febrile Neutropenia  
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HIV 
Human Immunodeficiency Virus 
hrs 
Hours 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IP 
Investigational Product 
IRB 
Institutional Review Board 
Ltd. 
Limited 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minutes 
ºC 
Degree Celsius 
ºF 
Degree Fahrenheit 
PCT 
Pre-clinical Toxicity 
PFS 
Pre filled syringe 
RP 
Reference Product 
SAE 
Serious Adverse Events 
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Abbreviation 
Full form 
SMP 
Safety Management Plan 
SUSAR 
Suspected Unexpected Serious Adverse Drug Reaction 
TEAE 
Treatment Emergent Adverse Events 
UPT 
Urine Pregnancy Test 
WHO 
World Health Organization 
WHO-DD 
World Health Organization –Drug Dictionary 
 
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3 
INTRODUCTION 
3.1 
Background 
The current treatment of cancer with combination of cytotoxic therapy targeting proliferating 
cells invariably leads to bone marrow damage, anaemia, thrombocytopenia and most 
importantly, neutropenia resulting in impaired host defence. Neutropenia is a significant 
hematologic complication induced by cancer chemotherapy. The clinical consequences of 
chemotherapy induced neutropenia are often severe and can be potentially life-threatening. 
Febrile neutropenia (FN) and other infectious complications are the most serious treatment-
related toxicities of chemotherapy, with a mortality rate up to 21%.1 
Chemotherapy-induced neutropenia (CIN) is the most common toxicity caused by the 
administration of anticancer drugs. In breast cancer patients, FN is relatively common. Up to 
23% of them experience at least 1 episode of FN secondary to standard chemotherapy, and this 
figure increase rapidly to 98% in patients exposed to high-dose chemotherapy regimens. An 
analysis of over 1,100 breast cancer patients treated with adjuvant cyclophosphamide, 
methotrexate, and fluorouracil (CMF), or doxorubicin and cyclophosphamide (AC), or other 
regimens showed that CIN was the most frequent cause of dose reductions and delays. In a 
large prospective registry, 37% of the breast cancer patients experienced an absolute neutrophil 
count (ANC) lower than 500 cells/mm3 over the first 4 cycles of treatment, and approximately 
70% of the initial episodes occurred in cycle 1.2 
Neutropenic complications associated with myelosuppressive chemotherapy are a significant 
cause of morbidity and mortality, possibly compromised treatment outcomes, and excess 
healthcare costs. The recovery of the bone marrow is stimulated by various growth factors. The 
prophylactic growth factors is recommended with such myelosuppressive drugs (e.g. 
docetaxel/ doxorubicin/ cyclophosphamide) where the risk of febrile neutropenia is 
approximately 20% or higher.3 Granulocyte colony stimulating factor (G-CSF) is one of the 
most important growth factor playing a role in recovery of neutrophils.4 
Pegfilgrastim (PegGCSF) is an approved, long-acting, next generation of granulocyte colony 
stimulating factor that has similar clinical benefits to Filgrastim but has novel pharmacokinetic 
properties. The "peg" in Pegfilgrastim refers to a polyethylene glycol, "PEG," unit that is added 
to enlarge the Filgrastim protein. This enlargement prolongs the length of time it stays in the 
body, and this allows for administration in a single dose per chemotherapy cycle. Various 
clinical trials have shown that once-per-cycle administration of Pegfilgrastim provides 
neutrophil support with safety and efficacy similar to that provided by daily injections of 
Filgrastim.5 
As per regulatory requirements, quality parameters have been established, a Pre-clinical 
Toxicity (PCT) studies has shown that Lupin’s Pegfilgrastim is safe in doses tested in this study 
and well tolerated. A Phase 3 comparative, clinical study to assess efficacy and safety of 
Lupin’s Pegfilgrastim versus Amgen’s Neulastim® as an adjunct to chemotherapy in patients 
with non-myeloid malignancies was conducted in India. This study compared the relative 
efficacy of Lupin’s Pegfilgrastim and Amgen’s Neulastim® and monitored the safety of 
patients. Based on the primary and secondary endpoint analysis, the efficacy & safety profile 
of Lupin’s Pegfilgrastim and Amgen’s Neulastim® were found to be comparable. DCGI (letter 
No.MF-186/ dated 03 September 2013) has given approval to market the product in India based 
on the result of Phase 3 study. Lupin is marketing its biosimilar product in India under the 
brand name Lupifil-P since 2015. Lupin, further intends to conduct a clinical study to market 
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its product in US. A PK- PD study and an immunogenicity & safety study are planned by Lupin 
in its development path of Lupin’s Pegfilgrastim. As, most of the biologic drug products elicit 
some level of anti- drug antibody. Hence, Lupin intends to know the immunogenicity and 
safety of Lupin’s Pegfilgrastim and Neulasta® in breast cancer patients. 
3.2 
Scientific Findings 
Innovator’s Pegfilgrastim (Neulasta®)/ the Reference Product (RP) was approved in 2002 in 
US. Neulasta® is indicated to decrease the incidence of infection, as manifested by febrile 
neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-
cancer drugs associated with a clinically significant incidence of febrile neutropenia and also 
indicated to increase survival in patients acutely exposed to myelosuppressive doses of 
radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome). It is contraindicated in 
patients with a history of serious allergic reactions to human granulocyte colony-stimulating 
factors such as pegfilgrastim or filgrastim.  
Neulasta® is supplied as prefilled syringe for manual subcutaneous injection or the On-body 
Injector containing 6 mg pegfilgrastim (based on protein weight) in a sterile, clear, colorless, 
preservative-free solution. It is recommended to store at 36- 46 oF (2- 8 oC). Pegfilgrastim 6 
mg (10 mg/ml) single dose is administered subcutaneously (SC) once in each chemotherapy 
cycle after at least 24 hrs of myelosuppressive chemotherapy. No Pegfilgrastim treatment is 
given within 14 days period before and within 24 hrs period after the chemotherapy. 
The pharmacokinetics of innovator’s pegfilgrastim was studied in patients with cancer. The 
pharmacokinetics of pegfilgrastim was nonlinear and clearance decreased with increases in 
dose. Neutrophil receptor binding is an important component of the clearance of pegfilgrastim, 
and serum clearance is directly related to the number of neutrophils. In addition to numbers of 
neutrophils, body weight appeared to be a factor. Patients with higher body weights 
experienced higher systemic exposure to pegfilgrastim after receiving a dose normalized for 
body weight. A large variability in the pharmacokinetics of pegfilgrastim was observed. The 
half-life of pegfilgrastim ranged from 15 to 80 hrs after subcutaneous injection. In healthy 
volunteers, the pharmacokinetics of pegfilgrastim was comparable when delivered 
subcutaneously.  
Renal dysfunction has no effect on PK of innovator’s pegfilgrastim thus; no special dose 
adjustment is required in renal impaired patients. In paediatric patients weight based dose 
adjust is required in patients below 45 kg weight. There are no adequate and well-controlled 
studies in pregnant women. Thus, Pegfilgrastim should be used during pregnancy only if the 
potential benefit to the mother justifies the potential risk to the foetus. Caution should be 
exercised when administered to a nursing woman as it is not known whether pegfilgrastim is 
secreted in human milk. 
The most common adverse reactions (≥5 %) (reported more frequently in innovator’s 
pegfilgrastim-treated subjects than control subjects) are bone pain and pain in extremity. 
Serious adverse events observed with pegfilgrastim administration are splenic rupture, Acute 
respiratory distress syndrome, Serious allergic reactions, Allergies to acrylics, Sickle cell crisis, 
Glomerulonephritis, Leucocytosis, Capillary leak syndrome, Potential for tumour growth 
stimulatory effects on malignant cells.  
The efficacy and safety data in patients with cancer receiving myelosuppressive chemotherapy 
is derived from three clinical trials. The results showed that the mean days of severe 
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neutropenia of innovator’s pegfilgrastim-treated patients did not exceed that of filgrastim 
treated patients by more than 1 day in cycle 1 of chemotherapy. 
The investigational biosimilar of Lupin Limited is also supplied as single-dose‚ pre-filled 
syringes containing fixed dose of 6 mg/0.6 ml (10 mg/ml) subcutaneous injection of 
Pegfilgrastim. The Pre-clinical Toxicity (PCT) study that has been conducted with Lupin’s 
Pegfilgrastim includes acute toxicity studies, repeated dose 28-day tests, skin sensitization test, 
and primary skin irritation test. 
Lupin’s pegfilgrastim was compared head-to-head with Neulastim®.as a part of extensive 
characterization program. Various non-clinical studies conducted so far, have established 
similarity of Lupin’s pegfilgrastim to Neulastim®. 
In Phase 3 open-label, multi-centre, randomized study conducted in India, in 170 patients with 
non-myeloid malignancies, the efficacy and safety of Lupin’s pegfilgrastim versus Neulastim® 
was found to be comparable. The primary endpoint, mean DSN in cycle 1 (0.127 days in 
Lupin’s pegfilgrastim arm and 0.197 days in Neulastim® arm) did not differ significantly (p = 
0.5167, unpaired t-test) between two treatment arms. The 95% CI of the differences in mean 
DSN between the two groups laid well within the predefined interval (-1 to +1 day) for 
equivalence [-0.2796, 0.1481 ANCOVA for PP population]. The 95% CI of the differences in 
mean DSN between the two groups for mITT population also laid well within the predefined 
interval. The two groups were found to be comparable and demonstrated equivalence with 
respect to secondary efficacy endpoints such as DSN for Cycle 2, proportions of patients with 
severe neutropenia, time to ANC recovery, incidence of febrile neutropenia, rates of 
hospitalization and antibiotics use due to febrile neutropenia and depth of ANC nadir.  
The incidence of AEs and AE profile were comparable between both the treatment groups 
across all cycles. The common ADRs experienced in Lupin’s Pegfilgrastim group were 
neutrophilia, bone pain, musculoskeletal pain, constipation, pain, pyrexia, pancytopenia, and 
leukocytosis. In Neulastim®, the ADRs observed were neutrophilia & musculoskeletal pain. 
The musculoskeletal pain of severe degree was the only ADR noted once in each arm. Out of 
SAEs reported, there was one fatal event (diseases related complications) in each of the 
treatment arm. No patient was withdrawn from the study due to AE in any of the arms. There 
were no statistically significant differences in the incidence of AE, ADR or SAEs in any of the 
cycles between Lupin’s Pegfilgrastim and Amgen’s Neulastim®.  
Therefore, Lupin, further intends to conduct a clinical study to market its product in US. 
3.3 
Rationale 
Pegfilgrastim is the pegylated form of recombinant methionyl human Filgrastim. Filgrastim is 
a water-soluble 175 amino acid protein with a molecular weight of approximately 19 kilo 
Daltons (kD). Filgrastim is obtained from the bacterial fermentation of a strain of Escherichia 
coli transformed with a genetically engineered plasmid containing the human G-CSF gene. To 
produce Pegfilgrastim, a 20 kD monomethoxypolyethylene glycol molecule is covalently 
bound to the N-terminal methionyl residue of Filgrastim. The average molecular weight of 
Pegfilgrastim is approximately 39 kD. 
Pegfilgrastim is a colony-stimulating factor that acts on hematopoietic cells by binding to 
specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, 
and end cell functional activation. 
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Pegfilgrastim is a valuable treatment option for patients with non-myeloid malignancies 
receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence 
of febrile neutropenia. Pegfilgrastim is an approved, long-acting, next generation of G-CSF 
that has similar clinical benefits to Filgrastim but has novel pharmacokinetic properties. The 
safety and tolerability of Innovator’s Pegfilgrastim has been studied in various Phase I –IV 
clinical studies. The results have demonstrated well accepted efficacy and safety profile. The 
pegfilgrastim is approved and available in the market globally since 2002. Therefore, the risks 
are well known and the benefits outweigh the risks for the treatment of incidence of febrile 
neutropenia.  
As with all therapeutic proteins, there is a potential for immunogenicity. Most biological drug 
products elicit some level of anti-drug antibody (ADA) response. This antibody response can, 
in some cases, lead to potentially serious side effects and/or loss of efficacy although no such 
effect was observed with Innovator’s product. In humans, ADA often causes no detectable 
clinical effects, but in the instances of some therapeutic proteins these antibodies have been 
shown to cause a variety of clinical consequences ranging from relatively mild to serious 
adverse events.6 The US FDA7 and EMEA8 in its guidelines recommend for evaluating and 
mitigating immune responses to or adverse immunologically related responses associated with 
therapeutic protein products that affect their safety and efficacy.  
The immunogenicity studies of binding antibodies to innovator’s pegfilgrastim were detected 
using a BIAcore assay. The approximate limit of detection for this assay was 500 ng/mL. Pre-
existing binding antibodies were detected in approximately 6% (51/849) of patients with 
metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at 
baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 
patients had evidence of neutralizing antibodies detected using a cell-based bioassay.9,10  
Lupin Limited has developed an investigational product similar to Pegfilgrastim. Pre-clinical 
studies of Lupin’s Pegfilgrastim were found to be safe and well tolerated. Phase 3 study 
conducted in India proved the efficacy & safety profile of Lupin’s Pegfilgrastim and Amgen’s 
Neulastim® were comparable. Lupin, further intends to conduct a clinical study to market its 
product in US. As, most of the biologic drug products elicit some level of anti- drug antibody. 
Thus, Lupin intends to know the immunogenicity and safety of Lupin’s Pegfilgrastim and 
Neulasta® in breast cancer patients. 
 
 
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4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
To assess the immunogenicity of Lupin’s Peg-filgrastim with Neulasta® in patients with 
breast cancer  
4.2 
Secondary Objectives 
To assess the safety of Lupin’s Peg-filgrastim with Neulasta® in patients with breast 
cancer  
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5 
STUDY ENDPOINTS 
5.1 
Primary Endpoints 
 Comparison of cumulative incidence of anti-pegfilgrastim antibodies (binding & 
neutralizing) to Pegfilgrastim between treatment groups at the end of cycle 4 (Day 84). 
5.2 
Secondary Endpoints 
5.2.1 
Secondary Immunogenicity Endpoint 
 Comparison of cumulative incidence of anti-peg antibodies (binding & neutralizing) 
between treatment groups at the end of cycle 4 (Day 84). 
 Comparison of incidence of anti-pegfilgrastim antibodies (binding & neutralizing) to 
Pegfilgrastim between treatment groups on Day 10, Day 21, Day 42, Day 63 and Day 
84. 
 Comparison of incidence of anti-peg antibodies (binding & neutralizing) between 
treatment groups on Day 10, Day 21, Day 42, Day 63 and Day 84. 
5.2.2 
Secondary Safety Endpoint: 
 Adverse event (AE) assessment  
 Vital signs 
 Physical & systemic examinations 
 Laboratory parameters: Blood (hematology & biochemistry) and urinalysis 
  
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6 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan 
This is a randomized, comparative, parallel group, two arms, open label, multi-center clinical 
study will be conducted in India. The objective of the study is to compare the immunogenicity 
and safety of Lupin’s Pegfilgrastim to that of Neulasta® in patients with breast cancer who are 
scheduled to receive myelosuppressive chemotherapy (like docetaxel/ paclitaxel/ doxorubicin/ 
cyclophosphamide/ epirubicin) and who are eligible to receive Pegfilgrastim. 
Approximately 30 sites in India, having qualified investigators (Oncologists or other qualified 
clinicians). Study will be initiated only after receipt of regulatory and EC approval. Screening 
investigations on patient will be done only after signing of written informed consent. Initially, 
approximately 150 patients will be randomized in the study. However, sample size will be re-
estimated based on interim analysis of ADA rate in first 75 patients (Section 12.9). 
Total 4 injections (Neulasta® or Lupin’s Pegfilgrastim 6 mg subcutaneous injection, once per 
chemotherapy cycle) will be given to each patient during the study. The chemotherapy cycle 
will be of 21±3 days each. The duration of the treatment will be of 84 days (up to 4 
chemotherapy cycle) during which the immunogenicity, safety, PK-PD (Peg-GCSF serum 
trough [pre-dose] concentrations and ANC) assessments will be done. The total study duration 
for each patient would be around 91 days. It will include 7 days of screening period and 84 
days of treatment & assessment period.   
The study consists of following parts (Figure 1): 
 Screening Period (maximum 7 full days) 
 Treatment and assessment period (84 days) which consists of 4 chemotherapy cycles 
where each chemotherapy cycle will be of 21± 3 days.   
o Day 1: First day of each cycle & also first day for chemotherapy 
o Randomisation Day: Day 1/2 of first chemotherapy cycle. 
o Day 2/ Day 3 of each cycle: Pegfilgrastim administration day 
o Day 10 of Cycle 1: Assessment of immunogenicity, safety and PK-PD 
o Day 21 of each cycle: Assessment of immunogenicity, safety and PK-PD (this 
can be clubbed with Day 1 of next cycle and can be done pre-dose of Day 1 of 
next cycle) 
o Day 84 i.e. Day 21 of cycle 4 (End of Study/Early Discontinuation) 
After signing the informed consent form, the patients will undergo screening assessments to 
confirm eligibility as mentioned in Section 6.3.1.1 and Table 1.  
Screening period will be of maximum 7 full days. The eligible patients will receive the 
chemotherapy on Day1/ 2. The patients will be randomized in 1:1 ratio on Day 1/ 2 to receive 
either Lupin’s Pegfilgrastim or Neulasta® as a subcutaneous injection once per chemotherapy 
cycle on Day 2/ 3. The patients will visit the clinical facility on Day 21 of each chemotherapy 
cycle for blood sampling for immunogenicity and safety assessment. In addition in cycle 1, 
patient will visit the clinical facility on Day 10 for immunogenicity, safety and PK-PD 
assessments. Day 21 of each chemotherapy cycle can be clubbed with Day 1 of subsequent 
cycle and assessments of Day 21 will be done prior to chemotherapy administration on Day 1 
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of next cycle. The investigational product will be administered by the investigator/ qualified 
person designated by the site. 
Assessment of immunogenicity and safety will be done periodically during the study as given 
in the schedule of assessment table (Table 1).  
Safety includes adverse event (AE) assessment, physical and systemic examination and 
assessment of vital signs and laboratory parameters.  
6.2 
Discussion of Study Design 
This is a prospective, open label, randomized, two arms, parallel group, multicenter, 
interventional study to be carried out in patients with breast cancer. The present study is 
designed in conformance with guidelines on biosimilar development which requires 
assessment of immunogenicity and safety between investigational biologic and the reference 
product, thus, Neulasta® has been chosen as a comparator. Randomization method will be used 
to avoid selection and evaluation bias. 
Breast cancer patients eligible for neo-adjuvant or adjuvant chemotherapy will be randomized 
in the study. The dose chosen for the study is 6 mg subcutaneous injection once per 
chemotherapy cycle which is also the approved and recommended dose of the Neulasta® for 
this indication. 
Therefore, to assess immunogenicity and safety of Lupin’s Pegfilgrastim with Neulasta® a 
randomized, open-label, two-arm, parallel, multi-center study design is deemed to be most 
appropriate. 
6.2.1 
Choice of Study Population 
Pegfilgrastim is indicated to decrease the incidence of infection, as manifested by febrile 
neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-
cancer drugs associated with a clinically significant incidence of febrile neutropenia. The 
efficacy, safety and immunogenicity of Neulasta® are well studied in breast cancer patients. 
Pre-existing binding antibodies were detected in patients with metastatic breast cancer with 
Neulasta®. Although, 0-6% incidence of binding anti-pegfilgrastim antibody was observed in 
various studies with Neulasta® conducted across the globe, none of the studies reported 
incidence of neutralizing anti-pegfilgrastim antibodies9-13. While conducting such a study may 
be possible in healthy subjects, it would require parallel group design doubling the healthy 
subjects and may not extrapolate real-life clinical setting. Therefore, conducting the study in 
breast cancer patients is well justified. As Lupin aims to assess immunogenicity and safety of 
its investigational product with Neulasta® and to have a homogenous patient population in 
accordance with the guidelines thus, breast cancer patients are chosen as study population in 
this study. 
Considering these factors, the chosen study population is appropriate for the study. 
6.2.2 
Appropriateness of Measurements 
The primary & secondary endpoints chosen for the study are the ones used during development 
of Neulasta® and well accepted by various regulatory agencies. Similarly, other safety 
parameters proposed are also in line with the conventional endpoints used in such type of 
studies. Biologic drugs commonly elicit immune responses, resulting in anti-drug antibodies. 
Formation of anti-drug antibodies can have a number of effects like reduced efficacy, rapid 
clearance etc. Pegfilgrastim is a biologically derived product thus, formation of antibodies 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                          Page 25 of 60 
 
 
(both binding and neutralizing) to pegfilgrastim or anti-peg antibodies and safety are 
considered as appropriate endpoint for this study. 
6.2.3 
Control Group 
The biosimilar development requires a comparative similarity with reference product at all 
steps of development. Accordingly, present study has reference product Neulasta® as the active 
control arm. 
6.2.4 
Duration of Study 
Since this study is designed to evaluate immunogenicity and safety of pegfilgrastim, the dosage 
schedule in this study is Pegfilgrastim single dose of 6 mg subcutaneous injection per 
chemotherapy cycle. The treatment period includes 4 chemotherapy cycles of 21± 3 days each 
cycle, which is considered to be sufficient for assessing the immunogenicity. 
Including the screening period of up to 7 days, the total duration is expected to be around 91 
days. Hence, treatment duration of 4 chemotherapy cycle (84 days) is proposed for the study. 
6.2.5 
Risk/ Benefit Ratio 
Neulasta® which is reference product for this study, approved first in 2002 by US-FDA, is well 
established for treatment of decrease the incidence of infection, as manifested by FN, in patients 
with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs which have a 
clinically significant incidence of febrile neutropenia; therefore, the risks and benefits are well 
known. The recommended dose is 6 mg to be administered subcutaneously once per 
chemotherapy cycle (each cycle of 21 days) after at least 24 hours of myelosuppressive 
chemotherapy.  
The efficacy and safety data is derived from three clinical studies in cancer patients receiving 
myelosuppressive chemotherapy. The results showed that the mean days of severe neutropenia 
of peg-filgrastim treated patients did not exceed than that of filgrastim-treated patients by more 
than 1 day in cycle 1 of chemotherapy. 
The most common adverse reactions (≥5 %) (reported more frequently in innovator’s Peg-
filgrastim-treated subjects than control subjects) are bone pain and pain in extremity. Serious 
adverse events observed with innovator’s peg-filgrastim administration are splenic rupture, 
acute respiratory distress syndrome, serious allergic reactions, allergies to acrylics, sickle cell 
crisis, glomerulonephritis, leukocytosis, capillary leak syndrome, potential for tumor growth 
stimulatory effects on malignant cells. In Phase 3 study conducted in India, the common ADRs 
experienced in Lupin’s Pegfilgrastim group were neutrophilia, bone pain, musculoskeletal 
pain, constipation, pain, pyrexia, pancytopenia, and leukocytosis. The SAE reported in Lupin’s 
Pegfilgrastim group were hemoptysis, gastroenteritis, abdominal discomfort, cellulitis of neck, 
musculoskeletal pain, asthenia, febrile neutropenia, pancytopenia, severe aspiration due to 
tumoral bleed, pyrexia. 
The purpose of this study is to compare the immunogenicity and safety of Lupin’s 
Pegfilgrastim versus Neulasta® in breast cancer patients. Based on the available preclinical 
information, Lupin’s pegfilgrastim is expected to show similarity in terms of immunogenicity 
and safety.  Therefore, participation in study is expected to yield benefit to the patients during 
the study similar to innovator i.e. preventing from febrile neutropenia. Besides, the safety of 
each patient will be monitored periodically by assessing vitals, laboratory and physical 
examination to minimize the risks. The cost of pegfilgrastim treatment and the investigations 
done for the study will be borne by the Sponsor. As confirmed from the preclinical and clinical 
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Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
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Phase 3 study conducted in India, risks due to Lupin’s Pegfilgrastim treatment is expected to 
be similar to those known to Neulasta® provided precautions are taken care of. Lupin’s 
Pegfilgrastim has been evaluated in a Phase 3 study in India and based on this marketing 
authorization has been granted by DCGI. Lupin’s Pegfilgrastim is available in Indian market 
and hence its safety has been well established. Thus, the risk benefit ratio seems favourable 
and the study is ethically justified. Additionally, the approval of biosimilar helps indirectly to 
whole society as it will open an additional cost-effective therapeutic option for patients with 
non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a 
clinically significant incidence of febrile neutropenia.  
6.3 
Schedule of Assessments 
The schedule of assessments to be performed at each visit is indicated in Table 1. For details, 
refer Section 6.3.1 given below. 
6.3.1 
Detailed Study Assessments 
The objective of this clinical study is to study immunogenicity and safety of Lupin’s 
Pegfilgrastim in comparison with Neulasta®.  
The following assessments will be performed at each study visit: 
6.3.1.1 
Screening Visit (Maximum 7 full days) 
Screening procedures are as follows: 
 Obtain written informed consent as per regulatory requirement 
 Record demographic data 
 Record medical and surgical history  
 Record concomitant medication/ treatment. 
 Record concurrent illness 
 Vital signs assessment 
 Perform physical & systemic examination  
 Record weight 
 Perform ECG 
 Perform chest X-ray 
 Perform abdominal ultrasonography 
 Perform clinical laboratory assessment (hematology and biochemistry) 
 Perform urinalysis 
 Assessment of serological tests for human immunodeficiency virus (HIV), Hepatitis B 
virus (HBsAg), Hepatitis C virus (HCV)  
 Perform urine pregnancy test and serum pregnancy test in females of child bearing 
potential only 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
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 Adverse event assessment 
 Assess patient eligibility against inclusion and exclusion criteria.  
 The eligible patients will be informed about Randomization  
6.3.1.2 
Treatment Period (84 days) 
The treatment period consist of 4 chemotherapy cycles (each cycle of 21± 3 days) 
6.3.1.2.1 CYCLE 1 (Study days 1-21 ± 3)  
6.3.1.2.1.1 Visit 1: Day 1 (Randomization and Chemotherapy Administration) 
 Perform physical & systemic examination 
 Vital signs 
 Blood sampling for Lab investigations (hematology and biochemistry) [Hematology 
tests not to be repeated if the gap between screening laboratory investigations and Cycle 
1-Day 1 is less than 7 days.] 
 Blood sampling for immunogenicity and PK-PD assessments (before chemotherapy 
administration) 
 Perform urinalysis 
 Randomization  
 Record concurrent illness 
 Record changes in concomitant medication/ treatment 
 Chemotherapy administration 
 Adverse event assessment 
6.3.1.2.1.2 Day 2 of Cycle 1 (Study drug administration day) 
 Record concurrent illness 
 Randomization (If not done on Day 1) 
 Record changes in concomitant medication/ treatment 
 Study drug administration 
 Adverse event assessment 
6.3.1.2.1.3 Visit 2: Day 10 of Cycle 1  
 Perform physical & systemic examination 
 Vital signs 
 Record concurrent illness 
 Blood sampling for immunogenicity and PK-PD assessments 
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Clinical Study Report version 1.0, 05 Dec 2019


 
 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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 Record changes in concomitant medication/ treatment 
 Adverse event assessment 
6.3.1.2.1.4 Visit 3: Day 21 of cycle 1/ Day 1 of cycle 2  
 Pre-chemotherapy administration 
o Perform physical & systemic examination 
o Vital signs 
o Record weight 
o Perform ECG 
o Blood sampling for Lab investigations (hematology and biochemistry) 
o Blood sampling for immunogenicity and PK-PD assessments  
o Perform urinalysis 
o Perform urine pregnancy test  
o Record concurrent illness 
 Chemotherapy administration 
 Record changes in concomitant medication/ treatment  
 Adverse event assessment  
6.3.1.2.2 CYCLE 2 (Study days 22-42 ± 3)  
6.3.1.2.2.1 Day 2 of cycle 2 (Day 23± 3) 
 Record concurrent illness 
 Record changes in concomitant medication/ treatment 
 Study drug administration 
 Adverse event assessment 
6.3.1.2.2.2 Visit 4: Day 21 of cycle 2/ Day 1 of cycle 3  
 Pre-chemotherapy administration 
o Perform physical & systemic examination 
o Vital signs 
o Record weight 
o Blood sampling for Lab investigations (hematology and biochemistry) 
o Blood sampling for immunogenicity and PK-PD assessments 
o Perform urinalysis 
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                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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o Perform urine pregnancy test 
o Record ECG 
o Record concurrent illness  
 Chemotherapy administration 
 Record changes in concomitant medication/ treatment 
 Adverse event assessment 
6.3.1.2.3 CYCLE 3 (Study days 43-63 ± 3) 
6.3.1.2.3.1 Day 2 of cycle 3 (Day 44± 3) 
 Record concurrent illness 
 Record changes in concomitant medication/ treatment 
 Study drug administration 
 Adverse event assessment 
6.3.1.2.3.2 Visit 5: Day 21 of cycle 3/ Day 1 of cycle 4 
 Pre-chemotherapy administration 
o Perform physical & systemic examination 
o Vital signs 
o Record weight 
o Perform ECG 
o Blood sampling for Lab investigations (hematology and biochemistry) 
o Blood sampling for immunogenicity and PK-PD assessments 
o Perform urinalysis 
o Perform urine pregnancy test 
o Record concurrent illness 
 Chemotherapy administration 
 Record changes in concomitant medication/ treatment 
 Adverse event assessment 
6.3.1.2.4 CYCLE 4 (Study days 64- 84 ± 3) 
6.3.1.2.4.1 Day 2 of cycle 4 (Day 65 ± 3) 
 Record concurrent illness 
 Record changes in concomitant medication/ treatment 
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                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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 Study drug administration 
 Adverse event assessment 
6.3.1.2.4.2 Visit 6: Day 21 of cycle 4 (Day 84 ± 3): End of Study /Early Discontinuation 
Visit 
 The following investigation should be done pre-chemotherapy administration (planned 
if any, for the further treatment of patients out of the study) 
o Perform physical & systemic examination 
o Vital signs 
o Record weight 
o Blood sampling for Lab investigations (hematology and biochemistry) 
o Blood sampling for immunogenicity and PK-PD assessments  
o Perform urinalysis 
o Perform urine pregnancy test 
o Record ECG 
 Record concurrent illness 
 Record changes in concomitant medication/ treatment 
 Adverse event assessment 
6.4 
Selection of Study Population 
6.4.1 
Inclusion Criteria 
Patients satisfying all of the following criteria will be included in the study: 
1. 
Patients must be able and willing to give written informed consent prior to any study 
related procedures 
2. 
Ambulatory, female patients with an age 18  years  
3. 
Patients with histologically or cytologically proven diagnosis of breast cancer who are 
eligible for neoadjuvant or adjuvant chemotherapy.  
4. 
Patients who are planned and eligible to receive/ receiving myelosuppressive 
chemotherapy regimen that contains at least one chemotherapeutic agent from 
docetaxel/ paclitaxel / doxorubicin/ cyclophosphamide/ epirubicin 
5. 
Patients who have not received any hematopoietic growth factors (e.g. G-CSF, 
PegGCSF, erythropoietin) or cytokines (e.g. interleukins, interferons) anytime in the 
past 
6. 
Patients with baseline WBC ≥ LLN/ 3.5 x 109/L, ANC of ≥ 1.5 x 109/L, platelet count 
≥ 100 x 109/L and hemoglobin ≥ 8.5 g/dL 
7. 
Patients with ECOG Performance status of ≤ 2. 
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Clinical Study Report version 1.0, 05 Dec 2019


 
 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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8. 
Patient who have estimated life expectancy of more than six months 
9. 
No evidences of hemorrhage 
6.4.2 
Exclusion Criteria 
Patients who meet any of the following criteria should be disqualified from entering the study: 
1. 
Male patients  
2. 
Hypersensitivity to any of the study drugs or its components like E.coli proteins or 
similar product.  
3. 
Patients weighing <45 Kg 
4. 
Patients with myeloid malignancies and myelodysplasia or evidence of metastatic 
disease in bone marrow or brain 
5. 
Patients currently receiving radiation therapy or have completed radiation therapy 
within 4 weeks before study entry or likely to receive radiotherapy during the study 
6. 
Patients with prior bone marrow or stem cell transplantation 
7. 
Patients with chronic use of oral corticosteroids (Except ≤ 20 mg/day dose of 
prednisolone/ equivalent steroids), immunotherapy, monoclonal antibody therapy 
and/or biological therapy or use of any other pegylated drug. 
8. 
Patients with history of systemic antibiotic use within 72 hours prior to 
chemotherapy* 
9. 
Patients with any active infection which may require systemic antimicrobial therapy. 
Patients with inadequate hepatic and renal function [defined as Alkaline Phosphatase 
> 2.5 X Upper limits of normal (ULN), serum SGOT > 2.5 X ULN, SGPT > 2.5 X 
ULN, Total bilirubin > 1.5 X ULN and Creatinine > 1.5 X ULN of the reference range 
at the screening assessment] 
10. Patients with seropositivity for HIV or HBV or HCV 
11. Known cases of Sickle Cell Anemia 
12. Patients with radiographic evidence of active pulmonary infections and/or recent 
history of pneumonia within 1 month of screening 
13. Patients with clinically evident splenomegaly confirmed subsequently by 
ultrasonography 
14. Patients with any other clinically significant disease(s) which, in the opinion of the 
investigator, could compromise the patient’s involvement in the study or overall 
interpretation of the data. [for e.g. uncontrolled hematologic, renal, hepatic, endocrine, 
neurologic, psychiatric, metabolic, pulmonary, cardiovascular disease/impaired 
functioning or history of any autoimmune disease] 
15. Patients who have participated in another therapeutic clinical study within the past 30 
days prior to screening, or are likely to simultaneously participate in another 
therapeutic clinical study 
16. Patients who are doubtful to comply with study procedures for mental, psychological 
or social reasons. 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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17. Women of child-bearing potential who are not willing to follow a reliable & effective 
contraceptive measure during the course of the study & at least 3 months after the last 
dose of study drug. 
18. Pregnant and Breast feeding women. 
*Refers to parenteral use 
6.4.3 
Withdrawal of Patients  
In accordance with the Declaration of Helsinki and the informed consent form, patients may 
discontinue the study at any time without any penalty or loss of benefits to which the patient is 
otherwise entitled. For all patients withdrawn from the study, efforts will be made to ascertain 
the reason for withdrawal. 
A withdrawn patient is one who meets any of the following withdrawal criteria stated below 
and whose study participation is discontinued. The reasons for patient withdrawal will be 
recorded in the case report form, signed and dated at the last assessment visit. 
General Criteria: 
 The patient is not willing to continue participation in the study (withdraws consent). 
 After the first dose, it becomes apparent that patient was ineligible. 
 The patient needs emergency treatment or is unable to continue participation in the trial 
due to the exacerbation of their symptoms at discretion of the investigator. 
 Inability of patient to comply with the Protocol for any reason. 
 The patient becomes pregnant during the study period. 
 In the opinion of the investigator or sub-investigator, the patient should be discontinued 
due to AEs (including progressing complications) or safety reasons. 
 Other reasons due to which the patient should be discontinued, in the opinion of the 
investigator or sub-investigator. 
The treatment options will be discussed with all patients who have discontinued or completed 
study (EOS) and the patients will be continued on/ shifted to appropriate standard therapy by 
the Investigator depending on the disease condition.  
6.4.4 
Rescreening of Patients 
Rescreening of a previously screen failed patient will be allowed for patients determined as 
screen failure due to inclusion and/ or exclusion criteria that could transiently change and do 
not compromise the patient’s safety. Rescreens may occur until the sites are open for 
recruitment. Only one rescreen is allowed per patient. When a rescreen is authorized by the 
Sponsor or its designee, patient is to be consented again and all screening procedures should 
be completed (serology not required to be repeated (HIV, HBV, HCV), if rescreened within 
one month). Patients who discontinue the study after randomization and after receiving study 
medication are not eligible for rescreening. 
6.4.5 
Other Patient Restrictions 
Patients may not participate in another clinical study that involves an IP during this study.  
Females patient currently pregnant or breast feeding or planning to conceive are not allowed 
to be included in the study. Females should refrain from becoming pregnant during the study 
period and should use adequate contraception during the study and 3 months after the last dose 
of study drug. 
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Clinical Study Report version 1.0, 05 Dec 2019


 
 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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For concomitant medications/ treatments which are restricted during the study, please see 
Section 7.1.6 
6.4.6 
Early Termination of Study/ Site 
This study may be terminated at any time by the Sponsor if any safety concerns arise, the 
Investigator does not adhere to the protocol, non-performance or inability to achieve 
recruitment or in the Sponsor's judgment there are no further benefits to be achieved from the 
study or if Sponsor does not wish to continue the development of drug for any reason. In this 
event, the Sponsor will inform about the decision along with reason to the study Investigators, 
Institutions, ECs and all applicable regulatory authorities. 
In such cases, patients will be continued on/ shifted to appropriate standard therapy by the 
Investigator depending on the disease condition. 
 
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Clinical Study Report version 1.0, 05 Dec 2019


 
 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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7 
TREATMENT OF PATIENTS AND INVESTIGATIONAL PRODUCT 
MANAGEMENT 
7.1 
Treatment of Patients 
7.1.1 
Dosages & Treatment Regimen 
Lupin’s Pegfilgrastim/ Neulasta® is supplied as single-use pre-filled syringe (PFS) designed to 
deliver 6 mg pegfilgrastim. Pegfilgrastim will be administered as subcutaneous injection once 
per chemotherapy cycle. Patients will be randomized to one of the two arms viz. Lupin’s 
Pegfilgrastim or Neulasta® arm (As per Table 2) 
Table 2 
Doses and Treatment Regimen 
Treatment 
Arm 
Dose 
Route 
Duration & Frequency 
Lupin’s 
Pegfilgrastim 
6 mg 
Subcutaneous injection  
Total four injections, 
one per chemotherapy 
cycle;  
Neulasta® 
6 mg 
Subcutaneous  injection  
Total four injections, 
one per chemotherapy 
cycle;  
7.1.2 
Precautions while Administering Investigational Product (IP) 
Pegfilgrastim will be administered by investigator or designee at the site to the patient. 
Pegfilgrastim will be given no less than 24 hours after the chemotherapy is administered. 
Pegfilgrastim treatment will not be given within 14 days period before and within 24 hours 
period after the chemotherapy. 
Pegfilgrastim is provided in a prefilled syringe. Pegfilgrastim should be stored in its carton to 
protect from light until use. Before administrating pegfilgrastim injection, always check to see 
that the expiration date on the prefilled syringe has not passed. The pegfilgrastim liquid should 
always be clear and colorless. Do not use pegfilgrastim if the contents of the prefilled syringe 
appear discolored or cloudy, or if the prefilled syringe appears to contain lumps, flakes, or 
particles. 
Before administration of drug remove the carton containing the prefilled syringe of 
pegfilgrastim from the refrigerator. Allow pegfilgrastim to reach room temperature. Remove 
the syringe from the carton before injection. Each prefilled syringe should be used only once. 
Do not shake the prefilled syringe. Shaking may damage pegfilgrastim. If the prefilled syringe 
has been shaken vigorously, the solution may appear foamy and it should not be used.  
Remove the prefilled syringe from the package and the tray. Check to see that the plastic needle 
guard is covering the barrel of the glass syringe. Do not push the needle guard over the needle 
cover before injection. This may activate or lock the needle guard. If the needle guard is 
covering the needle that means it has been activated. Do not use that syringe.  Check the syringe 
for air bubbles. If there are air bubbles, gently tap the syringe with your fingers until the air 
bubbles rise to the top of the syringe. Slowly push the plunger up to force the air bubbles out 
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of the syringe. After injection do not throw the container in the household trash. Do not recycle. 
Do not put the needle cover (the cap) back on the needle. 
7.1.3 
Randomization of Study Treatment(s) 
The treatment arm (test or reference) for each patient during the study will be determined 
according to randomization list. This randomization list will not be accessible to the study team 
involved in the study conduct. The treatment will be assigned at the time of randomization, 
after confirming patient’s eligibility. Patients will be randomized in a 1:1 ratio to either Lupin’s 
Pegfilgrastim or Neulasta®. Patients who qualify for study randomization will have a unique 
randomization number. Equal allocation of patients will be ensured in the study. After 
completion of required number (150 patients), some patients who qualify in screening may not 
be randomized in the study. 
7.1.4 
Blinding of Study Treatment 
Since the reference product is already a marketed formulation, achieving complete blinding is 
not possible. Hence, this study is an open label study. 
7.1.5 
Patient Compliance 
For this study-purpose the per protocol compliance to study medication will be defined as all 
those randomized patients who receive subcutaneous injections of 6 mg pegfilgrastim post 
chemotherapy up to 4 cycles. 
7.1.6 
Concomitant Therapy 
Prohibited Medications:  
Concomitant administration of 5-FU or other antimetabolites is prohibited. Immunization is 
prohibited as they may interfere with immune status of the patient. Concomitant use of Lithium 
is not allowed as Lithium may potentiate release of neutrophils. The details of concomitant 
medications used during the study will be entered in the CRF. 
Radiotherapy is prohibited in study patients during the study period. In case if the investigator 
decides to give radiotherapy patient should be discontinued from the study. 
Allowable Medications:  
No concomitant and rescue medication for treating neutropenia will be allowed during the 
study. Any other medications required by the patient and expected not to interfere with study 
drug assessments will be allowed on a case-by-case basis and as deemed appropriate by the 
investigator. The details of concomitant medications used during the study will be entered in 
the Case Report Form (CRF) 
 
 
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7.2 
IP MANAGEMENT 
7.2.1 
IP Dosage Form and Strength 
Lupin’s Pegfilgrastim/ Neulasta® for subcutaneous injection is supplied as single-use pre-filled 
syringe (PFS) designed to deliver 6 mg pegfilgrastim. The details of the study medications are 
given in Table 3 
Table 3 
IP Details 
Study 
Medication 
Dosage Form and Strength 
Manufacturer 
Lupin’s 
Pegfilgrastim 
Supplied as Single-dose‚ pre-filled 
syringes containing fixed dose of 6 
mg 
(10 
mg/ml) 
subcutaneous 
injection of Pegfilgrastim 
Lupin Limited (Biotech Division), 
Gat No: 1156, Village Ghotawade, Taluka 
Mulshi, Pune, Maharashtra, India – 412 115 
Neulasta® 
Supplied as a single-dose‚ pre-filled 
syringes containing fixed dose of 6 
mg 
(10 
mg/ml) 
subcutaneous 
injection of Pegfilgrastim. 
Amgen Inc. One Amgen Center Drive 
Thousand Oaks, California 91320-1799 
 
7.2.2 
IP Packaging and Labeling 
The 6 mg carton containing a single-use, pre-filled syringe (Lupin’s Pegfilgrastim or 
Neulasta®) are packaged individually. The packs will be labelled as per regulatory 
requirements. Each pack will have unique identification number. 
Each patient will be assigned a randomization number and IP pack containing either Lupin’s 
Pegfilgrastim or Neulasta® will be dispensed.  
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels shall contain appropriate information as per the local 
regulatory requirements including but not limited to product content and strength, batch No, 
manufacture date, retest/ expiry date, storage information, route of administration, statements 
like “For Clinical Trial Purpose Only”. 
7.2.3 
Storage 
Pegfilgrastim injection should be stored under refrigeration at 2º- 8 ºC (36º- 46 ºF) at all times. 
The following instructions will be given to the sites: 
 Keep the product in the original carton to protect from light until the time of use.   
 Do Not Freeze, if frozen, thaw in the refrigerator before administration. However, if it 
is frozen a second time, do not use.  
 Prior to use, the unopened PFS may be kept at room temperature (25°C) for up to 48 
hours. Do not use beyond the expiry date which is stated on the carton.  
 Do not use any pack if it is damaged. Pegfilgrastim prefilled syringe should be used 
once only and any unused portion left in the syringes should not be used.  
 Do not shake.  
 Do not leave Pegfilgrastim syringe in direct sunlight. 
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7.3 
IP Supply, Handling and Accountability 
The Sponsor/ designee will arrange for the supply, handling and management of IPs. Lupin 
Limited (Biotechnology Division) will supply sufficient quantity of IPs, for administration to 
randomized patients at each site. IP will be shipped under appropriate storage conditions to the 
Investigator sites. 
The designated study personnel must take the responsibility to keep a record of the IP 
management.  
Sites will receive IP with appropriate documents and store according to the storage 
requirements. Adequate records of IP for receipt, accountability, usage and disposal or return 
to sponsor will be maintained at respective Investigator site.  Investigational product will be 
administered to eligible patients according to randomization schedule. 
Pharmacist/ designated study personnel will dispense the IP for administration. The unused IP 
will be kept in their original containers. The sites will return any unused IP to the sponsor, or 
destroy on site (as mutually agreed between sponsor & sites), once the site’s monitor has 
reviewed and confirmed drug accountability or at the end of the study. 
Used IPs will also be kept in the original packing and will be returned/ destroyed on site (as 
mutually agreed) to sponsor after confirmed drug accountability. 
The IPs will not be used for purposes other than those conforming to this protocol. 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                          Page 38 of 60 
 
 
8 
ASSESSMENT OF IMMUNOGENICITY 
8.1 
Immunogenicity Endpoints 
Primary endpoint: Comparison of cumulative incidence of anti-pegfilgrastim antibodies 
(binding & neutralizing) to Pegfilgrastim between treatment groups at the end of cycle 4 (Day 
84). 
Secondary Immunogenicity endpoint:  
1. Comparison of cumulative incidence of anti-peg antibodies (binding & neutralizing) 
between treatment groups at the end of cycle 4 (Day 84). 
2. Comparison of incidence of anti-pegfilgrastim antibodies (binding & neutralizing) to 
Pegfilgrastim between treatment groups on Day 10, Day 21, Day 42, Day 63 and Day 
84. 
3. Comparison of incidence of anti-peg antibodies (binding & neutralizing) between treatment 
groups on Day 10, Day 21, Day 42, Day 63 and Day 84. 
8.2 
Immunogenicity Variables 
Presence of anti-pegfilgrastim antibodies and anti-peg antibodies at the end of each cycle will 
be analyzed for each patient. Those samples confirmed to be positive for binding antibodies 
will be analyzed for presence of neutralizing antibodies to Pegfilgrastim  
8.3 
Anti-Pegfilgrastim and Anti-Peg Antibodies Detection 
Immunogenicity will be assessed in patients at selected time points as mentioned in Table 1. 
Blood samples for immunogenicity will be collected from all sites and an appropriate validated 
single assay format will be used for immunogenicity assessments. Immunogenicity assay will 
be done in a sequential format which is broadly classified into ADA assay and Neutralizing 
Antibody (NAb) assay: 
ADA assay followed by NAb assays (if required), will be performed in the below mentioned 
sequential 3-Tier approach: 
1. Screening Assay: All samples will be subjected to screening assay to detect the anti-
Pegfilgrastim antibodies. 
2. Confirmatory Assay: Samples identified positive under screening assay will be analysed in 
confirmatory tier, to identify anti-pegfilgrastim and anti-peg antibodies.  
3. Titration Assay: All confirmed positive samples will be subjected to Titration assay. 
Neutralizing Antibody Assay (NAb): All samples found to be confirmed positive in ADA assay 
will be subjected to Neutralization assay. 
ADA assay will be done at Lupin Bioresearch Centre and NAb assay will be outsourced at a 
pre-qualified and sponsor-approved laboratory. 
8.3.1 
Collection, Handling and Analysis of Immunogenicity Samples 
For immunogenicity assessments, a 6mL of blood sample will be collected in a plain blood 
collection vacutainer (with clot activator) by vein puncture as per the scheduled time points 
mentioned in Table 1. Samples will be kept on bench for 45± 15 minutes to enable clotting and 
will be centrifuged at around 3800 ± 20 rpm for 10 minutes at 10± 2°C. 
Serum will be separated and transferred into three aliquots of equal volume for storage at -75 
± 10°C. 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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The samples will be shipped to Lupin Bioresearch Center, Pune with dry ice shipment & data 
logger with proper documentation related to the shipped samples.  
Anti-pegfilgrastim antibodies and anti-peg antibodies will be assayed and analyzed using an 
appropriate and validated single assay format.  
Note: Samples of different subjects can be stored interim at clinical facility below -75oC and 
shipped at regular intervals. All samples collected during the conduct of clinical trial (including 
dropout/withdrawals) will be analysed. The analysis of the samples will be done in sets which 
will be decided by the bioanalytical team based on the number of samples in periodic intervals. 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                          Page 40 of 60 
 
 
9 
ASSESSMENT OF SAFETY 
Following safety parameters will be assessed, 
 Adverse event assessment (as per NCI CTCAE)  
 Physical & systemic examination  
 Vital signs  
 Laboratory parameters: Blood (hematology & biochemistry) and urinalysis  
9.1 
Adverse Events 
9.1.1 
Definitions 
The definitions for AEs and SAEs are given in Sections 9.1.1.1 and 9.1.1.2, respectively. It is 
of the utmost importance that staff involved in the study is familiar with the content of this 
section. The Principal Investigator is responsible for ensuring this. 
9.1.1.1 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore, be any unfavourable and unintended 
sign, symptom or disease (including intercurrent illness), deterioration of a pre-existing illness, 
accident, any suspected drug reaction, or a clinically relevant change of laboratory values 
temporally associated with the use of a medicinal (investigation) product, whether or not 
related to the medicinal (investigational) product and/ or study treatment. 
A treatment emergent AE (TEAE) will be defined as an AE that begins or that worsens in 
severity after at least one dose of study drug has been administered. 
See Section 9.6 below for the instances where a pregnancy should be reported as an AE. 
9.1.1.2 
Serious Adverse Event (SAE) 
An SAE is defined as, any untoward medical occurrence that at any dose: 
 Results in death. 
 Is life-threatening. 
An adverse event or adverse reaction is considered “life-threatening” if, in view of 
either the investigator or sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might 
have caused death. 
 Requires in-patient hospitalization  or prolongation of hospitalization  
 Results in persistent or significant disability/ incapacity. 
 Is a congenital anomaly/ birth defect. 
 Consists of any other medically important condition. 
According to ICH E2A, CPMP/ICH/377/95: ‘Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other situations, such as 
important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.’ 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
                               CONFIDENTIAL                                                          Page 41 of 60 
 
 
Hospitalization or prolongation of hospitalization in following situations will not be considered 
as SAE: 
 Disease-related investigations (e.g., biopsy, scans, endoscopy, sampling for laboratory 
tests, bone marrow sampling). However, hospitalization or prolonged hospitalization 
for a complication of such procedures remains a reportable SAE 
 Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
9.1.2 
Recording and Collection of Adverse Events 
It is the responsibility of the investigator to collect all AEs (both serious and non-serious) 
derived from spontaneous, unsolicited reports of patients, by observation and by routine open 
questions. 
AE reporting will extend from date of informed consent until completion of the final visit 
(EOS). Any ongoing AE at end of study visit should be followed until the outcome is evident 
and resolved, clinically stabilized or a plausible explanation has been found. 
Pre-existing diseases (before participating in the study) are not considered to be AEs, unless 
the disease worsens during the study period. Concomitant diseases prior to randomization will 
be recorded in the CRF/ eCRF. 
Signs and symptoms clearly associated with the disease under study (including symptoms of 
disease progression) should be reported as AEs if they are newly emergent (i.e., findings not 
previously observed in the patients), or are determined by the investigator as severe or a 
worsening, or if the investigator considers deterioration of disease-related signs and symptoms 
to be caused directly by the study drug. 
Abnormal laboratory values/ ECGs/ vital signs/ physical & systemic examination should be 
reported as AEs only if the Investigator considers the abnormality as clinically relevant or 
significant or believes that the abnormality should be reported as an AE. 
Any dose (and associated symptoms) given to the patient that exceeds the dose prescribed to 
the patient has, at a minimum, to be recorded as a non-serious AE in the patient file and CRF/ 
eCRF. Any case of overdose leading to an AE or SAE should be reported to Medical Monitor 
according to reporting requirements.  
After completion of all scheduled visit assessments, the Investigator must document any AEs 
arising from these assessments. In case of an SAE, the Investigator must also complete an SAE 
report form and report it to safety contact, as described in Section 9.1.3.3. 
All AEs will be recorded in case report form (CRF/ eCRF) regardless of the causal relationship 
to the study drug. 
All AE records should contain AE term/ AE diagnosis, date of onset, severity, relationship to 
the study drug, outcome, date of recovery or outcome, action taken with the study drug, action 
taken with AE, AE leading to discontinuation of patient from study and whether the event is 
classified as serious. 
Breast cancer progression should not be recorded as AE/SAE. In cases of disease progression 
the relevant signs, symptoms and complications should be reported as an AE unless they meet 
the seriousness criteria. If any of the signs, symptoms and complications meets any of the 
seriousness criteria, they should be reported as an SAE. 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
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The categorization of action taken with IP, outcome and action taken for AE is described below: 
 
Categories of Actions 
Taken with IP 
Categories of Outcome* 
Categories of action 
taken for AE 
 Drug withdrawn 
permanently 
 Unknown 
 Not applicable 
 Recovered/ resolved 
 Recovered/ resolved 
with sequelae 
 Recovering/ 
resolving 
 Not recovered 
 Fatal 
 Unknown 
 None 
 Medication 
 Hospitalization 
 Non drug treatment 
 Patient withdrawn 
 Other 
*If there is more than one AE, only the AE leading to death will be attributed with a fatal 
outcome.  
 
In cases where multiple symptoms and signs can be described as one diagnosis (disease), the 
name of the diagnosis is reported as the name of the adverse event. 
For example, running nose, cough, sore throat: The 3 symptoms can be described as a series of 
symptoms of "common cold" 
⇒ Common Cold or Upper Respiratory Tract Infection (URTI) 
The investigator must continue to follow-up the patient with all AEs regardless of the causal 
relationship to the study drug until the AE has resolved or until the condition stabilizes to an 
acceptable level or is determined to pose no issue, or until follow-up is no longer feasible. 
9.1.3 
Evaluation of Adverse Events 
Each adverse event is evaluated depending on the following categories by the investigator. 
9.1.3.1 
Definition of severity of an AE 
Wherever possible, all observed AEs will be graded using the Common Terminology Criteria 
for Adverse Events (CTCAE) ver. 4.03. The severity of the AE shall be classified using the 
following grading. 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (preparing meals, shopping for groceries or 
clothes, using the telephone, managing money etc.). 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care (bathing, dressing and 
undressing, feeding self, using the toilet, taking medications and not bedridden). 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to an AE. 
Semicolon (;) indicates “or”. 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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Record the maximum intensity for AE occurring frequently than once a day. If the intensity 
category changes over a number of days, then those changes should be recorded as a new AE 
with the onset date of the new intensity. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 9.1.1.2. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may 
be considered severe nausea, but not an SAE. On the other hand, a stroke that results in only a 
limited degree of disability may be considered a mild stroke but would be an SAE. 
9.1.3.2 
Relationship to the Study Drug 
The assessment of the relationship of an adverse event to the administration of study drug is 
based on the presence or absence of a “reasonable possibility” that investigational drug has 
caused the AE. An AE is considered to be “related” to the study medication if a causal 
relationship between the IP and an AE is at least a reasonable possibility (i.e., the relationship 
cannot be ruled out). An AE related to the study drug is referred to as an adverse drug reaction 
(ADR). 
The expression “reasonable causal relationship” is meant to convey that there are facts 
(evidence) or arguments to suggest a causal relationship (ICH E2A guideline) based on 
relationship to time of onset & drug administration, temporary withdrawal, not attributable to 
any other drug or condition, dechallenge & rechallenge information as available.  
The causal relationship between an adverse event and the study drug will be defined as below: 
Unrelated:  Clinical event with an incompatible time relationship to drug administration, and 
that could be explained by underlying disease or other drugs or chemicals or is incontrovertibly 
not related to the IP. 
Unlikely:  Clinical event whose time relationship to drug administration makes a causal 
connection improbable, but that could plausibly be explained by underlying disease or other 
drugs or chemicals.  
Possible:  Clinical event with a reasonable time relationship to IP administration, but that could 
also be explained by concurrent disease or other drugs or chemicals.  
Definite:  Clinical event with plausible time relationship to IP administration, and that cannot 
be explained by concurrent disease or other drugs or chemicals.  
In final evaluation for reporting, the relationship will be converted into “Binary 
Determination”.  Unrelated and Unlikely will be clubbed into “Unrelated” and Possible and 
Definite will be clubbed into “Related” for final reporting purpose. 
9.1.3.3 
Reporting of Serious Adverse Events 
All SAEs occurring after the time of informed consent until the final visit (End of Study visit 
or Early Discontinuation Visit) must be reported. 
All SAEs should be reported by the investigator to the Safety Contact via Email or telephone 
within 24 hours, regardless of the causal relationship with the IPs (following knowledge of the 
SAE). After receiving reports of the SAEs, the Safety Contact should communicate with the 
investigator to get additional information for evaluation of SAEs. 
The Investigator is responsible for reporting SAE (initial report, analysed report as well as 
follow up information) to the Ethics Committee and/ or applicable regulatory authority as per 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
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applicable local regulatory requirements of participant countries. All SAEs shall be reported 
by investigator/ Sponsor/ sponsor designee as per applicable regulatory requirements. 
The Details of Safety Contact: 
 
Name: Dr. Prabhat Singh 
Designation: Medical and Safety Monitor 
Address: Drug Safety & Risk Management 
(DSRM), Lupin Limited,  
Kalpataru Inspire, 5th Floor,  
Off Western Express Highway, 
Santacruz (East). Mumbai 400055 
Contact Details:  
Mobile: +91 7045 347 051 
Tel/Fax: +91 22 6640 2833 
Email: prabhatsingh@lupin.com 
9.1.3.4 
Follow-Up of Serious Adverse Events (SAEs) 
The investigator must continue to follow the patient until the SAE has resolved or until the 
condition stabilizes to an acceptable level or is determined to pose no issue, or until follow-up 
is no longer feasible. Any ongoing SAE at end of study visit should be followed until the 
outcome is evident and resolved, clinically stabilized or a plausible explanation has been found. 
9.1.3.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
An SAE that is also an unexpected adverse drug reaction is called a Suspected Unexpected 
Serious Adverse Drug Reaction (SUSAR). Unexpected adverse reactions are adverse reactions, 
of which the nature, or severity, is not consistent with the applicable product information (e.g., 
IB for an unapproved investigational medicinal product or the Summary of Product 
Characteristics for an authorized medicinal product or available literature). 
SUSARs will be reported in compliance with regulatory reporting requirements of participating 
countries. The details of reporting of SAE, significant AEs & SUSARs will be captured in the 
Safety Management Plan (SMPs). 
9.2 
Physical and Systemic Examination 
A physical and systemic examination will be performed at the time of screening and after 
screening according to the schedule of procedures described in Table 1. 
Physical examinations will include, but are not limited to, the below items: 
General findings, HEENT exam (head, eyes, ears, nose and throat), assessment of respiratory, 
cardiovascular, gastrointestinal, nervous, musculoskeletal and renal/ urinary systems, lymph 
nodes and dermatologic examination (including skin appendages) and other findings/ physical 
conditions of note. Any abnormal findings will be evaluated for clinical significance. 
9.3 
Vital Signs 
Vital signs, including blood pressure, pulse rate, respiratory rate and axillary body temperature 
will be measured at screening and after screening according to the schedule of procedures 
described in Table 1. These parameters are measured in a sitting position after resting for at 
least 3 minutes. Any abnormal findings will be evaluated for clinical significance. 
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Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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9.4 
Electrocardiogram Assessments (ECGs) 
A 12-lead ECG will be performed at screening and after screening according to the schedule 
of procedures described in Table 1. It will be recorded by qualified personnel after the patient 
has been resting in the supine position for at least 3 minutes. Any abnormal findings will be 
evaluated for clinical significance. QTc ≥ 500 msec or any change from baseline of > 60 msec 
will be considered significant. 
9.5 
Clinical Laboratory Examinations 
Hematology tests, biochemistry tests including serological test (HIV, HBV, and HCV) and 
urine analysis tests for safety assessment will be performed at screening and after screening 
according to the schedule of procedures described in Table 1. 
The list of tests for safety laboratory assessment is shown in Table 4. 
Serum and Urine Pregnancy test for females of child bearing potential will be performed at 
screening and as scheduled in Table 1. 
9.5.1 
Central Laboratory Samples 
Sample collection and handling for laboratory tests will be conducted in accordance with the 
laboratory manuals and collected samples will be sent to the central laboratory. Not more than 
200 mL of blood will be collected during this study for planned study assessments (until EOS). 
Table 4 
Clinical Laboratory Parameters 
Hematology 
Biochemistry 
Urinalysis 
Serology 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count  
White blood cell count 
Differential white blood 
cell count: 
Neutrophils 
Basophils  
Eosinophils  
Lymphocytes 
Monocytes 
Absolute 
neutrophil 
count 
Albumin 
Globulin 
Total protein 
Alkaline phosphatase 
ALT 
AST 
Bilirubin (total,  
Direct & Indirect) 
BUN 
Urea 
Uric Acid 
Creatinine 
Random Glucose 
LDH 
 
 
Routine Examination 
Color 
Appearance 
pH 
Urobilinogen 
Occult blood 
Glucose 
Protein 
Ketone 
Specific gravity 
 
Microscopic 
Examination (if 
abnormality is 
suspected) 
Red Blood Cells 
Pus cells  
Crystals  
Cast 
Bacteria 
Yeast 
Other  
HIV 
HBV (HBsAg) 
HCV 
 
Serum and urine pregnancy test will be done in females of child bearing potential. 
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Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
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Any clinical test results outside the reference value range are evaluated for clinical significance. 
After dosing, laboratory abnormalities considered by the investigator to have worsened 
compared to that prior to dosing will be recorded as AEs. 
9.6 
Pregnancy 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. 
Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions. Hospitalization for normal delivery of a healthy new born should not be 
considered an SAE. 
If a pregnancy or a positive pregnancy test is reported for a patient during study participation, 
the study drug must be immediately discontinued. 
Pregnancies occurring during the study until EOS must be reported. All pregnancies must be 
reported to the sponsor within 24 hours after becoming aware of the pregnancy, using the initial 
pregnancy report form. The investigator should counsel the patient; discuss the risks of 
continuing with the pregnancy and possible effects on the fetus. The investigator must follow 
up and document the course and outcome of all pregnancies, even if the patient was 
discontinued from the study or if the study has finished. 
All outcomes of pregnancy must be reported by the investigator to the sponsor on the pregnancy 
outcome report form within 30 days after he/ she becomes aware of the outcome. 
Any SAE that occurs during a pregnancy must be recorded on the SAE report form (e.g. 
maternal serious complications, spontaneous or therapeutic abortion, ectopic pregnancy, 
stillbirth, neonatal death, congenital anomaly, or birth defects) and reported in accordance with 
the procedure for reporting of SAEs. 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
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10 
ASSESSMENT OF PHARMACOKINETICS  
10.1 
PK Parameters 
Serum drug concentrations for Lupin’s Peg-filgrastim and Neulasta® will be measured at Day1 
(baseline/pre-dose) Day 10 and at trough (pre-dose) on Day 21 of cycle 1 and at the end of 
cycle 2 (Day 42), cycle 3 (Day 63) and cycle 4 (Day 84). 
10.2 
Blood Sampling 
Blood samples (approximately 1 x 4 mL) will be collected by venipuncture or cannulation at 
the selected time points as mentioned in Schedule (Table 1) into vacutainers with clot activator.  
The blood samples in vacutainers with clot activator will be kept aside for 45 ± 15 minutes so 
as to allow the coagulation process. Then the blood samples will be centrifuged at 3800 ± 20 
rpm for 10 minutes at 10 ± 2°C to separate serum. 
The separated serum will be collected in 2 tubes/aliquots. The serum samples will be stored -
75 ± 10°C. The samples will be transported in dry ice to Lupin Bioresearch Center,, Pune for 
further analysis.  
For details about sample processing and methodology, refer bioanalytical protocol. 
10.3 
Bioanalysis 
Serum Pegfilgrastim concentrations will be measured using an appropriate validated 
quantitative sandwich enzyme immunoassay method at Lupin Bioresearch Centre. Enzyme 
immunoassay method will be developed and validated as per Global Bioanalytical Method 
Validation Guidelines8,11 and in house SOP of LBC.  
In sandwich enzyme immunoassay, initially serum sample will be added to the wells of 
microtiter plate. Specific monoclonal antibody for human Peg G-CSF will be used as a capture 
antibody to which Peg-G-CSF will bind. An enzyme-linked polyclonal antibody specific for 
human Peg G-CSF shall be added in each well. The solution will be washed to remove unbound 
antibodies and then a suitable substrate solution will be added to quantify the primary antibody 
through a color change. The concentration of primary antibody present in the serum samples 
will be measured using suitable 96-well micro plate reader. The concentration of primary 
antibody present in the serum directly correlates with the intensity of the color. 
A baseline level subtraction will be applied to normalize Peg-GCSF concentrations measured 
in study samples (If required). 
For details about sample processing and methodology, refer bioanalytical protocol. 
Note:  
 PK samples will be assayed and data will be analyzed only in the case of an imbalance 
in the frequency of ADA between Lupin’s Pegfilgrastim and Neulasta® arm.  
 Samples of different subjects can be stored interim at clinical facility below -75oC and 
shipped at regular intervals. All samples collected during the conduct of clinical trial 
(including dropout/withdrawals) will be analyzed. The analysis of the samples will be 
done in sets which will be decided by the bioanalytical team based on the number of 
samples in periodic intervals. 
 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
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11 
ASESSMENT OF PHARMACODYNAMICS  
11.1 
PD Parameters 
Absolute neutrophil count (ANC) will be assessed at Day1 (pre-dose), Day 10, Day 21 of cycle 
1 and at the end of cycle 2 (Day 42), cycle 3 (Day 63) and cycle 4 (Day 84). 
11.2 
Blood Sampling 
Blood samples (approximately 1 x 3 mL) for PD assessments will be collected by venipuncture 
or cannulation at the selected time points as mentioned in Schedule (Table 1) into K2EDTA 
vacutainers. Collected blood samples for pharmacodynamic evaluation will be transferred to 
central pathology laboratory for further analysis. 
For the details of sample processing and storage, refer central laboratory manual. 
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Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019


 
 
Protocol Number: LRP/PegGCSF/2016/004 
Ver. No.: 2.2; Dated 02 Jul 2018 
 
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12 
STATISTICAL EVALUATION 
12.1 
Sample Size and Power 
The primary endpoint is comparison of cumulative incidence of anti-pegfilgrastim antibodies 
(binding & neutralizing) to Pegfilgrastim at the end of cycle 4 (Day 84).  Noninferiority of 
Lupin’s Pegfilgrastim versus Neulasta® will be assessed based on the one-sided 95% 
confidence interval for the difference between proportions using a noninferiority margin of 10 
percentage points.  For a two-arm, parallel-group trial with 1:1 randomization, and assuming 
true rates of 2% in each of the two arms, the required total sample size for 90% power is 128 
patients.14 The expected rate for incidence of anti-pegfilgrastim antibody is based on the 
various studies with Neulasta® conducted across the globe.9,10,12,13 In order to allow for a 15% 
dropout rate, the planned total sample size is 150 patients.   
12.2 
Statistical Methods 
This section describes the statistical analysis as it is foreseen at the time of planning the study. 
Any major deviations from this plan, the reasons for such deviations, and all alternative or 
additional statistical analyses will be provided in a Statistical Analysis Plan (SAP) as 
applicable. 
All statistical analyses will be performed using SAS version 9.1.3 or higher. Continuous 
variables will be presented in summary statistics of number of patients (n), mean, SD, median, 
minimum and maximum by appropriate group and time point. Categorical variables will be 
described using the frequency count of the events, and the number and proportion of responding 
patients. 
Detailed methodology on summary and statistical analysis of the data collected in this study 
will be provided in the SAP which will be finalized prior to the database lock. 
All statistical tests will be one-sided and evaluated at a 5 % level of significance. 
12.3 
Handling of Missing Data 
There are many possible reasons for missing data (e.g. patient refusal to continue in the study, 
treatment failures and successes, adverse events etc.), not all of which are related to the IP. 
Different degrees of data incompleteness can occur i.e. measurements may be available only 
at baseline, or may be missed for one or several follow up assessments. Such missing data will 
be handled by using LOCF (Last Observation Carried Forward) or other appropriate methods. 
These methodologies will be described in details in the SAP. 
12.4 
Patient Disposition 
A detailed description of the patient disposition will be provided. It will include the number of 
patients screened, randomized, completed, as well as the number of dropouts, with reasons for 
discontinuation and major protocol deviations. All patients entered in the study will be 
accounted for this. 
12.5 
Analysis Population 
The analysis populations are described below. The study being conducted at multiple sites, the 
data collected from individual sites will be pooled for analysis. Detailed listings will be 
produced for all relevant immunogenicity and safety data by treatment and by visits wherever 
applicable. 
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12.5.1 
Intention to Treat (ITT) 
The Intention-to-Treat (ITT) population will include all patients who receive at least one dose 
of study medication and subsequently provide any post-baseline immunogenicity variable data. 
The ITT population will be used for all immunogenicity analyses. 
12.5.2 
Per Protocol (PP) 
The Per Protocol (PP) population will include all patients who satisfactorily complete the study 
and comply with the requirements of the protocol. It is a subset of the ITT population without 
any major protocol deviations. The PP population will also be used for all immunogenicity 
analyses. 
12.5.3 
Immunogenicity Population 
Immunogenicity will be assessed in the IIT and PP populations. The ITT will be the primary 
immunogenicity analysis population. 
12.5.4 
Safety Population 
Safety population will include all patients who receive at least one dose of study medication 
and subsequently provide any post-baseline safety variable data. The Safety population will be 
used for all safety analyses. 
12.5.5 
Pharmacokinetic Population 
The Pharmacokinetic population will include all patients who receive at least one dose of study 
medication and have evaluable PK data without any major deviations or events that may impact 
the quality of the data or alter the evaluation of the PK. 
12.5.6 
Pharmacodynamic Population 
The Pharmacodynamic population will include all patients who receive at least one dose of 
study medication and have evaluable pharmacodynamics measurements. 
12.6 
Immunogenicity Analysis 
12.6.1 
Primary Endpoint 
Comparison of cumulative incidence of anti-pegfilgrastim antibodies (binding & neutralizing) 
to Pegfilgrastim between study groups at the end of cycle 4 (Day 84). 
The difference in cumulative incidence of anti-pegfilgrastim antibodies (binding & 
neutralizing) to Pegfilgrastim between study groups at the end of cycle 4 will be calculated, 
along with the one-sided 95% confidence interval for the difference in proportions.  
Noninferiority will be assessed using a noninferiority margin of 10 percentage points. 
12.6.2 
Secondary Immunogenicity Endpoint 
 Comparison of cumulative incidence of anti-peg antibodies (binding & neutralizing) 
between treatment groups at the end of cycle 4 (Day 84). 
 Comparison of incidence of anti-pegfilgrastim antibodies (binding & neutralizing) to 
Pegfilgrastim between treatment groups on Day 10, Day 21, Day 42, Day 63 and Day 84. 
 Comparison of incidence of anti-peg antibodies (binding & neutralizing) between treatment 
groups on Day 10, Day 21, Day 42, Day 63 and Day 84. 
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12.7 
Safety Analysis 
The safety data will be summarized and listed. Detailed statistical methodology will be 
described in SAP. 
12.7.1 
Parameters for Assessment of Safety 
12.7.1.1 
Adverse Events 
All AEs will be coded by System Organ Class (SOC) and Preferred Term (PT) according to 
the Medical Dictionary for Regulatory Activities (MedDRA) version 17.1 or higher. Events 
will be classified as TEAEs if they start on or after the date of the first dose of study medication. 
The number of AEs and the number and percentage of patients experiencing AEs will be 
summarized by severity and relationship to the study medication. SAEs and AEs leading to 
premature study discontinuation will be summarized. The corresponding listings will be 
provided. Study drug injection sites will be observed during the assessment of injection sites 
in each arm and the characteristics of injection site reactions/ inflammatory reactions will be 
observed and assessed at each study visit. 
12.7.1.2 
Physical & Systemic Examinations and Electrocardiogram Measurements 
Changes in the physical & systemic examinations from screening to the end of IP will be listed. 
12.7.1.3 
Electrocardiogram Measurements 
Changes in the 12-lead ECG findings from screening to the end of IP will be listed. 
12.7.1.4 
Laboratory Data 
Descriptive statistics will be performed for laboratory parameters at each visit and for the 
changes from baseline. In addition, shift tables for hematology and biochemistry laboratory 
parameters comparing values (low, normal, high) using the standard reference ranges will be 
presented for the baseline laboratory measurements vs. EOS measurements. Abnormal values 
in each treatment arm will be determined and listed using reference ranges provided by the 
central laboratory. Patients with an incidence of clinically significant abnormalities occurring 
during treatment, as well as those that occur prior to the start of the IP will be listed. All 
laboratory results will be listed, including data from the unscheduled visits. 
12.7.1.5 
Vital Signs 
Changes in vital signs (pulse rate, respiratory rate, body temperature, blood pressure) from 
screening to each vital signs assessment will be summarized. The corresponding listing will be 
provided. 
12.7.1.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO-DD classification and a 
listing will be prepared. All concomitant medications received after the start of dosing will be 
summarized. 
12.7.1.7 
Extent of Exposure 
Study compliance and the extent of exposure to the study medication will be summarized 
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12.7.1.8 
Patient Discontinuation 
All patients who discontinued from treatment and study will be listed and the reasons for 
discontinuation will be tabulated. 
12.7.1.9 
Baseline and Demographic Characteristics 
Demographic data and other baseline characteristics will be summarized for the safety 
population. Categorical data will be summarized as frequencies, percentages and continuous 
data as descriptive statistics (number of patients, mean, SD, median, minimum value and 
maximum value). Demographic data will include age, gender, race, ethnicity, weight etc. and 
disease specific baseline characteristics including presence of anti-pegfilgrastim antibodies to 
Pegfilgrastim and anti-peg antibodies that will be detailed in SAP. 
12.8 
Exploratory Analysis 
PK-PD analysis will be performed only in the case of an imbalance in the frequency of ADA 
between Lupin’s Pegfilgrastim and Neulasta® arm. Analyses of PK-PD data will be described 
in a separate PK-PD analysis plan. 
12.9 
Interim Analysis for sample size adaptation 
An interim analysis will be conducted when primary endpoint data are available for 
approximately 50% of the planned total sample size (approximately 75 patients).  The overall 
proportion of patients with anti-pegfilgrastim antibodies (binding & neutralizing) to 
Pegfilgrastim at the end of cycle 4 will be estimated at interim analysis.  Based on the overall 
proportion, the sample size required for 90% power will be re-estimated using the approach of 
Farrington and Manning (1990)14, as mentioned in Table 5. Safety of the drug will be also 
evaluated, in above set of patients, before the sample size re-estimation to rule out any drug 
related safety concerns. Descriptive statistics will be provided for safety analysis.  
Table 5 
Projected sample size adaptations for different proportions of anti-
pegfilgrastim antibodies (actual data) at interim analysis 
Blinded 
 
Pegfilgrastim Rate <Neulasta® 
Rate 
Pegfilgrastim Rate >Neulasta® 
Rate 
Overall 
ADA Rate 
0% 
1% 
2% 
3% 
4% 
5% 
1% 
2% 
3% 
4% 
5% 
1% 
98 
84 
 
 
 
 
118 
 
 
 
 
2% 
128 
108 
94 
80 
 
 
154 
188 
236 
 
 
3% 
154 
130 
112 
98 
86 
76 
186 
230 
292 
384 
532 
4% 
180 
152 
130 
112 
98 
86 
218 
272 
346 
458 
640 
5% 
206 
174 
148 
128 
112 
98 
250 
312 
400 
532 
746 
6% 
232 
194 
166 
142 
124 
110 
282 
352 
452 
604 
854 
7% 
258 
216 
182 
158 
136 
120 
314 
392 
506 
678 
960 
8% 
282 
236 
200 
172 
150 
132 
346 
432 
558 
750 
1066 
9% 
308 
256 
218 
186 
162 
142 
376 
472 
610 
822 
1170 
10% 
332 
276 
234 
200 
174 
152 
408 
512 
662 
892 
1272 
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Ver. No.: 2.2; Dated 02 Jul 2018 
 
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13 
DATA MANAGEMENT 
13.1 
Data Handling 
Data will be recorded at the site in source documents / CRF/ eCRFs promptly in English and 
the investigator shall verify the accuracy of data in the CRF/ eCRF. 
The Investigator shall maintain source documents, such as laboratory reports, ECGs, 
consultation reports, and complete medical history and physical examination. 
Data from external sources (such as laboratory data) will be appropriately handled into the 
database. Medical information will be coded using MedDRA and WHO DD. 
The monitor assigned to the site will verify the data recorded in the CRF/ eCRF with source 
documents. The monitor confirms whether reporting is complete and that there are no 
contradictions by inspecting the CRF/ eCRF. The monitor checks for contradictions between 
documents based on data in the CRF/ eCRF by source data verification. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the CRF/ 
eCRF system. 
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14 
CLINICAL STUDY MANAGEMENT 
14.1 
Conduct of the Study 
Lupin Limited/ designee will conduct the study according to written standard operating 
procedures to ensure that the study is conducted and data are generated, documented and 
reported in compliance with the protocol, ICH GCP and applicable regulatory requirements. 
14.2 
Direct Access to Source Data 
During the course of the study, the monitor will visit study sites to review protocol compliance, 
compare CRF/ eCRFs and individual patient medical records, assess drug accountability 
records and ensure that the study is being conducted according to applicable regulatory 
requirements. The review of medical records will be performed in a manner to ensure that 
patient confidentiality is maintained. 
A review of the CRF/ eCRFs for completeness, accuracy, legibility, timeliness and clarity, as 
well as with source documents will be required to monitor the progress of the study. Moreover, 
the applicable regulatory authorities, Institutional Review Boards (IRBs), Institutional Ethics 
Committees (IECs) and/ or the sponsor designated Clinical Quality Assurance team may 
perform source data checks and/ or on-site audits/ inspections to confirm the validity of the 
trial conduct and the integrity of data collected. Direct access to the source data will be required 
for these inspections and audits; these will be carried out giving due consideration to data 
protection and medical confidentiality. The investigator must ensure provision of the necessary 
support to the sponsor/ sponsor’s representative, regulatory or IEC/ IRBs at all times.  
14.3 
Amendments to the Protocol 
Important changes to the protocol and study design require a mutual agreement between the 
investigator and sponsor and will be effective following approval of the IRB/ IEC and 
regulatory authorities (as necessary). These changes are to be described in the revised protocol 
and a list of changes detailing the pre-change and post-change versions will be prepared. 
14.4 
Guidance and Supervision of Sub-Investigators 
The principal investigator shall maintain the list of appropriately qualified sub-investigators 
and study support staff (e.g. pharmacists, nurses and other staff) to whom significant trial-
related duties have been delegated. 
The principal investigator shall ensure that all sub-investigators and study support staff 
participating in the trial are adequately trained on the protocol, the IP(s) and their trial-related 
duties and functions and they are timely informed of any new information pertaining to the 
study. 
14.5 
Archiving Study Records 
The essential study documents should be retained and archived until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. However, these documents should 
be retained for a longer period, if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/ 
institution as to when these documents no longer need to be retained. 
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15 
QUALITY ASSURANCE AND QUALITY CONTROL 
The Sponsor/ designee will implement and maintain quality control and quality assurance 
procedures to ensure that the study is conducted and data are generated, documented and 
reported in compliance with the protocol, ICH GCP, applicable regulatory requirements and 
institutional research policies and procedures. 
15.1 
Monitoring 
The investigator acknowledges that the monitor has the responsibility to review the clinical 
trial data for verification of proper recording and to verify the source data against the CRF/ 
eCRF and to review the conduct of the clinical trial in compliance with the protocol and GCP. 
The Investigator will permit the site monitor to review study data as frequently as deemed 
necessary.  
The Investigator may not recruit patients into the study until such time that a visit has been 
made by a Sponsor monitor/ representative, or with the agreement of the Sponsor/ formal 
training by Sponsor, to conduct a detailed review of the protocol and CRF/ eCRF. 
The investigator must cooperate with the sponsor to ensure that the conduct of the clinical trial 
is GCP compliant. 
15.2 
Agreement and Compliance with the Protocol 
Prior to trial initiation, the protocol/ other related documents must be approved by the IEC/ 
IRB/ regulatory authority in compliance with applicable regulatory requirements. Before the 
first patient is allowed to participate in the clinical trial, the sponsor/ designee must ensure that 
all the ethical and legal requirements are met. 
The investigator should not deviate from the protocol approved by the IRB/ IEC, except when 
the changes are necessary to eliminate a risk to the patients. This trial must accurately comply 
with the protocol. If changes to the protocol are required the changes must be made in writing 
and notified or submitted for approval by the IRB/ IEC/ regulatory authorities (as necessary). 
15.3 
Audits and Inspections 
An auditor from the sponsor/ designee, the regulatory authorities, or the IEC/ IRBs may 
conduct an audit or inspect the clinical sites. 
The purpose of audits and inspections is to systematically and independently verify that study-
related activities are performed, data in clinical studies are accurately recorded, analyzed and 
reported and that the study has been conducted in accordance with protocol, ICH- GCP 
guidelines and the applicable regulatory requirements. 
Regulatory authorities will communicate the purpose of the audit to the investigator and the 
investigator should notify the sponsor/ designee of the audit. The sponsor/ designee may 
provide support to the investigator so that the site is inspection ready. 
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16 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
This study will be conducted in compliance with the protocol and with the International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines for Technical 
Requirements for Registration of Pharmaceuticals for Human use, the World Medical 
Association Declaration of Helsinki (2013) and in compliance to the specific local regulatory 
requirements wherever applicable and required. 
16.1 
IEC/ IRB Approval 
Prior to the start of the study, the Investigator is responsible for ensuring that the protocol, 
informed consent document and other applicable study documents have been reviewed and 
approved by an EC. The EC will be appropriately constituted and perform its functions in 
accordance with ICH GCP and local requirements as applicable. 
16.2 
Written Informed Consent 
The nature and purpose of the study will be fully explained to each patient (or their legally 
responsible guardian). Before each patient is randomized into the study, informed consent will 
be obtained from the patient (or his/ her legally authorized representative) according to the 
most current applicable regulatory and legal requirements. The consent will be obtained on the 
IEC/ IRB approved and most recent version of consent form in language best comprehended 
by the patient. The consent documents to be used for the study will include all the elements of 
informed consent as outlined in the applicable regulatory guideline and should adhere to GCP 
and to the ethical principles that have their origin in the Declaration of Helsinki and be reviewed 
and approved by the appropriate EC prior to use at each site. 
The patients should be informed in a timely manner if new information becomes available that 
may be relevant to the patient’s willingness to continue participation in the trial. The patients 
will be re-consented as required. 
16.3 
Confidentiality 
All study findings and documents will be regarded as confidential. The investigator and 
members of his/ her research team must not disclose such information without the prior written 
approval from the sponsor. The anonymity of the participating patients must be maintained. 
Patients will be identified on the CRF/ eCRF and other documents submitted to the CRO or the 
independent data management center by unique coded patient identification/ registration 
number but not by name. The confidentiality of records that could identify patients (e.g., the 
signed informed consent) should be protected, respecting the privacy and confidentiality rules 
in accordance with the applicable regulatory requirement(s) and should only be disclosed to 
the authorized study personnel/ sponsor representative/ IEC/ Regulatory authorities if required. 
16.4 
Liability and Insurance 
The sponsor will obtain a reasonable third-party liability insurance coverage in accordance with 
all local legal regulatory requirements.  
The sponsor will provide for insurance coverage with respect to liability caused by trial-related 
injuries caused by IPs being tested or by study-related procedures/ medical steps taken in the 
course of the study in accordance with the applicable regulatory requirement(s). The terms and 
conditions will apply as specified in the insurance policy document. 
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16.5 
Publication Policy 
Lupin shall retain the sole and exclusive ownership of any and all Data arising (whether directly 
or indirectly) out of the conduct of clinical trials in relation to the study (“Data”).  Upon 
completion of the Study, Lupin may, at its sole discretion, arrange the analysis and tabulation 
of the Data.  Lupin shall be entitled to utilize the Data and CSR in any manner whatsoever 
including using the same for publication, presentation at scientific meetings or for submission 
with regulatory authorities in the manner it deems fit.  Investigator hereby agrees and 
acknowledges that it shall not use and/or publish the Data and/or any reports, presentation, 
information arising out of or in relation to the clinical trial without prior written approval of 
Lupin.  
Since such studies are published with data of all patients pooled and analyzed together, isolated 
and independent publications at study center/country level may provide inaccurate 
representation of safety, efficacy or immunogenicity of the investigational product.  Hence, if 
the Investigators would like to publish/present any paper/poster, the Investigators should 
provide Lupin the draft material to review for approval any such proposed 
publication/presentation or other type of disclosure before it is submitted or disclosed in order 
to ensure against any inadvertent disclosure of confidential information or unprotected 
invention.  For approval by Lupin, the Investigator shall send such reports, presentation, 
information and/or Data for Lupin review and approval at least 90 (ninety) days prior.  It is 
hereby agreed that all proposed publications based on the study shall be subject to Lupin’s 
written approval with a possibility of denial for any reason including the reasons given above.  
If approved with comments from Lupin, the Investigator shall incorporate all such comments 
suggested by Lupin in the publication.  By signing this Protocol, the Investigator agrees to 
unequivocally release the Data from the study to the Lupin without conditions and 
acknowledges this publication policy. 
 
 
 
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17 
APPENDICES 
17.1 
Appendix 1: Study Management Details 
Study management/ study administrative details are provided below  
Sponsor  
Lupin Limited (Biotech Division), 
Gat No. 1156, Village Ghotawade, 
Taluka Mulshi, Pune. 412115, 
Maharashtra, (India),Office  
Telephone:+91 66549800 
Medical Expert 
Dr. Chirag Shah 
Lupin Limited (Research Park), 
46A/47A, Nande Village, Mulshi Taluka, 
Pune 412115, Maharashtra, (India) 
Telephone: +91-020-66749068 
Central Laboratory 
Metropolis Healthcare Ltd, 
250-D Udyog Bhavan, Hind Cycle Marg, 
Worli, Mumbai – 400030, Maharashtra, 
India 
Laboratory Analysis of Immunogenicity and 
Pharmacokinetics 
Lupin Bioresearch Center, 
Sai Trinity A Wing, 
Unit 1, 2, 3 & 4, 
Survey No. 146/2/1B, 
Pashan, Pune – 411021, 
Maharashtra, India 
Telephone: +91-20-66219200 
OR  
Appropriate Laboratory 
Clinical Data Management  
Syneos Health 
3201 Beechleaf Ct,  
Raleigh, North Carolina, USA, 27604 
Project Management  
Lupin Limited (Research Park), 
46A/47A, Nande Village, Mulshi Taluka, 
Pune 412115, Maharashtra, (India) 
AND 
Syneos Health 
3201 Beechleaf Ct,  
Raleigh, North Carolina, USA, 27604 
Safety Monitoring  
Drug 
Safety 
& 
Risk 
Management 
(DSRM), Lupin Limited,  
Kalpataru Inspire, 5th Floor,  
Off Western Express Highway, 
Santacruz (East). Mumbai 400055 
 
Medical Writing and Statistics 
Lupin Limited (Research Park), 
46A/47A, Nande Village, Mulshi Taluka, 
Pune 412115, Maharashtra, (India) 
AND 
Syneos Health 
3201 Beechleaf Ct,  
Raleigh, North Carolina, USA, 27604 
Manufacturer of Investigational Bio-
similar Product  
Lupin Limited (Biotech Division) 
Gat No: 1156, Village Ghotawade, 
Mulshi Taluka, Pune. Pin: 412115 
Maharashtra, (India) 
Telephone:+91 66549800 
Packaging 
Bilcare Limited, 
Global Clinical Services 
1028, Shiroli, Rajgurunagar, Pune 410505 
Maharashtra, India 
 
 
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17.2 
Appendix 2: Investigator’s Signature Page 
 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: An open-label, randomized, comparative, parallel group study to assess 
the Immunogenicity of Lupin’s Peg-filgrastim versus Neulasta® as an Adjunct to 
Chemotherapy in Patients with Breast Cancer 
 
PROTOCOL NUMBER: LRP/PegGCSF/2016/004 
 
I have read this protocol and agree that it contains all necessary details for carrying out the 
study as described. I will conduct this study as outlined therein, including all statements 
regarding confidentiality. I will make a reasonable effort to complete the study within the time 
designated. I will provide copies of the protocol and access to all information furnished by the 
Sponsor to study personnel under my supervision. I will discuss this material with them to 
ensure that they are fully informed about the drug and the study. I understand that the study 
may be terminated or enrolment suspended at any time by the Sponsor, with or without cause, 
or by me if it becomes necessary to protect the best interests of the study patients. I agree to 
conduct this study in full accordance with the protocol, all applicable regulations and Good 
Clinical Practice (GCP) guidelines. 
 
 
 
Principal Investigator Name and Job Title:_____________________________________  
_______________________________________________________________________ 
 
Institution/Clinic: ________________________________________________________  
 
Address: ________________________________________________________________ 
 
Signature: ______________________________________________________________  
                                                                                             Date (day/month/year) 
 
 
 
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18 
REFERENCE LIST  
1. 
Clark OA, Lyman GH, Castro AA, Clark LG, Djulbegovic B. Colony-stimulating 
factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized 
controlled trials. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology. 2005;23(18):4198-4214. 
2. 
Fontanella C, Bolzonello S, Lederer B, Aprile G. Management of breast cancer patients 
with chemotherapy-induced neutropenia or febrile neutropenia. Breast care (Basel, 
Switzerland). 2014;9(4):239-245. 
3. 
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth 
Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2015;33(28):3199-3212. 
4. 
Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, 
consequences, and new directions for its management. Cancer. 2004;100(2):228-237. 
5. 
Biganzoli L, Untch M, Skacel T, Pico JL. Neulasta (pegfilgrastim): a once-per-cycle 
option for the management of chemotherapy-induced neutropenia. Seminars in 
oncology. 2004;31(3 Suppl 8):27-34. 
6. 
Shankar G, Devanarayan V, Amaravadi L, et al. Recommendations for the validation 
of immunoassays used for detection of host antibodies against biotechnology products. 
Journal of pharmaceutical and biomedical analysis. 2008;48(5):1267-1281. 
7. 
Guideline on Immunogenicity assessment of biotechnology-derived therapeutic 
proteins. In: European Medicines Agency CfMPFHUC, ed2006. 
8. 
Guideline on bioanalytical method validation. In: European Medicines Agency 
CfMPFHUC, ed2012. 
9. 
Neulasta® Prescribing Information. Amgen Inc. One Amgen Center Drive Thousand 
Oaks, California 91320-1799; 2016. 
10. 
Summary of Product Characteristics (SmPC) of Neulasta. Marketed by Amgen Europe 
B.V. Minervum 7061, 4817 ZK Breda, The Netherlands; 2015. 
11. 
FDA guidance for industry: bioanalytical method validation. In: US Department of 
Health and Human Services FaDA, Center for Drug Evaluation and Research: 
Rockville, MD, ed2001. 
12. 
Green MD. A randomized double-blind multicenter phase III study of fixed-dose 
single-administration pegfilgrastim versus daily filgrastim in patients receiving 
myelosuppressive chemotherapy. Annals of Oncology. 2003;14(1):29-35. 
13. 
Holmes FA, O'Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter 
study to evaluate single administration pegfilgrastim once per cycle versus daily 
filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage 
III/IV breast cancer. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2002;20(3):727-731. 
14. 
Farrington CP, Manning G. Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non-zero risk difference or non-unity relative 
risk. Statistics in medicine. 1990;9(12):1447-1454. 
 
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SoC for Protocol Version 2.2 
Confidential 
 
Protocol No.: LRP/PegGCSF/2016/004 Version 2.2, Dated 02 Jul 2018 
 
 
Page 1 of 4 
 
 
Summary of changes (SoC) made in the Clinical Study Protocol: LRP/PegGCSF/2016/004 
Version 2.1 Dated 16 Oct 2017 
 
This document indicates the summary of changes made to the Clinical Study Protocol No.: LRP/PegGCSF/2016/004 Version 2.1, Dated 16 Oct 
2017. These changes will be reflected in Protocol No.: LRP/PegGCSF/2016/004 Version 2.2, Dated 02 Jul 2018.  
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Report version 1.0, 05 Dec 2019


 
SoC for Protocol Version 2.2 
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Protocol No.: LRP/PegGCSF/2016/004 Version 2.2, Dated 02 Jul 2018 
 
 
Page 2 of 4 
 
Protocol Sec No (pg. No) 
Current Text 
Updated Text 
Reason For Change 
Synopsis (Page 4); Section 
6.1 Overall Study Design 
and 
Plan 
(Page 
23); 
Section 6.3.1.1 Screening 
Visit (Page 26) 
Screening Period (Maximum 7 Days) 
Screening Period (Maximum 7 full Days) 
Corrections have been made for better 
clarity. 
6.3.1.1 Screening 
Visit 
(Page 26) 
 
Adverse Event assessment details are 
added at screening visit. 
Missing assessment has been added. 
6.4.2 
Exclusion Criteria 
(Page 31)  
8. 
Patients with history of 
systemic antibiotic use within 72 hours 
prior to chemotherapy 
8. 
Patients with history of systemic 
antibiotic use within 72 hours prior to 
chemotherapy* 
*Refers to parenteral use 
The 
definition 
of 
systemic 
as 
envisaged in the original protocol has 
been clarified to mean parenteral.  
Section 7.2.2 
IP 
Packaging and Labeling 
(Page 36) 
Labels will be prepared in accordance 
with Good Manufacturing Practice 
(GMP) and local regulatory guidelines. 
The label text will be translated into 
local language. The labels shall contain 
appropriate information as per the local 
regulatory requirements including but 
not limited to product content and 
strength, batch No, manufacture date, 
retest/ expiry date, storage information, 
route of administration, statements like 
“For Clinical Trial Purpose Only”. 
Labels will be prepared in accordance with 
Good Manufacturing Practice (GMP) and 
local regulatory guidelines. The label text 
will be translated into local language. The 
labels 
shall 
contain 
appropriate 
information as per the local regulatory 
requirements including but not limited to 
product content and strength, batch No, 
manufacture date, retest/ expiry date, 
storage 
information, 
route 
of 
administration, 
statements 
like 
“For 
Clinical Trial Purpose Only”. 
Since the product is marketed and the 
same pack being used in an open label 
study, translation in local language is 
not required. 
 
Section 8.3.1 
Collection, 
Handling and Analysis of 
Immunogenicity Samples 
(Page 38) 
For immunogenicity assessments, a 
6mL of blood sample will be collected 
in a plain blood collection vacutainer 
(with clot activator) by vein puncture as 
per the scheduled time points mentioned 
in Table 1. Samples will be kept on 
bench for 30-45 minutes to enable 
For immunogenicity assessments, a 6mL 
of blood sample will be collected in a plain 
blood collection vacutainer (with clot 
activator) by vein puncture as per the 
scheduled time points mentioned in Table 
1. Samples will be kept on bench for 45± 
15 minutes to enable clotting and will be 
 
To bring in consonance with the 
sample processing method used for 
PK samples as it has no consequences 
on immunogenicity assay. Based on 
the 
communication 
from 
the 
bioanalytical laboratory to this effect, 
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SoC for Protocol Version 2.2 
Confidential 
 
Protocol No.: LRP/PegGCSF/2016/004 Version 2.2, Dated 02 Jul 2018 
 
 
Page 3 of 4 
 
Protocol Sec No (pg. No) 
Current Text 
Updated Text 
Reason For Change 
clotting and will be centrifuged at 
around 3000 rpm for 10 minutes at 
10°C. 
Serum will be separated and transferred 
into three aliquots of equal volume for 
storage below -75°C. 
centrifuged at around 3800 ± 20 rpm for 10 
minutes at 10± 2°C. 
Serum will be separated and transferred 
into three aliquots of equal volume for 
storage at -75 ± 10°C 
the change was implemented at all 
sites (Relevant communication from 
the Bioanalytical laboratory enclosed). 
 
 
Section 9.1.3.3 Reporting 
of Serious Adverse Events 
(Page 44)  
The Details of Safety Contact: 
 
Name: Dr. Anish Sule 
Designation: Medical and Safety Monito
Address: Drug Safety & Risk Managem
(DSRM), Lupin Limited,
Kalpataru Inspire, 5th Floor,  
Off Western Express Highway, 
Santacruz (East). Mumbai 400055 
Contact Details:  
Mobile: +91 7045 347 051 
Tel/Fax: +91 22 6640 2731 
Email: anishsule@lupin.com 
 
The Details of Safety Contact: 
 
Name: Dr. Prabhat Singh 
Designation: Medical and Safety Monitor 
Address: Drug Safety & Risk Management
(DSRM), Lupin Limited,  
Kalpataru Inspire, 5th Floor,  
Off Western Express Highway, 
Santacruz (East). Mumbai 400055 
Contact Details:  
Mobile: +91 7045 347 051 
Tel/Fax: +91 22 6640 2833 
Email: prabhatsingh@lupin.com 
 
Administrative change 
10.2 
Blood 
Sampling 
(Page 47) 
The blood samples in vacutainers with 
clot activator will be kept aside for 45 ± 
15 minutes so as to allow the 
coagulation process. Then the blood 
samples will be centrifuged at 3800 ± 
20 rpm for 10 minutes at 10 ± 2°C to 
separate serum. 
The collected blood sample will be 
centrifuged at 10 ± 2°C at 3800 rpm for 
10 minutes and the separated serum will 
be collected in 2 tubes/aliquots. The 
serum samples will be stored -75 ± 10 
The blood samples in vacutainers with clot 
activator will be kept aside for 45 ± 15 
minutes so as to allow the coagulation 
process. Then the blood samples will be 
centrifuged at 3800 ± 20 rpm for 10 
minutes at 10 ± 2°C to separate serum. 
The collected blood sample will be 
centrifuged at 10 ± 2°C at 3800 rpm 
for 10 minutes and The separated 
serum will be collected in 2 
tubes/aliquots. The serum samples will 
be stored -75 ± 10 
Redundant text is removed. 
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Lupin Limited (Biotechnology Division) 
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Clinical Study Report version 1.0, 05 Dec 2019


 
SoC for Protocol Version 2.2 
Confidential 
 
Protocol No.: LRP/PegGCSF/2016/004 Version 2.2, Dated 02 Jul 2018 
 
 
Page 4 of 4 
 
Protocol Sec No (pg. No) 
Current Text 
Updated Text 
Reason For Change 
Across all document 
 
• Logistic and administrative changes are 
made. 
• Typographical 
errors 
and 
inconsistencies have been corrected. 
Administrative 
changes: 
Due 
to 
finalization of vendors. 
Corrections have been made for better 
clarity. 
Across all document 
 
Page No. updated and formatting done. 
Page 
No. 
updated 
across 
the 
document.  
Across all document 
Protocol No.: LRP/PegGCSF/2016/004 
Version No.: 2.1, Dated 16 Oct 2017;  
Supersedes: Version No. 2.0, Dated 29 
May 2017 
Protocol No.: LRP/PegGCSF/2016/004 
Version No.: 2.2, Dated 02 Jul 2018;  
Supersedes: Version No.: 2.1, Dated 16 
Oct 2017 
Version, date in header and page 
numbering updated. 
 
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Lupin Limited (Biotechnology Division) 
Pegfilgrastim (PegGCSF)  
                   LRP/PegGCSF/2016/004
Clinical Study Report version 1.0, 05 Dec 2019