An Assessor-blind, Balanced, Parallel, Randomized, Two-treatment, Comparative Immunogenicity Study of Multiple Doses of INTP5 of Intas Pharmaceuticals Limited, India Against Neulasta® of Amgen Inc., USA Administered Subcutaneously in Healthy, Adult, Human Subjects Under Fed Condition.
Phase: PHASE1
Conditions: Immunogenicity, Healthy Volunteers
Sponsor: Intas Pharmaceuticals, Ltd.

 
PROJECT NO. 0554-17 
 
PROTOCOL 
 
AN ASSESSOR-BLIND, BALANCED, PARALLEL, RANDOMIZED, TWO-TREATMENT, 
COMPARATIVE IMMUNOGENICITY STUDY OF MULTIPLE DOSES OF INTP5 OF INTAS 
PHARMACEUTICALS LIMITED, INDIA AGAINST NEULASTA® OF AMGEN INC., USA 
ADMINISTERED SUBCUTANEOUSLY IN HEALTHY, ADULT, HUMAN SUBJECTS UNDER FED 
CONDITION  
 
INVESTIGATIONAL MEDICINAL PRODUCTS: 
Test Product-T 
: INTP5 (INTP5 is an internal code assigned to Pegfilgrastim manufactured 
by Intas Pharmaceuticals Limited)  
Active content: Pegfilgrastim, Strength: 6 mg/0.6 ml  
Dose for administration: 6 mg/0.6 ml 
Marketing Authorization Holder: Intas Pharmaceuticals Ltd., India  
Reference Product-R 
: Neulasta® (Pegfilgrastim) (US Licensed product) 
Active content: Pegfilgrastim, Strength: 6 mg/0.6 ml  
Dose for administration: 6 mg/0.6 ml 
Marketing Authorization Holder: Amgen Inc., Thousand Oaks, California, 
USA 
 
Version No. 
: 2.0 
 
Principal Investigator: 
Date 
: 22 January 2018 
Supersedes 
: 1.0 
Dated 
: 23 August 2017 
 
Sponsor Address: 
 
Study centre:  
Intas Pharmaceuticals Ltd,  
 
 
 
 
 
 
CONFIDENTIAL: 
 
The content of this document as well as the objectives and the results of this study are confidential and must 
not be made accessible to third parties without permission of Intas Pharmaceuticals Limited (Biopharma 
Division). 
 
 
 
 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 2 of 50 
 
 
TABLE OF CONTENTS 
1.0 
STUDY SYNOPSIS ...............................................................................................................................8 
2.0 
INVESTIGATOR’S DECLARATION .............................................................................................17 
3.0 
SPONSOR'S APPROVAL ..................................................................................................................18 
4.0 
MEDICAL EXPERT ..........................................................................................................................19 
4.1 
Sponsor’s Medical Expert: ....................................................................................................................19 
4.2 
Sponsor’s Safety Expert: .......................................................................................................................19 
5.0 
FACILITIES ........................................................................................................................................19 
5.1 
Clinical facility, Pharmacodynamics, Biostatistics and programming, Clinical Data management, 
Quality Assurance and clinical safety laboratory Services: ............................................................................19 
6.0 
BACKGROUND INFORMATION ...................................................................................................20 
6.1 
Investigational Medicinal Products .......................................................................................................20 
6.1.1 
Test Product-T ............................................................................................................................... 20 
6.1.2 
Reference Product–R ..................................................................................................................... 20 
6.2 
Investigational Medicinal Product Summary 1, 2 ...................................................................................20 
6.2.1 
General pharmacology ................................................................................................................... 20 
6.2.2 
Absorption, Distribution, Metabolism, Excretion and Food Effects ............................................. 20 
6.2.3 
Adverse Effects .............................................................................................................................. 21 
6.2.4 
Indications ...................................................................................................................................... 21 
6.2.5 
Contraindications ........................................................................................................................... 22 
6.2.6 
Dosage............................................................................................................................................ 22 
6.3 
Risks and Benefits .................................................................................................................................22 
6.4 
Rationale ................................................................................................................................................22 
7.0 
STUDY OBJECTIVES .......................................................................................................................23 
7.1 
Primary objectives .................................................................................................................................23 
7.2 
Secondary objectives .............................................................................................................................23 
8.0 
STUDY DESIGN .................................................................................................................................23 
8.1 
Design ....................................................................................................................................................23 
8.2 
Numbers of subjects ..............................................................................................................................23 
8.3 
Randomization .......................................................................................................................................23 
8.4 
Blinding .................................................................................................................................................24 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 3 of 50 
 
 
8.5 
Housing .................................................................................................................................................24 
8.6 
Duration of Fasting and Distribution of Meals .....................................................................................24 
8.7 
Restrictions ............................................................................................................................................25 
8.7.1 
Medications .................................................................................................................................... 25 
8.7.2 
Diet ................................................................................................................................................. 25 
8.7.3 
Postural Restrictions ...................................................................................................................... 25 
8.8 
Dosing Procedures and Compliance Assessment ..................................................................................26 
8.8.1 
Dosing ............................................................................................................................................ 26 
8.8.1.1 Test Product-T .............................................................................................................................. 26 
8.8.1.2 Reference Product-R ..................................................................................................................... 26 
8.8.2 
Assessment of compliance for dosing............................................................................................ 26 
8.9 
Blood Sampling for Pharmacokinetic/ Pharmacodynamics/ Immunogenicity Analysis ......................26 
8.9.1 
Procedure of Blood Sampling and Collection ............................................................................... 26 
8.9.2 
Sampling Schedule......................................................................................................................... 28 
8.10 Sample Handling and processing ..........................................................................................................29 
8.11 Clinical Safety Measures .......................................................................................................................29 
8.12 Termination of the Study .......................................................................................................................31 
9.0 
HANDLING, STORAGE, DISPENSING AND ACCOUNTABILITY PROCEDURES FOR 
INVESTIGATIONAL MEDICINAL PRODUCTS ......................................................................................31 
9.1 
Investigational Medicinal Product Receipt and Storage .......................................................................31 
9.2 
Dispensing .............................................................................................................................................32 
9.3 
Unused Investigational Medicinal Products ..........................................................................................32 
9.4 
Retention Samples .................................................................................................................................32 
10.0 
SELECTION & WITHDRAWAL CRITERIA ................................................................................33 
10.1 Inclusion Criteria ...................................................................................................................................33 
10.2 Exclusion Criteria ..................................................................................................................................33 
10.3 Withdrawal Criteria ...............................................................................................................................35 
11.0 
EVALUATION PARAMETERS .......................................................................................................36 
11.1 Immunogenicity, Pharmacokinetic and Pharmacodynamic Analyses ..................................................36 
11.2 Immunogenicity Data Analysis .............................................................................................................36 
11.3 Pharmacokinetic parameters ..................................................................................................................36 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 4 of 50 
 
 
11.4 Pharmacodynamic parameters ...............................................................................................................37 
11.5 Assessment of Eligibility/Safety ...........................................................................................................38 
11.5.1 Safety data ...................................................................................................................................... 38 
11.5.2 Eligibility Assessments .................................................................................................................. 38 
11.5.3 Study Assessments ......................................................................................................................... 38 
11.5.3.1Determining the severity of the adverse event: .......................................................................... 40 
11.5.3.2 Causality Assessment of the Adverse Event to the Investigational Medicinal Product. ........... 40 
11.5.4 Post Study Assessments ................................................................................................................. 41 
11.5.5 Evaluation Criteria for Laboratory Parameter ............................................................................... 42 
12.0 
ASSESSMENT SCHEDULE: ............................................................................................................43 
13.0 
LIST OF LABORATORY PARAMETERS .....................................................................................45 
14.0 
RESPONSIBILITIES OF PERSONNEL INVOLVED IN THE STUDY .....................................46 
15.0 
ETHICAL CONSIDERATIONS .......................................................................................................47 
15.1 Basic Principles .....................................................................................................................................47 
15.2 Independent\Institutional Ethics Committee (IEC) ...............................................................................47 
15.3 Written Informed Consent .....................................................................................................................47 
15.4 Subject Compensation ...........................................................................................................................47 
16.0 
INSURANCE POLICY .......................................................................................................................47 
17.0 
AMENDMENT TO THE PROTOCOL ............................................................................................48 
18.0 
SOURCE DATA ACCESSIBILITY ..................................................................................................48 
19.0 
QUALITY ASSURANCE AUDITS ...................................................................................................48 
20.0 
DATA HANDLING & RECORD KEEPING...................................................................................48 
21.0 
REPORT ..............................................................................................................................................48 
22.0 
ARCHIVING .......................................................................................................................................49 
23.0 
CONFIDENTIALITY OF DATA ......................................................................................................49 
24.0 
PUBLICATION POLICY ..................................................................................................................49 
25.0 
STANDARDIZED VEGETARIAN BREAKFAST MENU ............................................................50 
26.0 
REFERENCES ....................................................................................................................................50 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 5 of 50 
 
 
LIST OF ABBREVIATIONS 
Abbreviation 
: Full Name 
A/G ratio 
: Albumin/Globulin ratio 
C 
: Degree Celsius 
F 
: Degree Fahrenheit 
ADR 
: Adverse Drug Reaction 
AE 
: Adverse Event 
ALT 
: Alanine Amino Transferase 
ANOVA 
: Analysis of Variance 
AST 
: Aspartate Amino Transferase 
AUC 
: Area under Curve 
AUC0-t 
: Area under the serum concentration versus time curve from time zero to the last 
measurable concentration as calculated by linear trapezoidal method 
AUC0-∞ 
: Area under the serum concentration versus time curve from time zero to infinity 
AUC_% Extrap_obs 
: % of the Area under the Curve that has been derived after Extrapolation or % 
Residual Area 
BA 
: Bioavailability 
BE 
: Bioequivalence 
ß-hCG 
: Beta-human chorionic gonadotropin 
BLQ 
: Below Limit of Quantification 
BMI 
: Body Mass Index 
CDSCO 
: Central Drugs Standard Control Organization 
CL 
: Confidence Limit 
Cmax 
: Maximum Measured Serum Concentration 
CNS 
: Central Nervous System 
COA 
: Certificate of Analysis 
CPMA 
: Clinical Pharmacology and Medical Affairs 
CPMP 
: Committee for Proprietary Medicinal Products 
CRO 
: Contract Research Organization 
C.V. 
: Coefficient of Variation 
CVS 
: Cardiovascular System 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 6 of 50 
 
 
CS 
: Clinically Significant 
DCGI 
: Drug Controller General of India 
e-CRF 
: electronic case report forms 
e-CTD 
: Electronic Common Technical Document 
ECG 
: Electrocardiogram 
GCP 
: Good Clinical Practices 
GCLP 
: Good clinical laboratory practices 
G-CSF 
: Granulocyte -Colony Stimulating Factor 
HCV 
: Hepatitis C Virus 
HBsAg 
: Hepatitis B surface antigen 
HIV 
: Human Immunodeficiency Virus 
hr/hrs 
: hour/hours 
ICH 
: The International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMR 
: Indian Council of Medical Research 
ICF 
: Informed consent form 
IEC 
: Independent\Institutional Ethics Committee 
IMP 
: Investigational Medicinal Product 
IMPRAR 
: Investigational Medicinal Product Receipt And Accountability Record 
IMPDR 
: Investigational Medicinal Product Dispensing Record 
IU 
: International Unit 
Kg 
: Kilogram 
LAR 
: Legally acceptable representative 
ln 
: Logarithmic Value to the Base ‘e’ 
LC-MS/MS 
: Liquid Chromatography – Tandem Mass spectroscopy 
 
L/hr 
: Liter/hour 
m2 
: Meter Square  
Mg 
: Milligram 
mL/ml 
: Milliliter 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 7 of 50 
 
 
mm Hg 
: Millimeter of Mercury 
MSR 
: Medical Screening Record 
NTF 
: Note to File 
NA 
: Not Applicable 
NCS 
: Not Clinically Significant 
NR 
: Non Reportable 
NSAIDs 
: Non-steroidal Anti-inflammatory Drugs 
P/A 
: Postero-anterior 
PC 
: Project Coordinator 
PI 
: Principal Investigator 
QC 
: Quality Control 
QA 
: Quality Assurance 
RBCs 
: Red Blood Cells 
SAE 
: Serious Adverse Event 
SAP 
: Statistical Analysis Plan 
SAS 
: Statistical Analysis System 
SGPT 
: Serum Glutamic Pyruvic Transaminase 
SGOT 
: Serum Glutamic Oxaloacetic Transaminase 
SOP 
: Standard Operating Procedure 
t1/2 
: Terminal half-life 
Tmax 
: Time of the maximum measured serum concentration 
T/R 
: Test to Reference ratio 
USFDA 
: United States Food and Drug Administration  
WNL 
: Within Normal Limits 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 8 of 50 
 
 
1.0 
STUDY SYNOPSIS 
1.1 
Project number 
: 0554-17 
1.2 
Background 
: Pegfilgrastim is the pegylated form of a colony stimulating factor (Granulocyte 
colony stimulation factor; G-CSF) that acts on hematopoietic cells by binding to 
a specific cell surface receptor, thereby stimulating proliferation, differentiation, 
commitment, and end cell functional activation.  
The sponsor, Intas Pharmaceuticals Ltd., India, is developing a biosimilar of 
Pegfilgrastim (INTP5) and is planning to compare the immunogenicity of INTP5 
with Neulasta of Amgen Inc, USA.  
In this study, immunogenicity after multiple doses of INTP5 will be compared 
with that of Neulasta®. 
1.3 
Investigational 
Medicinal 
Products 
: Test Product-T 
INTP5 (INTP5 is an internal code assigned to Pegfilgrastim manufactured by 
Intas Pharmaceuticals Limited)  
Active content: Pegfilgrastim, Strength: 6 mg/0.6 ml  
Dose for administration: 6 mg/0.6 ml 
Marketing Authorization Holder: Intas Pharmaceuticals Ltd., India 
Pharmaceutical form: Pre-filled syringe  
Route of administration: Subcutaneous  
Storage: 2ºC - 8ºC  
Reference Product-R 
Neulasta® (Pegfilgrastim) (US Licensed Product) 
Active content: Pegfilgrastim, Strength: 6 mg/0.6 ml  
Dose for administration: 6 mg/0.6 ml 
Marketing Authorization Holder: Amgen Inc., Thousand Oaks, California, USA 
Pharmaceutical form: Pre-filled syringe  
Route of administration: Subcutaneous  
Storage: 2ºC - 8ºC  
1.4 
Objective 
: Primary objectives: 
• To assess and compare multiple-dose immunogenicity of INTP5 and 
Neulasta® in healthy, adult, human subjects. 
 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 9 of 50 
 
 
Secondary objective: 
• To assess and compare the safety and tolerability of INTP5 and Neulasta® in 
healthy, adult, human subjects. 
• If any subject develops immunogenicity, impact of immunogenicity on 
pharmacokinetics (PK) and pharmacodynamics (PD) would be evaluated for 
that subject. 
1.5 
Study Design 
: An assessor-blind, balanced, parallel, randomized, two-treatment, comparative 
immunogenicity study of multiple doses of INTP5 of Intas Pharmaceuticals 
Limited, India against Neulasta® of Amgen Inc., USA (US Licensed Product) 
administered subcutaneously in healthy, adult, human subjects under fed 
condition.  
1.6 
Number of 
subjects 
: 200 Subjects (100 subjects per treatment arm)* 
Efforts will be made to recruit equal number of healthy male and female 
volunteers.  
*Study will be conducted in multiple groups. 
1.7 
Dose 
: Two doses of Pegfilgrastim 6 mg/0.6 ml [either of the Test product (T) or 
Reference product (R)] will be administered subcutaneously to the outer area of 
right upper arm in each subject at an interval of 3 weeks (21 days) between each 
dose. 
1.8 
Fasting Criteria 
:
  
For Each dose: 
➢ Pre-dose: At least 10 hours prior to serving standardized vegetarian breakfast 
and 1 hour (±10 minutes) after starting of the meal   
➢ Post-dose: 4 hours 
➢ Further meals will be provided to the subjects at appropriate times during 
their housing period. 
1.9 
Water restriction 
: For Each dose: 
➢ 1 hour pre dose 
➢ 1 hour post dose 
1.10 Method of 
administration 
: For Each dose: 
➢ After an overnight fasting of at least 10 hours, subject will be served 
standardized vegetarian breakfast which they are required to consume within 
30 minutes. Each subject will receive 6 mg/0.6 ml dose of Pegfilgrastim 
(either test product or reference product) subcutaneously in the outer area of 
the right upper arm at 1 hour (±10 minutes) after serving standardized 
vegetarian breakfast in sitting position. 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 10 of 50 
 
 
➢ Method of drug administration will be as per the procedure defined in a 
separate drug administration manual.  
➢ Standardized vegetarian breakfast will be provided at 1 hour (±10 minutes) 
prior to each dose. 
1.11 Posture 
Restriction 
: For Each dose: 
➢ The study medicine will be administered to subjects while in sitting posture. 
➢ Subjects will be in sitting or ambulatory posture for the first 4 hours post dose 
unless medically necessary due to adverse event or procedurally required or 
natural exigency; in such cases it would not be considered as protocol 
deviation. In case of adverse event, appropriate position will be given to the 
subjects. 
➢ Thereafter, the subjects will be allowed to engage only in normal activities 
while avoiding any strenuous physical activity. 
1.12 Housing 
: For Each dose: 
➢ Pre-dose: 11 hours  
➢ Post-dose: 72 hours 
➢ Subject will have to stay in the clinical facility for 4 consecutive nights for 
each dose.  
➢ The subjects will have to report to the facility at and after 96 hours post dose 
for ambulatory blood sample collection for each dose. 
➢ Subjects will also have to report to the clinical facility for laboratory 
estimation (as per details mentioned in Section 13.0) along with complete 
clinical examination within 3 working days prior to receiving the second 
dose. 
➢ In case of adverse event, subjects may be housed in the clinical facility 
beyond 72 hours based on the principal investigator's discretion, and 
necessary action will be taken till the event subsides. 
1.13 Clinical 
Safety 
Measurements 
: ➢ Clinical examination (including recording of vital signs [i.e. sitting blood 
pressure, radial pulse rate, respiratory rate and oral body temperature]): 
• Screening 
• After check-in for each dose 
• Before checkout of each dose 
• Within 3 working days prior to dose-2. 
• End of the study (after last ambulatory sample after dose-2) 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 11 of 50 
 
 
(Note: Clinical examination before checkout may be started 120 minutes prior 
to the schedule time of checkout of each subject). 
➢ Subject will be instructed not to participate in other clinical trial or donate 
blood anywhere else during the study. 
➢ Vitals (Sitting blood pressure and radial pulse): 
▪ Pre-dose (within 60 minutes prior to each dose) and at 2, 4, 10, 24, 30, 
36, 48 and 60 hrs after each dose.  
(Note: All the post-dose vitals will be performed within ± 40 minutes of the 
scheduled time) 
➢ Well-being: At the time of clinical examinations, during ambulatory samples 
and at the time of recording of vital signs for each dose. 
➢ Chest X-ray (P/A view; within the last 6 months) at the time of screening. 
➢ 12-lead ECG recording will be performed at the time of screening, within 
three working days prior to receiving dose-2 and at the end of the study 
(after last ambulatory sample after dose-2). 
➢ Abdominal ultrasonography will be done at the time of screening. 
➢ Injection site assessment will be performed after 30 minutes, and at 2, 6 and 
12 hours of injection after each dose.  
➢ Injection site scoring (Scoring to be done separately for Pain, Erythema 
and Induration/Swelling): 
None 
0 No reaction 
Mild 
1 
Pain: 
Pain or tenderness causing no or minimal limitation of use 
of limb  
Erythema: 
2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area 
AND Symptoms causing no or minimal interference with 
usual social & functional activities  
Induration/Swelling: 
2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area 
AND Symptoms causing no or minimal interference with 
usual social & functional activities  
Moderate 
2 
Pain: 
Pain or tenderness causing greater than minimal limitation 
of use of limb  
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 12 of 50 
 
 
Erythema: 
≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface 
area OR Symptoms causing greater than minimal 
interference with usual social & functional activities  
Induration/Swelling: 
≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface 
area OR Symptoms causing greater than minimal 
interference with usual social & functional activities  
Severe 
3 
Pain: 
Pain or tenderness causing inability to perform usual social 
& functional activities  
Erythema: 
≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR 
Ulceration OR Secondary infection OR Phlebitis OR Sterile 
abscess OR Drainage OR Symptoms causing inability to 
perform usual social & functional activities  
Induration/Swelling: 
≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR 
Ulceration OR Secondary infection OR Phlebitis OR Sterile 
abscess OR Drainage OR Symptoms causing inability to 
perform usual social & functional activities  
Potentially 
life-
threatening  
 
4 
Pain: 
Pain or tenderness causing inability to perform basic self-
care function OR Hospitalization indicated  
Erythema: 
Potentially life-threatening consequences (e.g., abscess, 
exfoliative dermatitis, necrosis involving dermis or deeper 
tissue)  
Induration/Swelling: 
Potentially life-threatening consequences (e.g., abscess, 
exfoliative dermatitis, necrosis involving dermis or deeper 
tissue)  
➢ If there is a lump, swelling or bruising at the injection site, subjects will be 
instructed to consult the investigator. 
➢ Paracetamol or other NSAIDS can be given in case of bone pain or pain in 
extremities, which is the most common side effect of Pegfilgrastim. 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 13 of 50 
 
 
➢ The needle cover on the single-use prefilled syringe contains dry natural 
rubber (latex); subjects with latex allergies should not be administered with 
this product. 
➢ Urine Scan for drug of abuse: 
▪ Screening and before check-in for each dose 
➢ Breath test for alcohol consumption: 
▪ Screening and before check-in for each dose 
➢ For female subjects, serum pregnancy test will be performed at the time of 
screening, prior to check-in of each dose and at the end of the study (after 
last ambulatory sample after dose-2). 
1.14 Laboratory 
Assessments 
: • Screening: Hematology, biochemistry, urine analysis, sickling test 
immunological tests and serum pregnancy test (for female subjects). 
• Prior to check-in of each dose: Serum pregnancy test for female subjects. 
• Pre-check-in: Estimation of hematology (except sickling test), biochemistry 
and urine analysis will be done within 3 working days prior to receiving dose-
2. 
• End of the study (after last ambulatory sample after dose-2): Hematology 
(except sickling test), biochemistry (except sodium, potassium, calcium, and 
chloride), and urine analysis and serum pregnancy test (for females). 
1.15 Sample 
Collection 
: Blood samples will be collected through an indwelling intravenous cannula 
(Venflon) placed in the forearm vein of the subjects. If required, it may also be 
collected through a fresh vein puncture. Cannula will be removed after collection 
of blood sample at 24 hrs after each dose. Samples after 24.000 hrs post dose 
will be collected through fresh vein puncture. 
4 ml of blood per sample for PK evaluation, 2 ml of blood per sample for PD 
evaluation and 8 mL of blood per sample for immunogenicity assessment will be 
withdrawn using syringe/adaptor at respective time points 
1.16 Sampling 
Schedule 
: A total of 23 blood samples will be collected for PK and 23 blood samples will 
be collected for PD evaluations. (Note: The last sample of the previous dose and 
the pre-dose sample of the following dose will be the same). 
A total of 8 blood samples will be collected for immunogenicity analysis, 
including sample at screening.  
For Pharmacokinetic evaluation: 
1st and 2nd doses: Venous blood samples (04 ml each) will be withdrawn at pre-
dose (0.000) and at 8.000, 16.000, 24.000 (Day 2), 48.000 (Day 3), 72.000 (Day 
4), 96.000 (Day 5), 120.000 (Day 6), 144.000 (Day 7), 240.000 (Day 11), 
336.000 (Day 15) and 504.000 (Day 22) hours following 1st and 2nd dose 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 14 of 50 
 
 
administration. Blood samples will be collected in a pre-labeled serum separator 
vacutainer.  
(Note: Post-dose sample of 1st dose at 504.000 (Day 22) hours will be considered 
as pre-dose sample of 2nd dose, which should be collected within 5 minutes prior 
to 2nd dose). 
For Pharmacodynamic evaluation: 
1st and 2nd dose: Venous blood samples (02 ml each) will be withdrawn at pre-
dose (0.000) and at 8.000, 16.000, 24.000 (Day 2), 48.000 (Day 3), 72.000 (Day 
4), 96.000 (Day 5), 120.000 (Day 6), 144.000 (Day 7), 240.000 (Day 11), 
336.000 (Day 15) and 504.000 (Day 22) hours following 1st and 2nd dose 
administration. Blood samples will be collected in pre-labeled sample collection 
tubes containing K2EDTA as anticoagulant.  
(Note: Post-dose sample of 1st dose at 504.000 (Day 22) hours will be considered 
as pre-dose sample of 2nd dose, which should be collected within 5 minutes prior 
to 2nd dose).  
For Immunogenicity evaluation: 
Venous blood samples (08 ml each) will be withdrawn at screening, pre-dose, 
and at 336.000 (Day 15, week 2), 504.000 (Day 22, week 3, within 60 minutes 
before 2nd dose), 840.000 (Day 36, week 5), 1176.000 (Day 50, week 7), 
1680.000 (Day 71, week 10) and 2016.000 (Day 85, week 12) hours after the 
first dose. Blood samples will be collected in a pre-labeled serum separator 
vacutainer.  
Note: Pre-dose sample will be collected within 60 minutes before the scheduled 
time. Post- dose in-house blood samples will be collected within ± 02 minutes 
and ambulatory blood samples will be collected within ± 01 hours from the 
scheduled time. Samples for PK and PD at and after 96.000 hours after each 
dose will be collected on an ambulatory basis.  
Samples for immunogenicity evaluation at 336.000 (Day 15, week 2), 504.000 
(Day 22, week 3, within 60 minutes before 2nd dose), 840.000 (Day 36, week 
5), 1176.000 (Day 50, week 7), 1680.000 (Day 71, week 10) and 2016.000 (Day 
85, week 12) hours after the first dose will be collected on an ambulatory basis. 
1.17 Total Blood Loss 
: Not exceeding 232 mL for male subjects and 236 mL for female subjects, as 
follows: 
 
 
Subjects 
Male 
Female 
+ 
Blood volume for PK evaluation (23 samples of 4 mL 
each). 
: 
92 mL 
92 mL 
+ Blood volume for PD evaluation (23 samples of 2 mL 
each). 
: 
46 mL 
46 mL 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 15 of 50 
 
 
+ Blood volume for the immunogenicity assessment (8 
samples of 8 mL each). 
: 
64 mL 
64 mL 
+ Discarded normal saline containing blood (8 × 0.5 
mL) 
: 
4 mL 
4 mL 
+ Blood withdrawn for screening prior to study. 
: 
10 mL 
10 mL 
+ 
Blood withdrawn for post-study safety assessment 
(including serum pregnancy test in case of female 
subjects) 
: 
8 mL 
8 mL 
+ Estimation of hematology and biochemistry (within 
three working days prior to receiving dose-2) 
: 
8 mL 
8 mL 
+ Serum pregnancy test prior to check in each dose (for 
female subjects). 
: 
-- 
4 mL 
Total Blood Loss for each Subject 
: 232 mL 236 mL 
 
1.18 Sample handling 
and processing 
 
Separate 
laboratory 
manual 
will 
be 
prepared 
for 
pharmacokinetic, 
Pharmacodynamic and Immunogenicity sample handling, separation process and 
analytical procedure. 
1.19 Analytical 
Procedure 
: For immunogenicity evaluation:  
The anti-PegG-CSF antibodies will be detected using a validated screening 
assay. All samples deemed positive by the screening assay shall be re-assessed 
using a validated confirmatory assay, and confirmed positive samples will be 
submitted for neutralizing antibody (NAb) assay. 
The presence of NAbs to PegG-CSF shall be assessed using a validated NAb 
assay 
For PK evaluation: 
Serum samples will be analyzed for Pegfilgrastim using a validated method. 
Samples from subjects who are positive for immunogenicity will be analyzed.  
For PD evaluation: 
Pharmacodynamic marker ANC will be analyzed on automated cell counter 
using a validated method. All subject’s samples will be analyzed. 
1.20 Immunogenicity 
data analysis 
 
Immunogenicity (Anti-drug antibody; ADA) data will be presented for all 
subjects’ samples collected. 
Descriptive analysis will be provided for immunogenicity (ADA) data. 
Percentage incidence within + 10% of the expected ADA positivity incidence of 
Test (6% ADA in Test is anticipated from literature) would not be considered 
clinically significant. 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 16 of 50 
 
 
In 
case 
any 
subject 
develops 
positive 
immunogenicity, 
impact 
of 
immunogenicity on PK and PD would be evaluated for that subject. Pooled PD 
data along with variability will be presented. PK and PD data of individual 
subjects having positive immunogenicity will be presented separately 
1.21 Pharmacokinetic 
and 
Pharmacodynamic 
Parameters 
: If decided (decision based on Immunogenicity results) to analyze PK data by 
analytical laboratory, PK parameters would be calculated. PD parameters will be 
estimated for all subjects. 
Employing the measured concentration vs. time profiles of Pegfilgrastim, the 
following PK parameters will be calculated for the samples collected after the 
first dose and second dose, separately:  
PK parameters: Cmax, AUC0-t, AUC0-∞, Tmax, AUC_% Extrap_Obs, R2adjusted, 
z and t½ 
Employing the estimated concentration vs. time profiles of absolute neutrophil 
counts (ANC), the following PD parameters will be calculated based on baseline 
non-adjusted and baseline-adjusted data for samples collected after the first and 
second doses, separately:  
For ANC (Baseline Non-Adjusted): 
Emax and AUEC0-t  
For ANC (Baseline-Adjusted): 
Emax, AUEC0-t, Tmax, z and t½ 
The pre-dose levels will be used for the baseline adjustment of the post-dose 
levels of ANC.  
Baseline adjustment will be done for both the dosing-related values separately, 
by subtracting the baseline value (i.e. pre-dose value) from all the pre and post-
dose values. If any negative concentrations result will be obtained after 
adjustment, it would be set to zero. 
1.22 Ethical Issues 
: The study will commence only after a written approval is obtained from the 
Independent\Institutional Ethics Committee. 
The study will be conducted as per Schedule Y (with subsequent amendments) 
of CDSCO (Central Drugs Standard Control Organization), Ministry of health 
and family welfare, Government of India; Ethical guidelines for biomedical 
research on human participants, Indian Council of Medical Research (2017); 
ICH (The International Council for Harmonization of Technical Requirements 
for Pharmaceuticals for Human Use) E6 (R2) Guideline for Good Clinical 
Practice, (2016); Good Clinical Laboratory practices (GCLP); Declaration of 
Helsinki (Brazil, October 2013).  

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 19 of 50 
 
 
4.0 
MEDICAL EXPERT 
4.1 
Sponsor’s Medical Expert: 
 
 
 
Name 
: 
Address 
 
 
 
: 
Tel. No. 
: 
Fax No. 
: 
4.2 
Sponsor’s Safety Expert: 
 
Name 
: 
Address 
 
 
 
: 
Tel. No. 
: 
Fax No. 
: 
 
5.0 
FACILITIES 
5.1 
Clinical facility, Pharmacodynamics, Biostatistics and programming, Clinical Data management, 
Quality Assurance and clinical safety laboratory Services: 
Address 
: 
 
Tel. No. : 
Fax No. : 
Note: In case of emergency or adverse event management, back-up contractual lab can be used for lab 
investigations, if required. Monitoring, pharmacokinetic analysis and immunogenicity may also be 
done at 
  

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 20 of 50 
 
 
6.0 
BACKGROUND INFORMATION 
6.1 
Investigational Medicinal Products  
6.1.1 Test Product-T 
INTP5 (INTP5 is an internal code assigned to Pegfilgrastim manufactured by Intas Pharmaceuticals 
Limited)  
Active content: Pegfilgrastim, Strength: 6 mg/0.6 ml  
Dose for administration: 6 mg/0.6 ml 
Marketing Authorization Holder: Intas Pharmaceuticals Ltd., India 
Pharmaceutical form: Pre-filled syringe  
Route of administration: Subcutaneous  
Storage: 2ºC - 8ºC 
6.1.2 Reference Product–R 
Neulasta® (Pegfilgrastim) (US Licensed Product) 
Active content: Pegfilgrastim, Strength: 6 mg/0.6 ml  
Dose for administration: 6 mg/0.6 ml 
Marketing Authorization Holder: Amgen Inc., Thousand Oaks, California, USA 
Pharmaceutical form: Pre-filled syringe  
Route of administration: Subcutaneous  
Storage: 2ºC - 8ºC 
6.2 
Investigational Medicinal Product Summary 1, 2 
6.2.1 General pharmacology 
Pegfilgrastim is the pegylated form of G-CSF that acts on hematopoietic cells by binding to a specific 
cell surface receptor, thereby stimulating proliferation, differentiation, commitment, and end cell 
functional activation. Human G-CSF is a glycoprotein, which regulates the production and release of 
neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of recombinant human G-
CSF (r-met HuG-CSF) with a single 20 kD polyethylene glycol (PEG) molecule. Pegfilgrastim is a 
sustained duration form of filgrastim due to decreased renal clearance. 
6.2.2 Absorption, Distribution, Metabolism, Excretion and Food Effects 
After a single subcutaneous dose of Pegfilgrastim, the peak serum concentration of Pegfilgrastim 
occurs at 16 to 120 hours after dosing and serum concentrations of Pegfilgrastim are maintained 
during the period of neutropenia after myelosuppressive chemotherapy. The elimination of 
Pegfilgrastim is non-linear with respect to dose; serum clearance of Pegfilgrastim decreases with 
increasing dose. Pegfilgrastim appears to be mainly eliminated by neutrophil-mediated clearance, 
which becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, the 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 21 of 50 
 
 
serum concentration of Pegfilgrastim declines rapidly at the onset of neutrophil recovery. Due to the 
neutrophil-mediated clearance mechanism, the pharmacokinetics of Pegfilgrastim is not expected to be 
affected by renal or hepatic impairment. The half-life of Pegfilgrastim ranges from 15 to 80 hours after 
subcutaneous injection. 
6.2.3 Adverse Effects 
Blood and lymphatic system disorders: Common: Thrombocytopenia, leukocytosis 
Uncommon: Sickle cell crisis, leukocytosis, splenomegaly, splenic rupture 
Immune system disorders: Uncommon: Hypersensitivity reactions (including skin rash, urticaria, 
angioedema, dyspnoea, flushing and hypotension), serious allergic reactions including anaphylaxis, 
splenomegaly and splenic rupture 
Metabolism and nutrition disorders: Uncommon: Elevations in uric acid 
Nervous system disorders: Very common: Headache 
Vascular disorders: Uncommon: Capillary leak syndrome 
Respiratory, thoracic and mediastinal disorders: Uncommon: Adult respiratory distress syndrome, 
pulmonary adverse reactions (interstitial pneumonia, pulmonary edema, pulmonary infiltrates and 
pulmonary fibrosis) 
Gastrointestinal disorders: Very common: Nausea 
Skin and subcutaneous tissue disorders: Uncommon: Sweet's syndrome (acute febrile dermatosis), 
cutaneous vasculitis 
Musculoskeletal and connective tissue disorders: Very common: Bone pain  
Common: Musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, neck pain) 
General disorders and administrative site conditions: Common: Injection site pain, non-cardiac 
chest pain 
Uncommon: Injection site reactions 
Investigations: Uncommon: Elevations in lactate dehydrogenase and alkaline phosphatase, transient 
elevations in LFT's for ALT or AST.  
Renal and urinary disorders: Uncommon: Glomerulonephritis 
6.2.4 Indications 
Pegfilgrastim is approved by FDA for the following indications: 
(1) 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 
(2) To increase survival in patients acutely exposed to myelosuppressive doses of radiation 
(Hematopoietic Subsyndrome of Acute Radiation Syndrome). 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 22 of 50 
 
 
6.2.5 Contraindications 
Patients with a known hypersensitivity to E coli-derived proteins, Pegfilgrastim, filgrastim or any 
other component of the product. 
6.2.6 Dosage 
Recommended dose: One 6 mg dose (a single prefilled syringe) of Pegfilgrastim is recommended for 
each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy. 
Proposed dose for the study: Two doses of Pegfilgrastim 6 mg/0.6 ml [either of Test product or 
Reference product] will be administered subcutaneously to the outer area of the upper right arm to 
each subject at an interval of 3 weeks (21 days) between each dose. 
The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with 
latex allergies should not be administered this product. 
The recommended dosage of Pegfilgrastim is a single subcutaneous injection of 6 mg administered 
once per chemotherapy cycle. 
6.3 
Risks and Benefits 
Participation in this study yields no direct benefit to the subjects. The risks as described above are 
reduced considering the fact that only two doses are to be administered at an interval of not less than 3 
weeks (21 days) between each dose. However, study-related health assessments are provided at no 
cost. 
6.4 
Rationale  
The objective of this study is to assess and compare the immunogenicity profile of INTP5 of Intas 
Pharmaceuticals Ltd., India and Neulasta® of Amgen Inc, USA after multiple dose administration of 
Pegfilgrastim in healthy, adult, human subjects.  
Through this study, we will prospectively collect the data on healthy subjects that are randomly 
assigned to receive either INTP5 or Neulasta® for the immunogenicity profiling. No additional tests 
apart from those already specified in this protocol, will be performed. The study will, therefore, not 
place any additional risk/burden on the subjects.  
Choice of the Pegfilgrastim dose:  
Each pre-filled syringe contains 6 mg of Pegfilgrastim in 0.6 ml solution for injection. The protein 
concentration is 10 mg/ml. One 6 mg dose (a single pre-filled syringe) of Pegfilgrastim is 
recommended for each chemotherapy cycle, administered as a subcutaneous injection approximately 
24 hours following cytotoxic chemotherapy.    
In this study, 6 mg dose will be evaluated to determine safety. 
Choice of the injection site:  
Outer area of the upper arms, abdomen, except for the two-inch area around the navel, front of the 
middle thighs and upper outer areas of the buttocks are easy accessible areas for subcutaneous 
injection. According to the Neulasta prescribing information, above mentioned site can be used for 
injection. With the aim to standardize the injection procedure through the clinical study, the area 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 23 of 50 
 
 
around the outer area of the right upper arm will be used for all subjects for the Pegfilgrastim 
injection. 
7.0 
STUDY OBJECTIVES 
7.1 
Primary objectives 
• To assess and compare multiple-dose immunogenicity of INTP5 and Neulasta® in healthy, adult, 
human subjects. 
7.2 
Secondary objectives 
• To assess and compare the safety and tolerability of INTP5 and Neulasta® in healthy, adult, human 
subjects. 
• If any subject develops immunogenicity, impact of immunogenicity on PK/PD would be evaluated 
for that subject. 
8.0 
STUDY DESIGN 
8.1 
Design 
An assessor-blind, balanced, parallel, randomized, two-treatment, comparative immunogenicity study 
of multiple doses of INTP5 of Intas Pharmaceuticals Limited, India against Neulasta® of Amgen Inc., 
USA administered subcutaneously in healthy, adult, human subjects under fed condition. 
8.2 
Numbers of subjects 
As per the data from prescribing information, 6% patients develop antibodies to Pegfilgrastim. Hence, 
we hypothesize that 94% patients will not develop antibodies, and based on this assumption, the 
sample size has been calculated. For a comparison of two independent binomial proportions using 
Pearson's Chi-square statistic with a Chi-square approximation with a two-sided significance level of 
5%, 89 completers per group achieves a power of at least 80% when the proportions are 94% for both 
test and reference and the null proportion difference is assumed as 10%.   
Considering dropouts/withdrawals, approximately 100 subjects per treatment group (approximately 
200 subjects for two treatment groups)* will be required.  
Subsequent dropouts if any after first dosing will not be replaced. 
*Study will be conducted in multiple groups. 
Note: Two extra subjects if available may be enrolled on the day of check-in for first dose in each 
group to compensate for any dropout prior to first dosing of each group. If there are no dropouts, these 
two subjects will be checked out without being dosed after completion of first dosing for each group. 
8.3 
Randomization 
 
The allocation to test (T) or reference (R) product for each subject during the study will be 
determined according to a balanced randomization schedule. The randomization schedule will be 
generated using SAS® Version 9.3 or higher (SAS Institute Inc., USA) by the biostatistician.  
Equal allocation of subjects in each treatment arm (i.e. ‘T’ or ‘R’) will be ensured. 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 24 of 50 
 
 
The personnel involved in dispensing of study drug and verification of dispensed study drugs will be 
accountable for ensuring compliance to the randomization schedule.  
This is an assessor-blind study so coded treatment blinding is not required.  
8.4 
Blinding 
The study staff taking care of subject’s safety and the laboratory personnel doing the sample analysis 
of pharmacokinetic, pharmacodynamic and immunogenicity data will be blinded.  
A list of blinded and un-blinded team members of the trial will be prepared and documented. 
8.5 
Housing 
Subjects will be housed in the clinical facility at least 11 hours before administration of the dose and 
will continue to remain in the clinical facility for at least 72 hours after each administration of 
investigational medicinal product.  
The subjects will have to stay in the facility for 4 consecutive nights in each dose. 
The subjects will have to report to the facility at and after 96 hours post dose for ambulatory blood 
sample collection in each dose. 
Subjects will also have to report to the clinical facility for laboratory estimation (as per details 
mentioned in Section 13.0) along with complete clinical examination within 3 working days prior to 
receiving the second dose. 
In case of adverse event, subjects may be housed in the clinical facility beyond 72 hours based on the 
principal investigator's discretion and necessary action will be taken till the event subsides. 
8.6 
Duration of Fasting and Distribution of Meals 
All subjects will be required to fast overnight for at least 10 hours prior to serving of standardized 
vegetarian breakfast and 4 hours post dose for each dose; drug administration will be at 1 hour (±10 
minutes) after starting of the meal.  
Standardized meal will be served to the subjects at appropriate times during their stay in the clinical 
facility. The contents of the meals served during each dose at various time points will be identical. The 
subjects will receive lunch at least 4 hours after dosing and further meals will be served at appropriate 
intervals from then on, until check-out. Information on the amount of meal consumed and the time 
taken for consuming the meal will be recorded in the source data forms.  The actual time of meal 
distributions will also be recorded. If meals and blood sample collection schedules coincide, samples 
will be collected at the scheduled time only.    
Subjects will refrain from drinking water from 1 hour before till 1 hour after each dosing. Prior to and 
thereafter, water shall be consumed as required. 
Non-compliance to above fasting and water restriction will be recorded as protocol deviation. 
Note: In case any subject has any adverse event and requires any change in diet, it will be done after 
consultation with the Principal Investigator. It will not be considered as protocol deviation. This will 
however be documented. 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 25 of 50 
 
 
8.7 
Restrictions 
8.7.1 Medications 
 
Paracetamol or other NSAIDS can be given in case of bone pain or pain in extremities which is the 
most common side effect of Pegfilgrastim. Dose administered will be documented. No other 
prescribed medicines other than paracetamol or NSAIDs for pain and the investigational medicinal 
product will be allowed within 1 month prior to first dosing until the last sample collection of trial for 
each group. Also, no over-the-counter (OTC) medicines will be allowed during the study until the last 
sample collection of trial, except vitamins, minerals and nutritional supplements that may be taken at 
the discretion of the Investigator. If drug therapy other than that specified in the protocol is required 
prior to or during the study including wash-out period (i.e. dosing interval), decisions shall be taken by 
the Principal Investigator to continue or discontinue the subject based on the following: 
a)   The pharmacology, immunogenicity impact, pharmacodynamics and pharmacokinetics of the non-
study medication. 
b) The 
likelihood 
of 
a 
drug–drug 
interaction, 
thereby 
affecting 
the 
immunogenicity, 
pharmacodynamic and pharmacokinetic comparison of Investigational medicinal products.  
c) The time and duration of administration of the non-study medicine. 
All such instances will be recorded and reported in the final report. 
Note: Any concomitant medication administered during the course of the trial will be documented 
appropriately in the source data forms. 
8.7.2 Diet 
All subjects will be instructed to abstain from any xanthine-containing food or beverages (like tea, 
coffee, chocolates or cola drinks), tobacco, tobacco-containing products (like pan, pan masala, 
gutkha) and smoking (beedi, cigarette) for 24 hours prior to each dose administration and throughout 
their stay in the clinical facility for each dose. 
Subject will be instructed to abstain from grapefruit, grapefruit products, recreational drugs, alcohol 
and alcoholic products from 72 hours prior to first IMP administration until the end of the study. 
Subjects should be instructed that they should not consume, an unusual diet, for whatever reason (e.g. 
low-sodium), for 4 weeks prior to receiving the first dose of study medicine till the completion of 
study. 
8.7.3 Postural Restrictions 
For Each dose: 
The study medicine will be administered to subjects while in sitting posture. 
Subjects will be in sitting or ambulatory posture for the first 4 hours post dose unless medically 
necessary due to adverse event or procedurally required or natural exigency; in such cases it would not 
be considered as protocol deviation. In case of adverse event, appropriate position will be given to the 
subjects. 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 26 of 50 
 
 
Thereafter, the subjects will be allowed to engage only in normal activities while avoiding any 
strenuous physical activity. 
8.8 
Dosing Procedures and Compliance Assessment  
8.8.1 Dosing 
Each dose administration as described below will be done under the supervision of trained study 
personnel.  
After an overnight fasting of at least 10 hours, subject will be served standardized vegetarian breakfast 
which they are required to consume within 30 minutes. Each subject will receive the dose of 
Pegfilgrastim 6 mg/0.6 ml [either test product or reference product] subcutaneously in the outer area of 
the right upper arm at 1 hour (±10 minutes) after serving standardized vegetarian breakfast in sitting 
position.  
The drug delivery device should be stored and should be destroyed only after written permission from 
the sponsor. 
 
Details related to the method of drug administration is as per the procedure defined in a 
separate drug administration manual. 
 
Standardized vegetarian breakfast will be provided at 1 hour (±10 minutes) prior to each dose. 
 
8.8.1.1 Test Product-T 
Single dose of INTP5 of Intas Pharmaceuticals Ltd., India will be administered subcutaneously in the 
outer area of the right upper arm to the subjects at a dose of 6 mg/0.6 ml in sitting posture at ambient 
temperature by the trained study personnel.   
8.8.1.2 Reference Product-R 
Single dose of Neulasta® of Amgen Inc; USA will be administered subcutaneously in the outer area of 
the right upper arm to the subjects at a dose of 6 mg/0.6 ml in sitting posture at ambient temperature 
by the trained study personnel.  
8.8.2 Assessment of compliance for dosing 
Compliance for dosing will be assessed by supervision of the entire dosing procedure by the trained 
study personnel. 
8.9 
Blood Sampling for Pharmacokinetic/ Pharmacodynamics/ Immunogenicity Analysis 
8.9.1 Procedure of Blood Sampling and Collection 
Blood samples will be collected through an indwelling intravenous cannula (Venflon) placed in the 
forearm vein of the subjects. If required, it may also be collected through a fresh vein puncture.  
Pain and redness may occur at the injection site. If there is a lump, swelling or bruising at the injection 
site that does not go away, subjects may consult the investigator. 
Pre-dose sample will be collected within 60 minutes before the scheduled time. Post-dose in-house 
blood samples will be collected within ± 2 minutes, and ambulatory blood samples will be collected 
within ± 1 hours from scheduled time. Samples for pharmacodynamic and pharmacokinetic at and 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 27 of 50 
 
 
after 96 hours after each dose will be collected on an ambulatory basis. The actual time of collection 
of each blood sample will be recorded immediately after blood collection.  
The blood samples will be kept at room temperature during sample collection activity. Post-dose 
samples not collected within this time frame from the scheduled time will be documented as sampling 
deviations.  
Intravenous indwelling cannula will be kept in situ as long as possible by injecting 0.5 mL of normal 
saline solution to maintain the cannula patent for collection of the all blood sample from pre-dose to 
post-dose samples up to 24 hours. In such cases, blood samples will be collected after discarding the 
first 0.5 mL of normal saline containing blood from the tubing. The blood samples will be collected 
using syringe or adaptor and transferred into appropriate different pre-labelled (mentioning Project 
number, Subject number, Sample ID No./Bar code ID no and sampling time point) serum separator 
vacutainer (for PK and immunogenicity evaluation) and/or K2EDTA sample collection tubes (for PD 
evaluation). 
Alternatively, if the cannula is blocked or there is difficulty in withdrawing blood through the cannula, 
blood samples may be withdrawn by a fresh vein puncture using a disposable sterile syringe and a 
needle at each time of collection. Cannula will be removed after collection of blood sample at 24 hrs 
after each dose. Samples after 24.000 hrs post dose will be collected through fresh vein puncture. The 
ambulatory samples, pre-check in sample for serum pregnancy test (for female subjects) in each dose 
and sample to be collected for laboratory estimation within 3 working days prior to receiving dose-2 
will be collected by a fresh vein puncture.  
 
 
Not exceeding 232 mL for male subjects and 236 mL for female subjects as follows: 
 
 
 
Subjects 
Male 
Female 
+ Blood volume for Pharmacokinetic evaluation (23 samples of 4 mL each). 
: 
92 mL 
92 mL 
+ Blood volume for Pharmacodynamic evaluation (23 samples of 2 mL each). : 
46 mL 
46 mL 
+ Blood volume for the Immunogenicity assessment (8 samples of 8 mL 
each). 
: 
64 mL 
64 mL 
+ Discarded normal saline containing blood (8 × 0.5 mL) 
: 
4 mL 
4 mL 
+ Blood withdrawn for screening prior to study. 
: 
10 mL 
10 mL 
+ Blood withdrawn for post-study safety assessment (including serum 
pregnancy test (in case of female subjects) 
: 
8 mL 
8 mL 
+ Estimation of hematology and biochemistry (within three working days 
prior to receiving dose-2) 
: 
8 mL 
8 mL 
+ Serum pregnancy test prior to check in each dose (for female subjects). 
: 
-- 
4 mL 
Total Blood Loss for each Subject  
: 232 mL 
236 mL 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 28 of 50 
 
 
8.9.2 Sampling Schedule 
The venous blood samples will be withdrawn at the following times, assuming that the dosing of a 
subject takes place at 0900.  
For PK/PD evaluation: 
 
Days 
Time points (hour) 
Proposed clock time 
Blood volume 
PK/PD evaluation 
1 
Pre-dose (0.000) 
Within 60 minutes 
prior to dosing 
06 ml 
(04 ml for PK and 
02 ml for PD 
evaluation) 
 
8.000 
1700 
2 
16.000 
0100 
24.000 
0900 
3 
48.000 
0900 
4 
72.000 
0900 
5 
96.000* 
0900 
6 
120.000* 
0900 
7 
144.000* 
0900 
11 
240.000* 
0900 
15 
336.000* 
0900 
22 
504.000* 
0900 
For Immunogenicity evaluation: 
Days 
Time points (hour) 
Proposed clock time 
Blood volume 
Immunogenicity evaluation 
Within 28 days 
before dosing 
Screening 
NA 
8 ml 
1 
Pre-dose (0.000) 
Within 60 minutes 
prior to dosing 
15 
336.000* 
0900 
22 
504.000 
0900 
36 
840.000* 
0900 
50 
1176.000* 
0900 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 29 of 50 
 
 
71 
1680.000* 
0900 
85 
2016.000* 
0900 
* Ambulatory samples 
Day 1: Day of dosing.  
Day 2-7, 11, 15, 22, 36, 50, 71, 85: Subsequent days after the day of dosing. 
8.10 
Sample Handling and processing 
 
Separate laboratory manual will be prepared for pharmacokinetic, Pharmacodynamic and 
Immunogenicity sample handling, separation process and analytical procedure. 
PK samples will be stored till immunogenicity evaluation is complete. PK analysis will be performed 
for only immunogenicity positive subjects. A validated assay will be used to analyze PK samples. 
8.11 
Clinical Safety Measures 
A physician will be available within the clinical facility whenever the subjects are housed (from 
check-in to checkout in each dose) and at the end of the study (after last ambulatory sample after dose-
2). A physician will be available on call during ambulatory sample after each dosing. A consultant 
physician will be always available on call during the study period.  
Clinical examination of the subjects [including recording of vital signs (i.e. sitting blood pressure, 
radial pulse rate, respiratory rate and oral body temperature)] will be done at screening, after check-in 
and before check-out of each dose, within 3 working days prior to dose-2 and at the end of the study 
(after last ambulatory sample after dose-2). The clinical examination before check-out in each dose 
may be started 120 minutes prior to the scheduled time of check-out of each subject.  
Subjects should meet the criteria for enrolment in the study. 
Subject will be instructed not to participate in other clinical trial or donate blood anywhere else during 
the study. 
Chest X-ray (P-A view; within the last 6 months) will be done at the time of screening. 
12-lead ECG recording will be performed at the time of screening, within 3 working days prior to 
receiving dose-2 and at the end of the study (after last ambulatory sample after dose-2). 
Abdominal ultrasonography will be done at the time of screening. 
Vital signs (Sitting blood pressure and radial pulse) will be measured at pre-dose (within 60 minutes 
prior to each dose) and at 2, 4, 10, 24, 30, 36, 48 and 60 hours after each dose.  
All post-dose vitals will be recorded within ± 40 minutes from the scheduled time.  
Subjects will be questioned for well being at the time of clinical examinations, during ambulatory 
samples and at the time of recording of vital signs for each dose. 
Injection site assessment will be performed after 30 minutes and at 2, 6 and 12 hours of injection after 
each dose. 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 30 of 50 
 
 
Injection site scoring 
(Scoring to be 
done 
separately 
for Pain, Erythema and 
Induration/Swelling): 
None 
0 No reaction 
Mild 
1 
Pain: 
Pain or tenderness causing no or minimal limitation of use of limb  
Erythema: 
2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area AND Symptoms 
causing no or minimal interference with usual social & functional activities  
Induration/Swelling: 
2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area AND Symptoms 
causing no or minimal interference with usual social & functional activities  
Moderate 
2 
Pain: 
Pain or tenderness causing greater than minimal limitation of use of limb  
Erythema: 
≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area OR Symptoms 
causing greater than minimal interference with usual social & functional 
activities  
Induration/Swelling: 
≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area OR Symptoms 
causing greater than minimal interference with usual social & functional 
activities  
Severe 
3 
Pain: 
Pain or tenderness causing inability to perform usual social & functional 
activities  
Erythema: 
≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration OR Secondary 
infection OR Phlebitis OR Sterile abscess OR Drainage OR Symptoms 
causing inability to perform usual social & functional activities  
Induration/Swelling: 
≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration OR Secondary 
infection OR Phlebitis OR Sterile abscess OR Drainage OR Symptoms 
causing inability to perform usual social & functional activities  
Potentially 
life-threatening  
 
4 
Pain: 
Pain or tenderness causing inability to perform basic self-care function OR 
Hospitalization indicated  

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 31 of 50 
 
 
Erythema: 
Potentially life-threatening consequences (e.g., abscess, exfoliative dermatitis, 
necrosis involving dermis or deeper tissue)  
Induration/Swelling: 
Potentially life-threatening consequences (e.g., abscess, exfoliative dermatitis, 
necrosis involving dermis or deeper tissue)  
If there is a lump, swelling or bruising at the injection site that does not go away, subjects may consult 
the investigator. 
Paracetamol or other NSAIDS can be given in case of bone pain or pain in extremities, which is the 
most common side effect of Pegfilgrastim. 
The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); subjects with 
latex allergies should not be administered this product. 
Laboratory assessments will be carried out at the time of screening and within 3 working days to 
receive dose 2.  
Serum pregnancy test for the female subjects will be done at the time of screening, prior to check-in of 
each dose and at the end of the study (after last ambulatory sample after dose-2). 
Breath test for alcohol consumption and urine scan for drugs of abuse will be carried out at Screening 
and prior to check-in of each dose.  
Laboratory tests for hematology (except Sickling Test), Biochemistry (except sodium, potassium, 
calcium, and chloride), urine analysis and Serum pregnancy test (for females) will be done at the end 
of the study (after last ambulatory sample after dose-2). 
8.12 
Termination of the Study 
(for safety reasons) and the sponsor reserve the right to 
discontinue the study at any time. The sponsor and the IEC will be immediately informed in case the 
study is terminated by 
Reasons for this termination will be provided to the subjects. The 
study may be terminated by the IEC (Independent\Institutional Ethics Committee) if there are major 
violations of ethical considerations or due to any serious adverse event.  
9.0 
HANDLING, STORAGE, DISPENSING AND ACCOUNTABILITY PROCEDURES FOR 
INVESTIGATIONAL MEDICINAL PRODUCTS 
9.1 
Investigational Medicinal Product Receipt and Storage 
The Sponsor shall supply adequate units of investigational medicinal product for dose administration 
and retention purpose. The received investigational medicinal products will be verified for the sealed 
condition of packs and adequacy of the label, including product name, strength, number of dosage 
units, lot number or batch number, expiry date/retest date and storage condition mentioned clearly. 
The Pharmacy custodian or his/her designated study personnel will receive the investigational 
medicinal products with certificates of analysis (COA). The investigational medicinal products will be 
transferred to the pharmacy, after labeling it for project number (as applicable), product type, quantity 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 32 of 50 
 
 
and date of receipt, batch number or lot number, manufacturing date, expiry date/retest date, for 
clinical study use only and storage conditions. 
A pre-defined quantity of drug will be randomly identified and stored as retention samples. 
Note: Information related to manufactured by/for, marketed/distributed by, marketing authorization 
holder etc. are based on details provided by the sponsor and/or available literature at the time of 
protocol development. Exact details will be captured in the investigational medicinal product (IMP) 
receipt and accountability form by the pharmacy while receiving the IMPs. The same details can be 
used in the clinical study report for accuracy and compliance purpose. 
9.2 
Dispensing  
The Pharmacy Custodian and Project Coordinator or his/her designated study personnel will dispense 
the required units of investigational medicinal products before dosing. Six additional units of IMPs 
(three test and three reference product) will be dispensed in addition to the required number and 
labeled accordingly. These will be used in any situation such as dropping the IMP etc., if unused they 
will be handled as described in Section 9.3 (Unused Investigational Medicinal Products). The 
remaining units of investigational medicinal products will be kept in their original containers as 
retention samples.   
Investigational medicinal product (test and reference products) will be transferred from pharmacy to 
the clinical facility prior to dose administration along with data logger as per in-house SOP. 
Dispensing will be performed in the clinical facility. 
• 
The strengths of the solution will be 6 mg/0.6 ml  
• 
Pegfilgrastim should be protected from light, so keep it in its carton until ready to use it.  
• 
Do not leave Pegfilgrastim in direct sunlight. 
Note: Pegfilgrastim should be stored in the refrigerator at 2°C to 8°C, but not in the freezer. 
The doses intended for administration to the subjects will be transferred to the drug-dispensing 
containers as per the randomization schedule, and properly labeled for the drug name with strength, 
dose, product type, project number, subject number, for clinical trial use only and 
Ahmedabad.  
The personnel involved in dispensing and verification of dispensed IMPs will be accountable for 
ensuring compliance to randomization schedule. The Pharmacy Custodian/designate will maintain 
complete accountability of the investigational medicinal products for the study. 
9.3 
Unused Investigational Medicinal Products 
Units of investigational medicinal products that have not been dispensed will be retained in their 
original containers. Any product that had been dispensed but not used (e.g. due to the subject being 
unwell or drop out from the trial etc.) will be labeled as ‘Not For Use’ and returned to the pharmacy 
and will be retained along with the other investigational medicinal products of its type. 
9.4 
Retention Samples  
 
Sufficient quantity of retention samples as communicated by the sponsor will be stored. Each reserved 
sample should be retained and stored under conditions consistent with the product labeling for a period 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 33 of 50 
 
 
of at least 5 years following the date on which the study is approved by USFDA or, if the study is not 
approved, at least 5 years following the date of completion of the study in which the investigational 
medicinal products were used. 
 
The sponsor will provide 
 with a supply of study drug and reference standard sufficient to 
complete the study and retain the appropriate number of dosage units as reserve samples. 
will 
randomly select the retention samples from the supply sent by the sponsor. 
10.0 
SELECTION & WITHDRAWAL CRITERIA 
All subjects will undergo physical and clinical screening procedure within 28 days prior to the first 
dose of IMP administration. The subjects will be selected based on the following inclusion and 
exclusion criteria.   
10.1 
Inclusion Criteria 
1. Normal, healthy adult human volunteers between 18 to 45 years of age (both inclusive) living in and 
around Ahmedabad city or western part of India. 
2. Having body weight ≥50 kg and body mass index (BMI) between 18.5 and 29.9 (both inclusive), 
calculated as weight in kg/height in meter2. 
3. Not having any significant disease in medical history or clinically significant abnormal findings during 
screening, abdominal ultrasonography, medical history, clinical examination, laboratory evaluations, 
12-lead ECG and X-ray chest (P/A view; within the last 6 months) recordings. 
4. Able to understand and comply with the study procedures, in the opinion of the investigator. 
5. Able to give voluntary written informed consent for participation in the trial. 
6. In case of female subjects: 
a. Surgically sterilized at least 6 months prior to study participation;  
Or 
If a woman of child bearing potential is willing to use a suitable and effective double barrier 
contraceptive method or intra uterine device during the study. 
b. Serum pregnancy test (for female subjects) must be negative. 
10.2 
Exclusion Criteria 
1. Known hypersensitivity to the study drug or its constituents and/or hypersensitivity to E. coli-derived 
proteins, and/or previous exposure to the study drug. 
2. History or presence of any disease or condition which might compromise the haemopoietic, renal, 
hepatic, endocrine, pulmonary, central nervous, cardiovascular, immunological, dermatological, 
gastrointestinal or any other body system. 
3. Known case of hereditary fructose intolerance. 
4. Subjects with latex allergies will be excluded as the needle cover on the single-use prefilled syringe 
contains dry natural rubber (latex). 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 34 of 50 
 
 
5. Any clinically significant laboratory finding including ANC, platelet, RBC count, and hemoglobin 
level at the time of screening. 
6. Prior exposure to any peptide colony stimulating or growth factor, including erythropoietin, 
filgrastim or Pegfilgrastim; Prior exposure to any vaccines, immunoglobulin preparations or 
immunomodulators within the past 6 months prior to receiving first dose; evidence of E coli diarrhea 
or diseases within 3 months. 
7. Any history or presence of asthma (including aspirin-induced asthma) or nasal polyp or NSAIDs 
induced urticaria. 
8. Subjects with a history of pulmonary infiltrate or pneumonia in the last 6 months. 
9. History of any hematologic disease including sickle cell disorders. 
10. Ingestion or use of any prescribed medication at any time within 1 month prior to receiving first 
dose. 
11. Receipt of over-the-counter medicines which have not yet cleared from the body (5 half-lives must 
have passed for the medicine to be considered to have cleared from the body).  
12. A recent history of harmful use of alcohol, i.e. alcohol consumption of more than 14 standard drinks 
per week for men and more than 7 standard drinks per week for women (A standard drink is defined 
as 360 ml of beer or 150 ml of wine or 45 ml of 40% distilled spirits, such as rum, whisky, brandy 
etc.) or consumption of alcohol or alcoholic products within 72 hours prior to receiving study 
medicine. 
13. Smokers, who smoke 10 or more than 10 cigarettes/day or inability to abstain from smoking during 
the study. 
14. Use of any recreational drugs or history of drug addiction or testing positive in pre-study drug scans. 
15. Donation of blood (1 unit or 350 mL) or equivalent amount of blood substitute. 
16. Receipt of an investigational medicinal product or participation in a drug research study within a 
period of 90 days prior to the first dose of study medication. Elimination half-life of the study drug 
should be taken into consideration for inclusion of the subject in the study. 
17. Positive result for human immunodeficiency virus (HIV I &/or II) and/or hepatitis B and C tests. 
18. History or presence of cancer because of which anticipated life span is less than 5 years as per the 
investigator’s assessment. 
19. History or presence of psychiatric disorders. 
20. Presence of tattoo or scars or any type of skin lesions due to infection, burning, wound or 
inflammation at the proposed site of injection. 
21. An unusual diet, for whatever reason (e.g. low-sodium), for 4 weeks prior to receiving the study 
medicine. In any such case, subject selection will be at the discretion of the Principal Investigator. 
22. Consumption of grape fruit or grape fruit products within 72 hours prior to receiving study drug. 
23. A history of difficulty in donating blood.  

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 35 of 50 
 
 
24. Females, pregnant or lactating, or planning to become pregnant during the time the subject is on 
study or found positive in pregnancy test at screening. 
 
25. Any infections in the last 4 weeks before receiving study medication. 
10.3 
Withdrawal Criteria 
The investigator may withdraw a subject from the study for any of the following: 
a) The subject suffers from significant inter-current illness or undergoes surgery during the course of the 
study or the subject has any significant symptoms or signs during the course of the study. 
b) Adverse event: Subject reports symptoms, which are considered unacceptable by the subject and/or 
the Investigator and due to safety concern or the nature of adverse event subject is not fit to continue 
in the trial. 
c) Any subject found to have entered the study in violation of this protocol. This would include pre-study 
directions regarding alcohol and drug use, fasting/fed or if the subject is uncooperative during the 
study. The individual details of violation of the protocol will be discussed with the sponsor. The final 
decision will be taken based on the impact of the protocol violation on the primary endpoint and 
safety. The decision should be taken in blinded manner before the exposure to the data on the key 
endpoints. 
d) Any subject found to hide important medical history which in opinion of Principal Investigator may 
compromise his/her safety during participation in this study. 
e) Any subject found as cross-participated in other drug trial or trial screening. 
f) Any subject who requires the use of an unacceptable concomitant medication (prescription medication 
other than paracetamol or NSAIDS for pain and OTC medicine). The individual details of such 
concomitant medications will be discussed with the sponsor. The final decision will be taken based on 
the impact of the concomitant medications on the primary endpoint and safety. The decision should be 
taken in blinded manner before the exposure to the data on the key endpoints. 
g) If it is felt in Principal Investigator’s opinion that it is not in the subject’s best interest to continue. 
h) Any subject who wishes to withdraw his/her consent for whatever reason.  
i) Any other justifiable reason, which would be adequately documented. 
j)  Found positive in serum pregnancy test (for female subjects)  
All instances of subject withdrawal, including the date and reason for withdrawal, will be documented 
and handled as per the in-house procedure. Any untoward effect reported by the subjects who 
withdraw will be incorporated into the final study report. These subjects will be followed up for their 
safety as per in-house SOP.  
 
 
 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 36 of 50 
 
 
11.0 
EVALUATION PARAMETERS 
11.1 
Immunogenicity, Pharmacokinetic and Pharmacodynamic Analyses 
A detailed statistical analysis plan (SAP) will be prepared prior to database lock.  
Immunogenicity and safety analysis will be performed using SAS® Version 9.3 or higher (SAS 
Institute Inc., USA).  
Pharmacokinetic and pharmacodynamic analysis will be performed on the available concentration 
data/ANC count of all the subjects. 
11.2 
Immunogenicity Data Analysis  
Immunogenicity (anti-drug antibody; ADA) data will be presented for all subjects’ samples collected.  
Descriptive analysis will be provided for immunogenicity (ADA) data.  
Percentage incidence within + 10% of the expected ADA positivity incidence of Test (6% ADA in 
Test is anticipated from literature) would not be considered clinically significant. 
If any subject develops positive immunogenicity, impact of immunogenicity on PK and PD would be 
evaluated for that subject. Pooled PD data along with variability will be presented. PK and PD data of 
individual subjects having positive immunogenicity will be presented separately. 
11.3 
Pharmacokinetic parameters 
If decided (decision based on Immunogenicity results) to analyze PK data by analytical laboratory, 
the following pharmacokinetic parameters would be computed for Pegfilgrastim for the samples 
collected after the first dose and second dose, separately using non-compartmental model of 
Phoenix® WinNonlin® Version 6.4 or higher (Certara L.P.):  
 
PK Parameter:  
Cmax 
: Maximum measured serum concentration. 
AUC0-t 
: Area under the serum concentration versus time curve from time zero to 
the last measurable concentration as calculated by linear trapezoidal 
method. 
AUC0- 
: Area under the serum concentration versus time curve from time zero to 
infinity. Where AUC0- = AUC0-t + Ct/z, Ct is the last measurable 
concentration and z is the terminal rate constant. 
Tmax 
: Time to reach the maximum measured serum concentration. 
z 
: First order elimination rate constant associated with the terminal (log-
linear) portion of the curve. This is estimated via linear regression of 
time vs. log concentration. 
This parameter will be calculated by linear least squares regression 
analysis using at least last 3 or more non-zero serum concentration 
values. 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 37 of 50 
 
 
t1/2 
: The terminal half-life will be calculated as 0.693/z. 
AUC_% Extrap_obs : The residual area in percentage will be determined by the formula, 
[(AUC0- -AUC0-t)/AUC0-] × 100. 
For all the above computations, actual time points of the sample collection will be used. 
All concentration values below the lower limit of quantification will be set to zero for the 
pharmacokinetic and statistical calculations. 
No value of λz, AUC0-, AUC_% Extrap_obs, R2adjusted and t1/2 will be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile.  
11.4 
Pharmacodynamic parameters 
Using the measured ANC, the following variables will be calculated on baseline non-adjusted and 
baseline-adjusted data for the samples collected after the first dose and second dose, separately using 
non-compartmental model of Phoenix® WinNonlin® Version 6.4 or higher (Certara L.P.):  
For ANC [Baseline Non-Adjusted]: 
Emax, and AUEC0-t  
For ANC [Baseline-Adjusted]: 
Emax, AUEC0-t, Tmax,  z and t½ 
 
Emax 
: Maximum measured ANC. 
AUEC0-t 
: Area under the ANC versus time curve from time zero to the last 
measurable concentration as calculated by linear trapezoidal method. 
Tmax 
: Time to reach the maximum measured ANC. 
z 
: First order rate constant associated with the terminal (log-linear) portion 
of the curve. This is estimated via linear regression of time vs. log 
concentration. 
This parameter will be calculated by linear least squares regression 
analysis using at least last three or more non-zero values. 
t1/2 
: The terminal half-life will be calculated as 0.693/z. 
For all the above computations, actual time points of the sample collection will be used. 
All concentration values below the lower limit of quantification will be set to zero for the 
pharmacodynamic and statistical calculations. 
No value of λz or t1/2 will be reported for cases that do not exhibit a terminal log-linear phase in the 
concentration versus time profile. 
The pre-dose levels will be used for the baseline adjustment of the post-dose levels for ANC.  
Baseline adjustment will be done by subtracting the baseline value (i.e. pre-dose value) from all the 
pre and post-dose values. If any negative concentrations result will be obtained after adjustment, it 
would be set to zero. 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 38 of 50 
 
 
11.5 
Assessment of Eligibility/Safety 
11.5.1 Safety data 
All subjects who have received at least one dose of the study medicine will be included in the safety 
evaluation. Results obtained when evaluating safety and tolerability [adverse events, ECG, vital signs, 
serum pregnancy test (for female subjects) and clinical laboratory tests that are out of the range] will 
be listed and evaluated descriptively.  
11.5.2 Eligibility Assessments 
 
The following assessments will be done before the entry of the subjects into the study: 
1. Demographic Data. 
 
Age, height, weight and BMI. 
2. Vital Signs. 
 
Blood pressure, radial pulse, respiratory rate, oral body temperature. 
3. Medical History and Current Status. 
 
The subject's status as a healthy volunteer will be confirmed. 
4. Medication and Therapy History 
 
Current medication and use of any concomitant therapy or ingestion of any prescription drugs (i.e 
medication other than paracetamol or NSAIDS for pain) for previous 1 month of dosing. Also no 
over-the-counter (OTC) medicines will be allowed during the study until the last sample 
collection of trial, except vitamins, minerals and nutritional supplements that may be taken at the 
discretion of the Investigator. 
5. Clinical Examination. 
 
A standard clinical examination will be conducted, including 12-lead ECG and chest X-ray (P-A 
view if not done within the last 6 months), abdominal ultrasonography and clinical significant 
finding will be recorded if any. 
6. Clinical Laboratory Screening. 
 
Blood and urine will be tested for standard parameters (Section 13: List of laboratory 
Parameters). 
11.5.3 Study Assessments 
The following will be recorded during the conduct of the study: 
1. Clinical examination and recording of vital signs at regular intervals; 
2. Concomitant therapy changes; 
3. Adverse event monitoring and reporting. 
 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 39 of 50 
 
 
Definitions: 
Adverse Event: 
Any untoward medical occurrence in a clinical investigation subject, administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An adverse 
event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product whether or not related to the medicinal (investigational) product.   
Serious Adverse Event (SAE): 
Any untoward medical occurrence that at any dose: 
a) results in death, 
b) is life-threatening, 
c) requires inpatient hospitalization or prolongation of existing hospitalization  
d) Results in persistent or significant disability/incapacity, 
e) Results in a congenital anomaly/birth defect. or 
f) It is a medically important event or reaction. This would include important medical events that 
may not be immediately life threatening or results in death or hospitalization but may jeopardize 
the patient/subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. 
(Note: The term “life threatening” in the definition of “serious adverse event” refers to an event 
in which the patient was at risk of death at the time of the event; it does not refer to an event, 
which hypothetically might have caused death if it was more severe). 
Handling of Adverse Events 
Subjects will be monitored throughout the study period for adverse events. Subjects will be instructed 
to bring to the notice of the nurse or the doctor or study personnel (e.g. Custodian), any adverse event 
that may occur during their stay at the clinical facility. 
Subjects will also be specifically asked about any adverse events throughout the study period during 
the recording of vital signs. A physician will be available 24 hours during the time of subjects 
stay/housing at the clinical facility. All adverse events will be treated by the attending physician at the 
clinical facility, or in a nearby reputed hospital. All adverse events will be followed up wherever 
possible until resolution or until the investigator believes there will be no further change. This may 
involve additional visits.  
All adverse events, including both observed or voluntarily reported problems; complaints, signs or 
symptoms occurring after the first dose administration shall be recorded on the "Adverse 
Event/Medical Event Record Form" irrespective of its association with the ongoing study medication. 
Prior to first dose administration in each subject, the event will be considered as a medical event and 
the aforementioned form will be completed by encircling “Medical Event” in the title. 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 40 of 50 
 
 
Each adverse event shall be evaluated for duration, severity, seriousness and unexpectedness, action 
taken, date and time of resolution and association with the study treatment. The study may be 
suspended or terminated depending on the seriousness of the adverse events. 
The IEC, regulatory bodies and the Sponsor shall be informed regarding the same as per local 
regulatory requirements. 
Handling of Serious Adverse Event:   
In case of Serious Adverse Events, the Sponsor or his representative, licensing authority and IEC will 
be informed by any available mode of communication within 24 hours of their occurrence or as soon 
as the initial treatment is provided. In case, the Investigator fails to report any serious adverse event 
within the stipulated period, he/she shall have to furnish the reason for the delay to the satisfaction of 
the Licensing Authority along with the report of the serious adverse event. The report of serious 
adverse event, after due analysis shall be forwarded by principal investigator to sponsor, Licensing 
Authority, as referred to in clause (b) of rule 21, the Chairman of the Ethics Committee (and the Head 
of the institution where the trial has been conducted, if applicable) within 14 days of the occurrence of 
the serious adverse event. 
Handling of pregnancy: 
Handling and reporting of pregnancy during the clinical study will be done as per in-house SOP. 
11.5.3.1 Determining the severity of the adverse event: 
Determine severity of the adverse event based on the following: 
a) Mild: The adverse event does not limit usual activities; the subject may experience slight 
discomfort. 
b) Moderate: The adverse event results in some limitation of usual activities; the subject may 
experience significant discomfort.  
c) Severe: The adverse event results in an inability to carry out usual activities; the subject may 
experience intolerable discomfort or pain. 
d) Life-threatening consequences 
e) Death related to AE 
11.5.3.2 Causality Assessment of the Adverse Event to the Investigational Medicinal Product. 
Causality assessment of the adverse event will be done based in the following criteria: 
Causality term 
Assessment criteria 
Certain 
• Event or laboratory test abnormality, with plausible time relationship to 
drug intake 
• Cannot be explained by disease or other drugs 
• Response to withdrawal plausible (pharmacologically, pathologically) 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 41 of 50 
 
 
• Event definitive pharmacologically or phenomenologically (i.e. an 
objective and specific medical disorder or a recognized pharmacological 
phenomenon) 
• Rechallenge satisfactory, if necessary 
Probable/Likely 
• Event or laboratory test abnormality, with reasonable time relationship to 
drug intake 
• Unlikely to be attributed to disease or other drugs 
• Response to withdrawal clinically reasonable 
• Rechallenge not required 
Possible 
• Event or laboratory test abnormality, with reasonable time relationship to 
drug intake 
• Could also be explained by disease or other drugs 
• Information on drug withdrawal may be lacking or unclear 
Unlikely 
• Event or laboratory test abnormality, with a time to drug intake that makes 
a relationship improbable (but not impossible) 
• Disease or other drugs provide plausible explanations 
Conditional/ 
Unclassified 
• Event or laboratory test abnormality 
• More data for proper assessment needed, or 
• Additional data under examination 
Unassessable/ 
Unclassifiable 
• Report suggesting an adverse reaction 
• Cannot be judged because information is insufficient or contradictory 
• Data cannot be supplemented or verified 
Unrelated 
• The adverse event is clearly NOT related to the investigational medicinal 
product 
• A clinical event with an incompatible time relationship and which could be 
explained by underlying disease or other drugs or chemicals 
11.5.4 Post Study Assessments 
A clinical examination including recording of vital signs, oral body temperature of the subjects will be 
conducted at the end of the study (after last ambulatory sample after dose-2). This examination also 
includes the assessment of blood samples for haematology, biochemistry tests and serum pregnancy 
test for females (Section 13 List of Laboratory Parameters). 
Post study laboratory parameters that are out of specified ranges would be individually assessed and 
repeated if deemed necessary by the medically qualified reviewer. If any out of range parameter is 
found clinically significant, an adverse event will be recorded for the same. The subject would be 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 42 of 50 
 
 
treated and/or followed up as advised by the physician in charge until resolution/stabilization of the 
adverse event. 
11.5.5 Evaluation Criteria for Laboratory Parameter 
Laboratory parameters obtained during the process of screening will be evaluated as follows:  
a) Out of range values of hematology, Sickling Test, biochemistry and urine parameters will be 
individually evaluated and/or repeated for their clinical significance. A subject will be 
enrolled only if the medically qualified reviewer deems the values clinically insignificant or 
acceptable. 
b) All safety immunology parameters are required to be negative. 
c) Serum pregnancy test for female subjects must be negative. 
Note: In case any extra tests are analyzed, it will not have any impact on the study if the parameters 
and the values are clinically insignificant. 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 43 of 50 
 
 
12.0 
ASSESSMENT SCHEDULE: 
Phase 
Screening* 
Dose-1  
Dose-2 
Procedure 
Day 
 
-1 
1 2 3 4 
5-7, 
11, 
15 
21 22 23 24 25 26-
28  
32, 
36 
43, 
50 71 85 
Attendance 
 
X 
  
 
 
 
X 
 
 
 
 
 
 
 
 
 
Urine Drug Scan 
X 
X 
  
 
 
 
X 
 
 
 
 
 
 
 
 
 
Breath test for alcohol 
consumption 
X 
X 
  
 
 
 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
X√ 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test for 
females 
X 
X 
  
 
 
 
X 
 
 
 
 
 
 
 
 
X# 
Compliance Assessment 
 
X 
  
 
 
X X 
 
 
 
 
X 
X 
X 
X 
X 
Baggage and Body search 
 
X 
  
 
 
 
X 
 
 
 
 
 
 
 
 
 
Sickling test 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Lab Investigation 
(Hematology/ 
Immunology/Biochemistry/ 
Urine analysis) + 
X 
 
  
 
 
 
X@  
 
 
 
 
 
 
 
 
Clinical Lab Investigation 
at post study 
(Hematology/Biochemistry/ 
urine analysis) + 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
X# 
Ultra sound scan of 
abdomen 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
  
 
 
 
X 
 
 
 
 
 
 
 
 
X# 
Chest X-ray$ 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Examination  
X 
X 
  
 X 
 
X 
 
 
 
X 
 
 
 
 
X# 
Local injection site 
examination** 
 
 
X  
 
 
 
 X 
 
 
 
 
 
 
 
 
Pre-dose vital sign 
 
 
X  
 
 
 
 X 
 
 
 
 
 
 
 
 
Dosing  
 
 
X  
 
 
 
 X 
 
 
 
 
 
 
 
 
Blood sampling 
 
 
X X X X X  
X X X 
X 
X 
X 
X 
X 
X 
Vital signs^ 
 
 
X X X  
 
 X X X 
 
 
 
 
 
 
Well being 
 
X 
X X X X X X X X X 
X 
X 
X 
X 
X 
X 
Standardized vegetarian 
breakfast 
 
 
X  
 
 
 
 X 
 
 
 
 
 
 
 
 
* Within 28 days prior to first dosing  
√Consent for screening      
Study specific consent 
^Post-dose vitals as mentioned in protocol 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 44 of 50 
 
 
+ Clinical lab investigation will be performed as per Section 13 (list of laboratory parameters) 
Meals will be provided to the subjects as mentioned in the protocol. 
#End study (after last ambulatory sample after dose-2) 
@ Estimation of hematology (except Sickling Test), biochemistry and urine analysis will be done within 3 
working days prior to receiving dose-2. 
$ Chest X-ray is valid up to 6 months. 
**At 30 minutes, and at 2, 6 and 12 hrs post dose 
Notes: 
1:-Check-in days (Day -1 (for dose 1), Day 21 (for dose 2))  
2:-Dosing Days (Day 1 (1st Dose), Day 22 (2nd Dose)) 
3:- Housing days (Day -1 to Day 3 (for dose 1), Day 21 to Day 24 (for dose 2)) 
 
4:-. Checkout day (Day 4 (for dose 1), Day 25 (for dose 2)  
5:-. Ambulatory sample (days 5-7, 11, 15, 26-28, 29, 43, 57, 85)   
6:-. End study (Day 85, after last ambulatory sample after dose-2) 
7:-. Sampling time-points 
Pharmacokinetic evaluation: 1st and 2nd dose: Venous blood samples (04 ml each) will be withdrawn at pre-
dose (0.000) and at 8.000, 16.000, 24.000 (Day 2), 48.000 (Day 3), 72.000 (Day 4), 96.000 (Day 5), 120.000 
(Day 6), 144.000 (Day 7), 240.000 (Day 11), 336.000 (Day 15) and 504.000 (Day 22) hours following 1st and 
2nd dose administration (Post-dose sample of 1st dose at 504.000 (Day 22) hours will be considered as pre-
dose sample of 2nd dose).  
For Pharmacodynamic evaluation: 1st and 2nd dose: Venous blood samples (02 ml each) will be withdrawn 
at pre-dose (0.000) and at 8.000, 16.000, 24.000 (Day 2), 48.000 (Day 3), 72.000 (Day 4), 96.000 (Day 5), 
120.000 (Day 6), 144.000 (Day 7), 240.000 (Day 11), 336.000 (Day 15) and 504.000 (Day 22) following 1st 
and 2nd dose administration (Post-dose sample of 1st dose at 504.000 (Day 22) hours will be considered as 
pre-dose sample of 2nd dose).  
For Immunogenicity evaluation: Venous blood samples (08 ml each) will be withdrawn at screening, pre-
dose, and at 336.000 (Day 15, week 2), 504.000 (Day 22, week 3, within 60 minutes before 2nd dose), 
840.000 (Day 36, week 5), 1176.000 (Day 50, week 7), 1680.000 (Day 71, week 10) and 2016.000 (Day 85, 
week 12) hrs after first dose.  
 
 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 45 of 50 
 
 
13.0 
LIST OF LABORATORY PARAMETERS 
 
HAEMATOLOGY 
BIOCHEMISTRY 
CBC (including RBC 
count, platelet count) 
along with ANC 
(absolute neutrophil 
count) and Sickling Test 
Total Protein 
Blood Urea 
Sodium 
Albumin 
SGOT (AST) 
 Potassium 
Serum Globulin 
SGPT (ALT) 
Chloride 
A/G ratio 
Creatinine 
               Calcium 
Bilirubin Total 
Random glucose 
 
GGT 
Alkaline phosphatase 
 
 
IMMUNOLOGICAL TESTS 
Anti HIV AB (I & II) 
Anti HCV 
HBsAg 
 
 
URINE PARAMETER 
Specific Gravity, pH, Glucose, Protein, Bilirubin, ketones, Urobilinogen, Erythrocytes, Leucocytes, Nitrite 
and, if necessary, microscopic examination 
 
HORMONAL ASSAY:  
β-HCG*  
 
AT SCREENING AND PRIOR TO CHECK-IN OF EACH DOSE 
(A) 
URINE SCAN FOR DRUG OF ABUSE 
Morphine (MOR) 
Cannabinoids (THC) 
Amphetamines (AMP) 
Cocaine (COC) 
Barbiturates (BAR) 
Benzodiazepines (BZD) 
(B) 
BREATH TEST FOR ALCOHOL CONSUMPTION  
 
Details: 
Screening: Hematology, biochemistry, urine analysis, sickling test, immunological tests and serum 
pregnancy test* 
Prior to check-in of each dose: Serum pregnancy test*  
Pre-check-in: Estimation of hematology (except Sickling Test), biochemistry and urine analysis will be 
done within 3 working days prior to receiving dose-2  
End of the study (after last ambulatory sample after dose-2): Hematology (except sickling test), 
biochemistry (except sodium, potassium, calcium and chloride), urine analysis and Serum pregnancy 
test (for females)* 
Note: All the laboratory tests will be done as per clinical/contractual laboratory SOPs 
* For female subjects only 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 46 of 50 
 
 
14.0 
RESPONSIBILITIES OF PERSONNEL INVOLVED IN THE STUDY 
Principal Investigator: 
will be responsible for overall conduct of the study. 
Protocol Author: 
 will be responsible for the preparation and finalization of the protocol and ICF.   
Clinical Research Physician: 
will be responsible for the selection of subjects, and Duty doctors will be responsible 
for the medical care of subjects during the study 
Clinical Laboratory: 
 will be responsible for the Clinical Laboratory component of the study. 
Pharmacokinetic and Pharmacodynamic Data analysis: 
will be responsible for the pharmacokinetic and pharmacodynamic data 
analysis. 
Biostatistics and Programming: 
 will be responsible for statistical data analysis. 
Quality Assurance: 
will be responsible for Quality Assurance. 
Quality Control: 
Project Coordinator along with the designated QC team will be responsible for quality control of the 
study. 
Sponsor’s responsible person(s): 
 will be responsible for overall conduct of the study in compliance to the protocol and 
applicable regulatory requirement on behalf of the sponsor. 
will be responsible for providing IMP for the study on behalf of the sponsor. 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 47 of 50 
 
 
15.0 
ETHICAL CONSIDERATIONS 
15.1 
Basic Principles 
The study will be conducted according to Schedule Y (with subsequent amendments) of CDSCO 
(Central Drugs Standard Control Organization), Ministry of health and family welfare, Government of 
India; Ethical guidelines for biomedical research on human participants, Indian Council of Medical 
Research (2017); ICH (The International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use) E6 (R2) Guideline for Good Clinical Practice, (2016); Good Clinical 
Laboratory practices (GCLP); Declaration of Helsinki (Brazil, October 2013).  
15.2 
Independent\Institutional Ethics Committee (IEC) 
This Protocol and the corresponding Informed Consent Form (ICF) to obtain consent of study subjects 
will be reviewed by the Independent\Institutional Ethics Committee and the study will commence only 
after a written approval is obtained from the Independent\Institutional Ethics Committee. 
15.3 
Written Informed Consent 
The Principal Investigator or his/her designate will explain the conduct of the study and information 
regarding the investigational medicinal product to the subjects before check-in of the study. This will 
be done through an oral presentation regarding the purpose, procedures to be carried out, potential 
hazards and rights of the subjects, in their local language. Subjects will be encouraged to ask 
questions and clarify their doubts regarding any aspect of the study. Subjects will be required to 
sign/put a thumb impression on the informed consent form summarizing the discussion prior to 
check-in for the study. Signature of the LAR/Impartial witness (if applicable) will be taken on the 
informed consent form in case the subject is not able to sign on the informed consent form. Subjects 
who fail to understand the informed consent procedure and/or are unable to communicate with the 
study personnel will not be enrolled.  
The subjects will give their consent for participation in the study by signing/putting a thumb 
impression on Informed Consent Form (ICF), which will also be signed by the LAR/Impartial witness 
(if applicable) and 
person conducting the ICF presentation, principal investigator or 
designate. A photocopy of signed informed consent form with the signature or thumb impression will 
be given to the subject for reference after the procedure is over, while the original will be retained at 
 
15.4 
Subject Compensation  
The subjects will be paid an adequate compensation on account of their contribution towards the 
conduct of this study.  In case of dropout/withdrawal of a subject before completion of the study, the 
recommendation of the Independent\Institutional Ethics Committee on compensation of the withdrawn 
subjects will be final and binding on both 
 and the study subjects. 
16.0 
INSURANCE POLICY 
 will take insurance and will ensure its effect throughout the study. The insurance will cover 
liabilities for professional indemnity in the current study. The sponsor will arrange for 
adequate insurance to cover treatment of (Serious) Adverse Events and provide compensation for 
clinical study related injury or death. 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 48 of 50 
 
 
In the case of an injury occurring to the subject during the study, free medical management will be 
provided to the subjects as long as required or till such time it is established that the injury is not 
related to the clinical trial, whichever is earlier. 
17.0 
AMENDMENT TO THE PROTOCOL 
Any significant change in the study procedure or study design will only be effected upon mutual 
agreement with the Sponsor and 
and after obtaining a favorable opinion from the Ethics 
Committee. All such changes will be documented in the amended version of the protocol and a list of 
changes with reference to the previous version will be generated and submitted to the IEC as soon as 
possible. In cases where there is an immediate safety hazard to the subjects, the amended protocol will 
be effective immediately and approval of the IEC will be obtained as soon as possible. If required 
based on the amendment, local regulatory approval will be obtained   
18.0 
SOURCE DATA ACCESSIBILITY  
The Independent\Institutional Ethics Committee, Sponsor, Quality Assurance and Regulatory 
Agencies such as USFDA, DCGI, etc will have the access to the raw data during inspection and audits. 
19.0 
QUALITY ASSURANCE AUDITS 
In-process audit of various clinical and bioanalytical activities and retrospective audits of 100% of the 
raw data generated during the course of the study including the final reports will be conducted by 
Quality Assurance Department of 
 These audits will be performed to ensure conformance to 
this protocol, GCP, GLP and the governing SOPs of 
In addition, each department will 
implement internal Quality Control measures.  
The study may be monitored at the discretion of the sponsor by any of its representatives. 
20.0 
DATA HANDLING & RECORD KEEPING   
All clinical raw data generated during conduct of the study will be directly entered in the respective 
electronic source forms. Electronic software (Biznet) will be used for capturing the data generated 
during conduct of the study as per in-house SOPs. A dynamic list of paper source/forms (if required to 
be used due to temporary non-functioning of software or no provision to document in software) will be 
maintained and filed with project specific Trial Master File. All source data and transcribed data forms 
will be compiled by the study personnel assisting in the study and will be checked wherever applicable 
for completeness.  
All bioanalytical raw data of sample processing will be directly entered in the respective source data 
forms. The data acquisition system software will be used for the quantitative determination and 
applicable software shall be used to review the chromatographic data as per in-house SOPs. All data 
related to the project will be in the custody of the designated study personnel until transferred to 
archives. 
21.0 
REPORT 
All appropriate data from the study will be reported in the final report in eCTD format. The report will 
contain data regarding the analytical methodology, the pharmacokinetic, pharmacodynamic, 
immunogenicity calculations, the statistical analysis of the data and a clinical report along with raw 
data. 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 49 of 50 
 
 
22.0 
ARCHIVING 
A representative sample of the drug supplies used in the study will be retained at the 
in 
accordance with contract obligations. All data generated in connection with this study, together with 
the copy of this protocol, Informed Consent Form (ICF) and the final report will be archived after 
issuance of the audited reports. 
All such material will be retained at 
 as mentioned in Research Service Agreement. Beyond 
this period, the sponsor will arrange for the maintenance of these materials. 
23.0 
CONFIDENTIALITY OF DATA 
The data identifying each study subject by name will be kept confidential and will be accessible only 
to the study personnel (involved in check-in, quality control and dosing procedure), Quality Assurance 
Auditor during audits, if necessary, to the IEC and various regulatory authorities such as USFDA, 
DCGI etc. The sponsor, while monitoring or auditing the study, will also have access to data without 
violating the confidentiality of the subjects, to the extent permitted by applicable laws and regulations. 
All data related to the project will be in the custody of the designated study personnel until transferred 
to archives.   
24.0 
PUBLICATION POLICY 
The results of the study including all obtained data will be the property of the sponsor. However, the 
investigator may seek permission to publish results of the study from the sponsor. Unpublished data 
cannot be disclosed to any third party by the investigators without written approval of the sponsor and 
as per the sponsor publication policy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 
       Confidential 
Comparative subcutaneous Immunogenicity study after 
multiple doses of Pegfilgrastim under fed condition 
Project No. 0554-17 
Version No. 2.0 
22 January 2018 
 
 
Page 50 of 50 
 
 
25.0 
STANDARDIZED VEGETARIAN BREAKFAST MENU 
 
 
Food 
Items 
Servings Ingredients 
Qty. Of 
Ingredients Calorie 
CHO 
Fats 
Proteins 
Aloo 
Paratha 
 
 
 
2 pcs 
(200gms) 
 
 
 
 
Wheat 
flour 
100 gms 
341.00 
69.40 
1.70 
12.10 
Potato 
100 gms 
97.00 
22.6 
0.10 
1.60 
Ghee 
1gm 
9.00 
0.00 
1.00 
0.00 
Oil 
15 ml 
135.00 
0.00 
15.00 
0.00 
Milk 
1 Glass 
Skim milk 
150 ml 
43.50 
6.90 
0.15 
3.75 
Total 
625.50 
98.90 
17.95 
17.45 
Nutrient Calories 
395.60 
161.55 
69.80 
Nutrient Calories As % Total 
63.24%  25.82%  11.16%  
 
Lemon, Green Chili (Fried & Salted), Rock Salt, Jeera Powder, Onion slices, etc. (whichever is 
available) will be served as meal enhancers 
 
26.0 
REFERENCES  
1. Prescribing information (Neulasta® (Pegfilgrastim) injection, for subcutaneous use. Revised: 
12/2017 
2. Summary of Product Characteristics (NEULASTA® 6 mg solution for injection). last updated on the 
eMC: Updated 24-Jun-2015.