A Randomized,Double Blind,Active Controlled Parallel Arm Multicenter Study Comparing Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Denosumab of Intas Pharmaceutical Limited (60 mg/mL) With Prolia® in Postmenopausal Women With Osteoporosis
Phase: PHASE3
Conditions: Osteoporosis, Postmenopausal
Sponsor: Lambda Therapeutic Research Ltd.

Clinical Study Protocol  
Protocol Title: A Randomized, Double-Blind, Active-Controlled, Parallel Arm, 
Multicenter Study Comparing Pharmacokinetics, Pharmacodynamics, 
and Immunogenicity of Denosumab of Intas Pharmaceutical Limited (60 
mg/mL) with Prolia® in Postmenopausal Women with Osteoporosis. 
Test Product: Denosumab 
Brief Title: Denosumab biosimilar injection in postmenopausal women with osteoporosis.  
Protocol Number: 0774-19 
Version No: 2.0 
Document Type: Clinical Study Protocol 
Document Status: Final 
Release Date: 14-Sep-2020 
Study Phase: Phase 3 
Sponsor Name: Intas Pharmaceutical Limited 
(Biopharma Division) 
Legal Registered Address: Plot No. 
423/P/A/GIDC, Sarkhej - Bavla Highway, 
Moraiya, Ahmedabad – 382213. Gujarat, India. 
Tel No.: +91-2717-660921 
Fax No.: +91-2717-660105 
CRO 
Name: 
Lambda 
Therapeutic 
Research Limited, Ahmedabad 
Legal Registered Address: Lambda 
House, Plot No. 38, Survey No. 388, 
Near Silver Oak Club, S. G. Highway, 
Gota, Ahmedabad – 382481. Gujarat, 
India. 
Tel. No.: +91-79-4020 2020  
Fax No: +91-79-4020 2021/22  
Confidentiality Statement 
The information contained in this document is trade secrets and commercial information that are privileged or confidential, 
especially unpublished data, and is the property of the Intas Pharmaceutical Limited (Biopharma Division) (or under its 
control), and therefore provided to you in confidence as an Investigator or consultant, for review by you, your staff and an 
applicable Institutional Ethics Committee. By accepting this document, you agree that this information will not be disclosed 
to others without written authorization from Intas Pharmaceutical Limited (Biopharma Division) unless such disclosure is 
required by applicable law or regulations or to the extent necessary to obtain informed consent from those persons (including 
their legally acceptable representatives as applicable) to whom the drug may be administered. In any event, persons to whom 
the information is disclosed must be informed that the information is privileged or confidential and may not be further 
disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential. 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
Page 3 of 107 
 
Sponsor's Approval Signature  
Protocol Title: A Randomized, Double-Blind, Active-Controlled, Parallel Arm, Multicenter 
Study Comparing Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Denosumab 
of Intas Pharmaceutical Limited (60 mg/mL) with Prolia® in Postmenopausal Women with 
Osteoporosis. 
Protocol Number: 0774-19 
I, on behalf of Intas Pharmaceutical Limited (Biopharma Division), have read, understood and 
approve this protocol.  
Intas Pharmaceutical Limited (Biopharma Division) agree to comply with all requirements 
regarding the obligations of the Sponsor and all other pertinent requirements of ICH E6 (R2) 
Guideline on Good Clinical Practice; New Drugs & Clinical Trial Rules, 2019 of CDSCO; 
Declaration of Helsinki (Fortaleza, 2013); as per any other applicable regulatory requirements. 
 
 
Authorized Signatory 
 
Date 
 
Name 
: 
Dr. Vinu Jose 
Designation : 
Head – Clinical Development and Medical Affairs 
Address 
: 
Intas Pharmaceutical Limited (Biopharma Division) 
Plot No: 423/P/A, Sarkhej-Bavla Highway, 
Moraiya, Sanand, Ahmedabad, 
Gujarat, India 382 213 
Tel. No. 
: 
+91-2717-660921 
Fax No. 
: 
+91-2717-660105 
Email 
: 
Vinu_jose@intaspharma.com  
 
 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
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List of Facilities 
Protocol Title: A Randomized, Double-Blind, Active-Controlled, Parallel Arm, Multicenter 
Study Comparing Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Denosumab 
of Intas Pharmaceutical Limited (60 mg/mL) with Prolia® in Postmenopausal Women with 
Osteoporosis. 
Protocol Number: 0774-19 
Contract Research Organization (CRO) Services 
Clinical 
Laboratory, 
Pharmacy, 
Project 
Management, 
Bioanalytical 
services 
(Pharmacodynamic, Pharmacokinetic and Immunogenicity assessments), Monitoring, Data 
Management, Biostatistics and Programming, Medical Writing, and Quality Assurance. 
Address 
: 
Lambda Therapeutic Research Limited, Ahmedabad 
Lambda House, Plot No. 38, Survey No. 388, Near Silver Oak 
Club, S. G. Highway, Gota, Ahmedabad – 382481. Gujarat, India 
Tel. No. 
: 
+91-79-4020 2020 
Fax No. 
: 
+91-79-4020 2021/22 
Note: Clinical Laboratory will be utilized for all laboratory investigations. ECG and/or 
ECHO will be performed locally. 
IMP Management  
Address 
: Lambda Clinical Services Limited 
Survey No. 530, Unit No. 22 to 31,  
Silver Industrial Estate – 3. 
Sarkhej-Bavla Road, 
Changodar, Sanand, Ahmedabad 382213,  
Gujarat, India. 
Clinical Facilities 
Clinical facilities will be of participating clinical investigators/ sites.  
Sponsor’s Safety Officer and Medical Monitor  
Name 
: Dr. Dharma Rao Uppada 
Address 
: Intas Pharmaceuticals Ltd. (Biopharma Division), 
Plot No: 423/P/A, Sarkhej-Bavla Highway, 
Moraiya, Sanand, Ahmedabad, Gujarat, India 382 213. 
Tel. No. 
: 02717-660948 
Fax No 
: 02717-660105 
E-Mail:   
: Dharma_Uppada@intaspharma.com 
TrialBioDrugSafety@intaspharma.com 
 
 
 
 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Type 
Amendment 2.0 
14-September-2020 
Major [substantial] 
Original Protocol 
26-March-2020 
 
Amendment number 2.0 dated 14 September 2020 
Overall Rationale for the Amendment: 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis (Investigational 
Medicinal Product), 
Section 6.1 
Bio analytical services (Pharmacodynamics, 
Pharmacokinetic and Immunogenicity assessments) 
has been kept at Lambda Therapeutic Research 
Limited, Ahmedabad only. 
Change in facility 
List of facilities: 
Sponsor’s medical 
monitor 
Updated the details of Sponsor’s medical monitor. 
 
Administrative 
change 
Synopsis: and section 3.0 
Objectives and Endpoints: 
 Addition of a secondary endpoint. 
Regulatory advice 
related strategy 
change 
Synopsis and Section 5.1 
Update in upper age cut-off of participants for 
inclusion 
 
Regulatory advice 
related strategy 
change 
Synopsis and section 4.1 
Overall Design 
 
An additional PK, PD and Immunogenicity samples 
will be collected after third dose of denosumab in 
prespecified participants. 
However, analysis of PK and PD samples will be 
performed only if there is immunogenicity identified 
in a particular patient either clinically or by 
immunogenicity analysis. 
Regulatory advice 
related strategy 
change 
Section 1.3 
Schedule of event has been updated based on 
changes in design. 
Subsequent related 
changes 
9.1. 
Sample Size 
Determination 
Sample size justification has been added for the 
transition extension period, based on 
Immunogenicity assessment 
Regulatory advice 
related strategy 
change 
Section 9.2: Populations 
for Analyses 
Updates in population set and addition of sensitivity 
analysis 
Regulatory advice 
related strategy 
change 
8. 
Study 
Assessments and 
Procedures 
Blood loss has been revised due to additional PK and 
PD sample collections after third dose in applicable 
participants only. 
Regulatory advice 
related strategy 
change 
Throughout  
Minor editorial and document formatting revisions  
Minor, therefore, 
have not been 
summarized  
 
 
 
 
 
 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
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Table of Contents 
CLINICAL STUDY PROTOCOL ....................................................................................................................... 1 
PROTOCOL SIGNATURE ........................................................................................................................................ 2 
SPONSOR'S APPROVAL SIGNATURE ..................................................................................................................... 3 
LIST OF FACILITIES .............................................................................................................................................. 4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE................................................................................... 5 
TABLE OF CONTENTS ........................................................................................................................................... 6 
ABBREVIATIONS .................................................................................................................................................. 9 
1. 
PROTOCOL SUMMARY ........................................................................................................................ 11 
1.1. 
SYNOPSIS ............................................................................................................................................ 11 
1.2. 
SCHEMA .............................................................................................................................................. 22 
1.3. 
SCHEDULE OF ACTIVITIES (SOA) ........................................................................................................ 23 
2. 
INTRODUCTION ..................................................................................................................................... 27 
2.1. 
BACKGROUND ..................................................................................................................................... 27 
2.2. 
STUDY RATIONALE ............................................................................................................................. 27 
2.3. 
BENEFIT/RISK ASSESSMENT ................................................................................................................ 27 
3. 
OBJECTIVES AND ENDPOINTS .......................................................................................................... 28 
3.1. 
HYPOTHESIS ........................................................................................................................................ 29 
4. 
STUDY DESIGN ........................................................................................................................................ 30 
4.1. 
OVERALL DESIGN ............................................................................................................................... 30 
4.2. 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ....................................................................................... 31 
4.2.1. 
Trial Design .................................................................................................................................. 31 
4.2.2. 
Selection of Endpoints ................................................................................................................. 31 
4.2.3. 
Blinding, Control, Study Phase/Periods, IMP Groups ............................................................. 31 
4.2.4. 
Selection of the Trial Population ................................................................................................ 32 
4.2.5. 
Choice of Control Group............................................................................................................. 32 
4.2.6. 
Study-Specific Ethical Design Considerations .......................................................................... 33 
4.2.7. 
Concomitant Medication ............................................................................................................. 33 
4.3. 
JUSTIFICATION FOR DOSE .................................................................................................................... 33 
4.4. 
END OF STUDY DEFINITION ................................................................................................................. 33 
5. 
STUDY POPULATION ............................................................................................................................ 34 
5.1. 
INCLUSION CRITERIA .......................................................................................................................... 34 
5.2. 
EXCLUSION CRITERIA ......................................................................................................................... 35 
5.3. 
LIFESTYLE CONSIDERATIONS .............................................................................................................. 37 
5.3.1. 
Alcohol and Tobacco ................................................................................................................... 37 
5.4. 
SCREEN FAILURES ............................................................................................................................... 37 
6. 
STUDY IMP AND CONCOMITANT THERAPY ................................................................................. 39 
6.1. 
STUDY IMP ADMINISTERED ................................................................................................................ 39 
6.2. 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ..................................................................... 40 
6.2.1. 
Investigational Medicinal Product Receipt and Storage .......................................................... 40 
6.2.2. 
Retention Samples ....................................................................................................................... 41 
6.3. 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ...................................................... 41 
6.3.1. 
Procedures for Screening and Randomization .......................................................................... 41 
6.3.2. 
Procedures of blinding ................................................................................................................ 42 
6.4. 
STUDY IMP COMPLIANCE ................................................................................................................... 44 
6.5. 
DOSE MODIFICATION .......................................................................................................................... 44 
6.6. 
CONTINUED ACCESS TO STUDY IMP AFTER THE END OF THE STUDY ................................................. 44 
6.7. 
TREATMENT OF OVERDOSE ................................................................................................................. 45 
6.8. 
CONCOMITANT THERAPY .................................................................................................................... 45 
7. 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .......................................................................................................... 47 
7.1. 
DISCONTINUATION OF STUDY IMP ..................................................................................................... 47 
7.2. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY ................................................... 47 
7.3. 
LOST TO FOLLOW UP ........................................................................................................................... 48 
8. 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................... 50 
8.1. 
STUDY PROCEDURE ............................................................................................................................. 51 
8.2. 
HOSPITALIZATION ............................................................................................................................... 51 
8.3. 
UNSCHEDULED VISITS ........................................................................................................................ 52 
8.4. 
EFFICACY ASSESSMENTS .................................................................................................................... 52 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
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8.4.1. 
Evaluations ................................................................................................................................... 52 
8.5. 
SAFETY ASSESSMENTS ........................................................................................................................ 54 
8.5.1. 
Demographic Characteristics ..................................................................................................... 54 
8.5.2. 
Medical History............................................................................................................................ 54 
8.5.3. 
Medication History ...................................................................................................................... 54 
8.5.4. 
Physical Examinations ................................................................................................................ 55 
8.5.5. 
Vital Signs..................................................................................................................................... 55 
8.5.6. 
Electrocardiograms ..................................................................................................................... 55 
8.5.7. 
Clinical Safety Laboratory Assessments .................................................................................... 55 
8.5.8. 
Pregnancy Testing ....................................................................................................................... 55 
8.5.9. 
Periodontal Examination ............................................................................................................ 56 
8.5.10. 
Injection site assessment ......................................................................................................... 56 
8.6. 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES), AND OTHER SAFETY REPORTING ...... 56 
8.6.1. 
Time Period and Frequency for Collecting AE and SAE Information ................................... 56 
8.6.2. 
Method of Detecting AEs and SAEs ........................................................................................... 57 
8.6.3. 
Follow-up of AEs and SAEs ........................................................................................................ 57 
8.6.4. 
Regulatory Reporting Requirements for SAEs ......................................................................... 57 
8.6.5. 
Pregnancy ..................................................................................................................................... 58 
8.6.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or SAEs 58 
8.6.7. 
Abnormal Laboratory Values .................................................................................................... 59 
8.6.8. 
Abnormal Vital Sign Values ....................................................................................................... 59 
8.6.9. 
Adverse Events of Special Interest ............................................................................................. 60 
8.7. 
PHARMACOKINETICS ........................................................................................................................... 60 
8.7.1. 
Evaluations ................................................................................................................................... 60 
8.7.2. 
Blood Sample Handling for PK, PD and Immunogenicity Analysis ....................................... 62 
8.7.3. 
Analytical Procedures ................................................................................................................. 62 
8.7.4. 
Pharmacokinetic Parameters and Evaluations ......................................................................... 62 
8.8. 
GENETICS AND/OR PHARMACOGENOMICS ........................................................................................... 64 
8.9. 
PHARMACODYNAMICS ........................................................................................................................ 64 
8.9.1. 
Evaluation .................................................................................................................................... 64 
8.9.2. 
Analytical procedure ................................................................................................................... 65 
8.9.3. 
Pharmacodynamic parameters & analysis ................................................................................ 65 
8.10. 
IMMUNOGENICITY ASSESSMENTS ....................................................................................................... 66 
8.10.1. 
Sampling Schedule for Immunogenicity evaluation ............................................................ 66 
8.10.2. 
Analytical Procedures ............................................................................................................. 66 
8.11. 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................................... 67 
9. 
STATISTICAL CONSIDERATIONS ..................................................................................................... 68 
9.1. 
SAMPLE SIZE DETERMINATION ........................................................................................................... 68 
9.2. 
POPULATIONS FOR ANALYSES ............................................................................................................. 69 
9.3. 
STATISTICAL ANALYSES ..................................................................................................................... 69 
9.3.1. 
PK and PD data ........................................................................................................................... 70 
9.3.2. 
Baseline and Demographic Characteristics ............................................................................... 72 
9.3.3. 
Efficacy / Pharmacodynamic Data ............................................................................................. 72 
9.3.4. 
Immunogenicity Data .................................................................................................................. 73 
9.3.5. 
Safety Data ................................................................................................................................... 73 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 74 
10.1. 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ............................ 74 
10.1.1. 
Regulatory and Ethical Considerations ................................................................................ 74 
10.1.2. 
Financial Disclosure ................................................................................................................ 77 
10.1.3. 
Informed Consent Process ..................................................................................................... 77 
10.1.4. 
Data Protection ....................................................................................................................... 78 
10.1.5. 
Publication Policy / Dissemination of Clinical Study Data .................................................. 79 
10.1.6. 
Data Quality Assurance .......................................................................................................... 79 
10.1.7. 
Case Report Form Completion .............................................................................................. 80 
10.1.8. 
Source Documents ................................................................................................................... 81 
10.1.9. 
Study and Site Start and Closure .......................................................................................... 82 
10.1.10. 
Monitoring ............................................................................................................................... 82 
10.1.11. 
On-Site Audits ......................................................................................................................... 83 
10.1.12. 
Record Retention .................................................................................................................... 84 
10.1.13. 
Insurance ................................................................................................................................. 84 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
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10.2. 
APPENDIX 2: CLINICAL LABORATORY TESTS ...................................................................................... 85 
10.3. 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING ........................................................................................................................... 87 
10.3.1. 
Definition of AE ...................................................................................................................... 87 
10.3.2. 
Definition of SAE .................................................................................................................... 88 
10.3.3. 
Recording and Follow-Up of AE and/or SAE....................................................................... 90 
10.3.4. 
Reporting of SAEs .................................................................................................................. 96 
10.4. 
APPENDIX 4: CENTRAL LABORATORY REFERENCE INTERVALS .......................................... 97 
10.5. 
APPENDIX 5: PROTOCOL AMENDMENT HISTORY .............................................................................. 100 
REFERENCES .................................................................................................................................................. 105 
INVESTIGATOR AGREEMENT ............................................................................................................................ 107 
 
 
 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
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Abbreviations 
z 
Terminal Rate Constant 
AE 
Adverse event 
ANOVA 
Analysis of Variance 
ANCOVA 
Analysis of Covariance 
AUC0-t 
Area under the concentration versus time curve from time zero to the last measurable 
concentration 
AUC0- 
Area under the concentration versus time curve from time zero to infinity 
AUC_%Extrap_obs 
Residual area 
AUEC0-t 
Area under the % reduction from baseline versus time curve from time zero to the last 
measurable concentration 
CI 
Confidence Interval 
Cl/F 
Total body clearance 
ClinRO 
clinician-reported outcome 
Cmax 
Maximum measured concentration 
CRF 
case report form(s) (paper or electronic as appropriate for this study) 
DMC 
Data Monitoring Committee 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders (5th edition) 
DXA 
Dual-energy x-ray absorptiometry 
ECG 
Electrocardiogram 
eDC 
electronic data capture 
Emax 
Maximum % reduction from baseline 
EMA 
European Medicines Agency 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLM 
General Linear Model 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
IAC 
Interim Analysis Committee 
IB 
Investigator Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IWRS 
interactive web response system 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
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mITT 
Modified Intent-To-Treat 
MRU 
Medical resource utilization 
NIMP 
Non-investigational medicinal product 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PQC 
Product Quality Complaint 
PRO 
patient-reported outcome(s) (paper or electronic as appropriate for this study) 
Ref 
Reference 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SoA 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
Terminal half-life 
Tmax 
Time of the maximum measured concentration/Time of the maximum % reduction from 
baseline 
USFDA 
United States Food and Drug Administration 
USP 
United States Pharmacopeia 
Vd/F 
Volume of distribution 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Randomized, Double-Blind, Active-Controlled, Parallel Arm, 
Multicenter 
Study 
Comparing 
Pharmacokinetics, 
Pharmacodynamics, 
and 
Immunogenicity of Denosumab of Intas Pharmaceutical Limited (60 mg/mL) with 
Prolia® in Postmenopausal Women with Osteoporosis. 
Denosumab of Intas is biosimilar denosumab candidate under development by Intas 
Pharmaceutical Limited (Biopharma Division). Denosumab of Intas is already approved by 
Indian drug licensing authority- Drug Controller General (India) for marketing in Indian 
population since 2018. 
Brief Title: Denosumab biosimilar injection in postmenopausal women with osteoporosis. 
Rationale:  
As per regulatory requirement, a comparative clinical study to establish Pharmacokinetic, 
Pharmacodynamic and Immunogenicity equivalence is required to conclude therapeutic 
equivalence to obtain marketing authorization of a biosimilar investigational product. This is a 
multicenter, randomized, double-blind, active-controlled study in approximately 552 
postmenopausal women with osteoporosis.  
An extension of the study is planned after completion of the initial 1 year of treatment. This 
extension is with the objective of submitting data on safety, and Immunogenicity, after 
switching of Prolia treatment arm to either Prolia or Intas denosumab for 6 months. This 
switching data is applicable only for FDA submission. Only patients who have undergone PK 
assessment will be eligible for the extension phase. 
Objectives and Endpoints: 
Objectives 
Endpoint Comparison 
Primary 
To compare the pharmacokinetic parameters 
of 
denosumab 
and 
denosumab-ref 
in 
postmenopausal women with osteoporosis. 
• Pharmacokinetics: Cmax, AUC0-t, and 
AUC0-∞ after first dose of denosumab and 
denosumab-ref 
To compare the pharmacodynamic effect of 
treatment with denosumab and denosumab-
ref on bone mineral density (BMD) and bone 
resorption marker in postmenopausal women 
with osteoporosis* 
• Mean percentage change in BMD at 
lumbar spine from baseline to 12 months 
between denosumab and denosumab-ref 
• Pharmacodynamics: Emax and AUEC0-t of 
% reduction from baseline serum C-
terminal telopeptide (CTX) after first dose 
of denosumab and denosumab-ref* 
*To be considered as secondary endpoint for 
USFDA submission. 
Secondary 
To compare the efficacy of treatment with 
denosumab 
and 
denosumab-ref 
in 
postmenopausal women with osteoporosis 
• Incidence of clinical fracture between 
denosumab and denosumab-ref over 12 
months. 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
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To compare the pharmacodynamic effects of 
the 
treatment 
with 
denosumab 
and 
denosumab-ref in postmenopausal women 
with osteoporosis 
• Mean percentage change in bone mineral 
density (BMD) of lumbar spine from 
baseline 
to 
06 
months 
between 
denosumab and denosumab-ref 
• Mean percentage change in BMD of 
femoral neck and total hip from baseline 
to 06 and 12 months between denosumab 
and denosumab-ref 
• Pharmacodynamics: Tmax of % reduction 
from 
baseline 
serum 
C-terminal 
telopeptide (CTX) after first dose of 
denosumab and denosumab-ref 
• Pharmacodynamics: Emax, AUEC0-t, Tmax 
of % reduction from baseline serum N-
terminal propeptide of type 1 collagen 
(P1NP) after first dose of denosumab and 
denosumab-ref 
• Mean percentage reduction in serum N-
terminal propeptide of type 1 collagen 
(P1NP) concentrations from baseline to 
06 and 12 months between denosumab 
and denosumab-ref 
• Mean percentage reduction in CTX 
serum concentrations from baseline to 06 
and 12 months between denosumab and 
denosumab-ref 
To 
compare 
the 
immunogenicity 
of 
denosumab 
and 
denosumab-ref 
in 
postmenopausal women with osteoporosis 
• Incidence of anti-denosumab antibody in 
denosumab and denosumab-ref arm over 
12 months.  
To compare the safety of treatment with 
denosumab 
and 
denosumab-ref 
in 
postmenopausal women with osteoporosis 
• Monitoring of adverse events and lab 
parameters 
in 
denosumab 
and 
denosumab-ref arm 
To evaluate the safety and immunogenicity 
of denosumab and denosumab-ref after 
single transition from denosumab-ref to 
denosumab 
and 
denosumab-ref 
in 
postmenopausal women with osteoporosis* 
 
*To be considered as secondary endpoint for 
USFDA submission. 
• Incidence of anti-denosumab antibody in 
denosumab and denosumab-ref arms 
after single transition from denosumab-
ref  
• Assessment for difference in PK or PD in 
patients 
who 
are 
found 
to 
be 
immunogenic 
• Monitoring of adverse events and lab 
parameters 
in 
denosumab 
and 
denosumab-ref arm arms after single 
transition from denosumab-ref 
 
Overall Design 

 
 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
Page 13 of 107 
 
This is a randomized, double-blind, active-controlled, parallel-arm, multicenter study 
comparing the pharmacokinetics, pharmacodynamics, and immunogenicity of Denosumab of 
Intas (60 mg/ml) with Prolia, in postmenopausal women with osteoporosis aged 55 to 90 years, 
both inclusive. 
After completion of 12 months of treatment period, participants who are (a) randomized in 
reference arm AND (b) undergone PK assessments during 12-month treatment period will be 
re-randomized in test and reference arm for additional follow up period of six months to assess 
the safety and immunogenicity. The PK, PD samples collected in these patients will be assessed 
for impact of immunogenicity on PK and PD only if there is immunogenicity identified in a 
particular patient either clinically or by immunogenicity analysis.  
Brief Summary: 
The purpose of this study is to compare and prove equivalence for the pharmacokinetic, 
pharmacodynamic parameters and Immunogenicity of denosumab against denosumab-ref. 
Study Duration: 381 days (approx. 12 months) including screening period.  For those patients 
who have been part of PK assessment and in Reference group and identified for single transition 
treatment the duration will be 541 days (approx. 18 months) for following up participants. 
Condition/Disease: Postmenopausal women with osteoporosis. 
Study Hypothesis: The primary clinical hypothesis is that in postmenopausal women with 
osteoporosis, the primary pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ after first dose 
of denosumab will be equivalent to denosumab-ref. Likewise, the primary pharmacodynamics 
parameter (Only for EMA) Emax and AUEC0-t of % reduction from baseline serum CTX after 
first dose of denosumab will be equivalent to that of those receiving denosumab-ref. It is further 
hypothesized that mean percentage change in BMD of lumbar spine from baseline to 12 months 
in participants receiving denosumab will be equivalent to that of those receiving denosumab-
ref. The safety hypothesis is that the safety profile of denosumab will be similar to denosumab-
ref in women with osteoporosis. 
Investigational Medicinal Product, Dose and Mode of Administration: Denosumab of Intas 
Biopharmaceuticals Limited is the test product and EU-Prolia is the reference product. Study 
drugs will be administered at a dose of 60 mg as a subcutaneous injection once every 6 months 
into the thigh, abdomen or upper arm as per Prescribing Information. 
IMP details 
ARM Name 
denosumab 
denosumab-ref 
Study IMP Name 
Denosumab 
Prolia®  
Manufacturer 
Intas 
Pharmaceuticals 
Ltd., 
India 
Amgen 
Europe 
B.V. 
(EU-
licensed product) 
Dose Formulation 
Solution for injection in single-
use prefilled syringe  
Solution for injection in single-
use prefilled syringe  
Unit Dose Strength(s) 60 mg/mL 
60 mg/mL 

 
 
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Dosage Level(s) 
60 mg once every 6 months 
60 mg once every 6 months 
Route 
of 
Administration 
Subcutaneous injection 
Subcutaneous injection 
Other Protocol-Required Therapies 
Other protocol-required drugs (ie, vitamin D and calcium supplements) that are commercially 
available will be provided by the Sponsor. The investigator will be responsible for obtaining 
supplies of these drugs. 
From screening to end of study, participants will receive daily calcium and vitamin D 
supplementation that at a minimum should be in the range of at least 1000 mg calcium and at 
least 400 IU vitamin D. In addition, participants with a serum 25 (OH) Vitamin D level of < 20 
ng/mL at screening will be repeated and retested during screening.  
Where available, vitamin D3 preparations should be used; if vitamin D3 is not available, use of 
vitamin D2 preparations is acceptable. 
If a participant develops hypercalcemia over the course of the study, the principal investigator 
may use his/her medical judgment and reduce the calcium and/or vitamin D supplementation 
to maintain serum calcium concentration within the normal range. If a participant develops 
hypocalcemia over the course of the study, appropriate additional supplementation should be 
instituted as deemed acceptable by local guidelines, to maintain serum calcium concentration 
within the normal range. If a participant is unable to tolerate the daily calcium or vitamin D 
supplementation, the formulation may be changed, or the dose lowered. The intolerance as well 
as the resolution (i.e., change in formulation or dosage) should be documented in the source 
documents. 
Visit Frequency: Visit have been scheduled at monthly frequency.  
Number of Participants: A total of 552 patients (276 patients/arm) in the BMD and 
immunogenicity assessment, 296 patients (148 patients/arm) in the PK assessment and PD 
(Percentage reduction from baseline for serum CTX) assessment will be included for initial 1-
year treatment. 136 patients (68 patients/arm) will be included in the immunogenicity 
assessment for extension 6-month phase of the study. 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria are met: 
1. Participant must sign an ICF to participate in the study indicating that she understands 
the purpose of, and procedures required for the study as described in this protocol and 
is willing to and will be able to adhere to requirement of the protocol.  
2. Participant must be 55 to 90 years of age (both inclusive), at the time of signing the 
informed consent. 
3. Participants who are medically/clinically stable on the basis of physical examination, 
medical history, vital signs, chest X-ray PA view, 12-lead ECG and clinical laboratory 
parameters performed at screening. Any abnormalities or deviation from normal, must 
be consistent with the underlying illness in the study population and judged by 
investigator to be not clinically significant. This determination must be recorded in the 
participant's source documents and initialed by the investigator. 

 
 
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4. Participants whose absolute bone mineral density T-score is ≤ -2.5 and ≥ -4.0 at the 
lumbar spine as measured by DXA (dual-energy x-ray absorptiometry), confirmed by 
the independent central imaging team.  
5. At least two vertebrae in the L1-L4 region and at least one hip joint are evaluable by 
DXA, confirmed by the independent central imaging team. 
6. Body weight between 50 kg and 90 kg (both inclusive) at screening. 
7. Postmenopausal ambulatory female and not considered to be of child-bearing potential 
if: 
a. Women are considered post-menopausal and not of child-bearing potential if,  
i. They have had 12 months of natural (spontaneous) amenorrhea (no 
vaginal bleeding or spotting) with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) OR  
ii. Six months of spontaneous amenorrhea with serum FSH levels >40 
mIU/mL; OR  
iii. Have had surgical bilateral oophorectomy (with or without 
hysterectomy) at least six months ago. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment if she is considered 
not of child-bearing potential.  
Exclusion criteria:  
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study: 
1. Documented medical history of clinically significant cardiac, vascular, pulmonary, 
gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or 
metabolic disturbances 
2. Documented medical history of known allergies, hypersensitivity, or intolerance to 
denosumab or its excipients (sorbitol, acetate, polysorbate 20, and sodium hydroxide 
3. History of any prior use of denosumab 
4. Documented medical history of metabolic or bone disease (except osteoporosis) that 
may interfere with the interpretation of the results, such as Paget’s disease, 
osteomalacia, osteogenesis imperfecta, osteopetrosis, rheumatoid arthritis, ankylosing 
spondylitis or any other joint disease limiting mobility, Cushing’s disease, 
hyperprolactinemia, malabsorption syndrome  
5. Documented medical history of latex or dry natural rubber allergy 
6. Contraindications to the use of denosumab or Vitamin D and Calcium as per 
Investigator brochure/local prescribing information at screening and/or baseline 
7. Documented medical history and/or current evidence of any of the following oral/dental 
conditions 
a) Prior history or current evidence of osteomyelitis or osteonecrosis of the jaw. 
b) Active dental or jaw condition which requires oral surgery. 
c) Planned invasive dental procedure expected during study period. 
d) Current evidence non-healed dental or oral surgery. 
e) Current evidence of poor oral hygiene 
f) Ill-fitting denture 
8. Current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium outside the 
normal range at screening. Serum calcium levels may be retested once in case of an 
elevated/low serum calcium level as assessed by the clinical laboratory. Final decision 
to include the patient based on the risk of hypocalcemia to be taken by the Investigator. 

 
 
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9. History of frequent occurrence of hypocalcemia, history of severe hypocalcemia or 
presence of diseases that can precipitate hypocalcemia frequently (like malabsorption 
syndromes (for example celiac disease, history of excision of small intestine etc.) and 
severe renal impairment) 
10. Current, uncontrolled hyper- or hypoparathyroidism and history of hypoparathyroidism, 
per participant report or chart review. PTH outside the normal range (15-65 pg/mL) as 
assessed by central laboratory  
11. Current, uncontrolled hyper- or hypothyroidism, defined as thyroid stimulating 
hormone outside of the normal range (TSH-0.465 to 4.68 mIU/L) at screening.  
12. 25 (OH) Vitamin D lower than 20 ng/mL as assessed by the central laboratory at 
Screening. Vitamin D repletion will be permitted, and participants may be rescreened 
once. 
13. History of external beam or implant radiation therapy involving the skeleton. 
14. History and /or presence of 1 severe fracture or 2 moderate vertebral fractures 
15. Patients with bone metastases or a history of malignancies affecting bones. 
16. Smokers or who have smoked within last 06 months prior to start of the study. 
17. Documented medical history of major surgery, (e.g. requiring general anesthesia) within 
12 weeks before screening, or will not have fully recovered from surgery, or has surgery 
planned during the time the participant is expected to participate in the study.  
Note: Participants with planned surgical procedures to be conducted under local 
anesthesia may participate. 
18. Documented medical history of hepatitis B surface antigen (HBsAg) or hepatitis C 
antibody (anti-HCV) positive, or other clinically active liver disease, or tests positive 
for HBsAg or anti-HCV at Screening. 
19. Documented medical history of human immunodeficiency virus (HIV) antibody 
positive, or tests positive for HIV at Screening. 
20. Documented medical history of drug or alcohol abuse according to Diagnostic and 
Statistical Manual of Mental Disorders (5th edition) (DSM-V) criteria within 1 year 
before Screening 
21. Lymphoma, leukemia, or any malignancy (current or suspected) within the past 5 years 
except for basal cell or squamous epithelial carcinomas of the skin that have been 
resected with no evidence of metastatic disease for 3 years; carcinoma in situ of the 
cervix; or malignancy, which is considered cured with minimal risk of recurrence 
22. QTc interval >470 msec or QT interval >480 msec in participants with bundle branch 
block.  
Note: The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB). It is either machine-read or manually over-read.  
23. Administration of bisphosphonate as follows: - 
a) IV Bisphosphonate in the past 3 years  
b) Oral bisphosphonates treatment for osteoporosis  
i. 
More than 3 years of cumulative use  
ii. 
Any dose received within 6 months prior to randomization 
iii. 
More than 1 month of cumulative use between 6 and 12 months prior to 
randomization 
24. Teriparatide or any PTH analog treatment received within 12 months prior to 
randomization. 
25. Systemic oral or transdermal estrogen, SERMs, or calcitonin treatment of more than 1 
month of cumulative use within 6 months prior to randomization. 
26. Androgen deprivation or hormonal ablation therapy of more than 1 month of cumulative 
use within 6 months prior to randomization. 

 
 
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27. Tibolone or cinacalcet treatment received within 3 months prior to randomization 
28. Systemic glucocorticoids: ≥ 5 mg prednisone equivalent per day for more than 10 days 
within 3 months prior to randomization. 
29. Abnormal laboratory values 
a. General: Any laboratory abnormality which, in the opinion of the Investigator, 
will prevent the patient from completing the study or interfere with the 
interpretation of the study results. 
b. Liver transaminases: 
i. 
Serum aspartate aminotransferase (AST) ≥3.0 × upper limit of normal 
(ULN) 
ii. 
Serum alanine aminotransferase (ALT) ≥3.0 × ULN 
c. Alkaline phosphatase and bilirubin ≥1.5 × ULN 
d. Creatinine clearance estimated using Cockcroft Gault formula is <30 mL/min 
30. Taken any prohibited therapies as noted in Section 6.8, Concomitant Therapy before the 
planned first dose of study IMP 
31. Received any investigational IMP 30 days or 5 half-lives (whichever is longer) before 
the signing the consent or is currently enrolled in an investigational study 
32. Unstable liver or biliary disease per investigator assessment defined by the presence of 
ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric 
varices, persistent jaundice, or cirrhosis. This includes but is not limited to hepatitis 
virus infections, drug- or alcohol-related liver disease, non-alcoholic steatohepatitis, 
autoimmune hepatitis, hemochromatosis, Wilson’s disease, α-1 antitrypsin deficiency, 
primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease 
considered clinically significant by the investigator.  
Note: Stable chronic liver disease (including Gilbert’s syndrome, asymptomatic 
gallstones) is acceptable if the participant otherwise meets entry criteria. 
33. Any other clinical/social/ psychiatric condition for which, in the opinion of the 
investigator, participation would not be in the best interest of the participant (eg, 
compromise the well-being) or that could prevent, limit, or confound the protocol-
specified assessments 
34. Employee of the investigator or study site, with direct involvement in the proposed study 
or other studies under the direction of that investigator or study site 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a participant's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study IMP is given such 
that he or she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. Refer to Section 5.4 for further information. 
Discontinuation of study IMP 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study IMP. If a participant discontinues study IMP for any reason before the 
end of the study, scheduled assessments of the study should be continued. 
Subjects meeting the following criteria will be withdrawn from the study treatment. All 
withdrawn subjects from the study treatment will be followed up till the end of study as per 
schedule of activities. 
• 
The participant withdraws consent to receive study IMP 
• 
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) 
it is in the best interest of the participant to discontinue study IMP 

 
 
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• 
Concomitant medications: Consumption of co-medication / requirement to consume co-
medication that can affect the safety of the participant continuing in the trial as per the 
investigator; Consumption of prohibited medication as mentioned in section 6.8 
If a participant discontinues study IMP definitely for any reason before the end of the study 
visit but is still willing to collaborate in providing further data by continuing on study, the 
participant will remain in the study to be evaluated for further collection of information on 
primary endpoint as well as immunogenicity. These participants to be provided Standard of 
Care as per investigator and participants agreement. 
Participant withdrawal 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
Investigator must determine the primary reason for a participant’s premature withdrawal from 
the study and record this information on the eCRF and in the source document. If premature 
withdrawal from the study occurs for any reason, if possible, End of Study visit as described in 
Section 1.3 (SoA) should be conducted. If the reason for withdrawal from the study is 
withdrawal of consent, then no additional assessments are allowed. 
A participant will be withdrawn from the study for any of the following reasons: 
• 
Consent is withdrawn: Subjects have the right to withdraw from the trial at any time for 
any reason. If withdrawal occurs, the subject will be requested to come for a complete 
follow-up examination. 
• 
Non-compliance: The subject may be withdrawn from the trial at the discretion of the 
Investigator if it is judged that participant is non-compliant to study assessment and 
schedule and it can cause safety concerns.  
• 
Protocol deviation:  
➢ Subject entered in the study in violation of the protocol.  
➢ Any deviations from the protocol-prescribed dose regimen and/or dose delay for the 
study drug. 
➢ Participant can be withdrawn from trial after consultation with the sponsor, if 
participant's continued participation in trial affects his/her safety due to protocol 
deviation   
• 
Pregnancy: A female participant with pregnancy will be withdrawn from the trial.   
• 
Lost to follow-up  
• 
Death 
If the participant withdraws consent for disclosure of future information, the sponsor can retain 
and continue to use any data collected before such a withdrawal of consent. 
The Investigator will discuss the appropriate therapy with each participant who withdraws 
early from this study. Determination of the appropriate follow-up therapy will be left to the 
discretion of the Investigator. 
Study Assessments:  
Various assessment related to PK, PD, safety, immunogenicity and efficacy will be performed 
at time points mentioned in SoA. 
Efficacy assessment includes DXA, lateral spine X-ray, and clinical fractures.  

 
 
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Safety assessment includes physical examination with vital signs, ECGs, clinical safety 
laboratory assessment, periodontal examination and immunogenicity. Denosumab levels will 
be assessed by validated method. Serum CTX and Serum P1NP will be the pharmacodynamic 
biomarker for denosumab. 
Sampling Schedule for PK and PD evaluation 
Sample collection after first dose and prior to second dose: 
The venous blood samples will be withdrawn at pre-dose (0.000 hour) and at 4.000, 12.000 
(Day 1), 24.000 (Day 2), 48.000 (Day 3), 72.000 (Day 4), 96.000 (Day 5), 120.000 (Day 6), 
168.000 (Day 8), 216.000 (Day 10), 240.000 (Day 11), 264.000 (Day 12), 312.000 (Day 14), 
360.000 (Day 16), 408.000 (Day 18), 504.000 (Day 22), 624.000 (Day 27), 792.000 (Day 34), 
1008.000 (Day 43), 1344.000 (Day 57), 1680.000 (Day 71), 2016.000 (Day 85), 2352.000 (Day 
99), 2688.000 (Day 113), 3024.000 (Day 127), 3360.000 (Day 141), 3840.000 (Day 161), 
4320.000 (Day 181) hours post dose following first dose administration.  
Sample collection after second dose: The venous blood samples will be withdrawn at 
5040.000 (Day 211; Month 7), 5760.000 (Day 241; Month 8), 6480.000 (Day 271; Month 9), 
7200.000 (Day 301; Month 10), 7920.000 (Day 331; Month 11), and 8640.000 (Day 361; 
Month 12) hours post dose following first dose administration.  
Sample collection after third dose: The venous blood samples will be withdrawn at pre third 
dose, 24.000 (Day 2), 720.000 (Day 31), 1440.000 (Day 61), 2160.000 (Day 91), 2880.000 
(Day 121), 3600.000 (Day 151) and 4320.000 (Day 181) hours post dose following third dose 
administration.  
Sampling Schedule for Immunogenicity evaluation 
8.5 ml of blood will be withdrawn for estimation of Immunogenicity parameters at Pre-dose 
(baseline), at day 14, 31, 61, 91, 181*, 211, 241, 271 and 361 with respect to first dosing. 
8.5 ml of blood will be withdrawn for estimation of Immunogenicity parameters at Pre- third 
dose (baseline), at day 2, 31, 61, 91 and 181 with respect to third dosing.*Note: Blood sample 
for immunogenicity on day 181 will be collected prior to 2nd dose administration and day 361 
before 3rd dose administration respectively. 
Bioanalytical Procedure:   
The PK measurement, PD analysis and Immunogenicity assessment will be performed by using 
validated bioanalytical methods and according to the bioanalytical laboratory’s standard 
operating procedures and applicable regulatory requirements. 
Note: Samples for PD evaluation [CTX and P1NP] should be collected in the morning under 
fasting condition. 
Pharmacokinetic Parameters  
The following pharmacokinetic parameters will be computed for denosumab. 
• 
Primary PK Parameters: Cmax, AUC0-t and AUC0-∞ of denosumab after first-dose 
• 
Secondary PK Parameters: Tmax, AUC_%Extrap_obs, λz, Vd/F, Cl/F, and t1/2 of denosumab 
after first dose; Tmax, Cmax, AUC0-t, AUC0-∞, λz, and t1/2 of denosumab after second and 
individual patient’s PK parameters after third dose 

 
 
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Pharmacodynamic Parameters  
For Serum C-terminal telopeptide (CTX): 
• 
Primary PD Parameters: Emax and AUEC0-t after first dose (These will be primary 
parameters for EMA Submission only) 
• 
Secondary PD Parameters: Tmax after first dose; Tmax, Emax and AUEC0-t after second and 
individual patient’s PD parameters after third dose 
For Serum N-terminal propeptide of type 1 collagen (P1NP): 
• 
Secondary PD Parameters: Tmax, Emax and AUEC0-t after first, second and individual 
patient’s PD parameters after third dose 
Note: Pharmacodynamic effect for Serum C-terminal telopeptide (CTX) and Serum N-terminal 
propeptide of type 1 collagen (P1NP) will be assessed as decrease from the baseline. 
Populations for Analyses  
Analysis populations are defined as below.  
• Safety set: The safety set is defined as all randomized patients who will receive at least 
one dose of study medication. 
• Pharmacokinetic (PK) set: The PK set is defined as all patients who will complete the 
study and has no major protocol deviation which can significantly influence the 
pharmacokinetic parameter estimation. 
• Pharmacodynamic (PD) set: The PD set is defined as all patients who will complete the 
study and has no major protocol deviation which can significantly influence the 
pharmacodynamic parameter estimation. 
• Intent-To-Treat (ITT) set: The ITT set is defined as all randomized patients who will 
receive at least one dose of study medication. 
 
Sensitivity analysis will be performed on patients in ITT set for primary endpoint mean 
percentage change in bone mineral density (BMD) of lumbar spine from baseline to 12 
months. For this analysis, missing values of individual BMD of lumbar spine at 12 
months will be imputed with value as baseline value ± 0.73 (i.e. half of equivalence 
limit 1.45 considered in the study). Imputation will be done with value as (baseline value 
- 0.73) for test and (baseline value + 0.73) for reference product. Additionally, 
imputation will be done with value as (baseline value + 0.73) for test and (baseline value 
- 0.73) for reference product. 
• Modified Intent-To-Treat (mITT) set: The mITT set is defined as all randomized 
patients who will receive at least one dose of study medication and will undergo at least 
one post-dose efficacy evaluation. Missing data will be imputed using last observation 
carried forward (LOCF) and other techniques if requested by the regulatory agency. 
• Per-protocol (PP) set: The PP set is defined as all randomized patients who will 
complete the study with no major protocol deviations. 
Statistical Analysis 
Descriptive statistics will be reported for pharmacokinetic and pharmacodynamic parameters. 
Baseline and demographic characteristics will be summarized using descriptive statistics by 
treatment. Categorical variable will be summarized with frequency distribution. Continuous 
variables will be summarized with mean, standard deviation, median, minimum and maximum. 

 
 
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ANOVA, 90% confidence interval, power and ratio analysis will be computed for ln-
transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of denosumab after first 
dose.  
ANOVA, 90 & 95% confidence interval, power and ratio analysis will be computed for ln-
transformed pharmacodynamic parameters Emax and AUEC0-t of % reduction from baseline 
Serum C-terminal telopeptide (Serum CTX) and % reduction from baseline Serum N-terminal 
propeptide of type 1 collagen (P1NP) after first dose. 
Bioequivalence criteria (PK and PD) 
For USFDA: 
Based on the statistical results of 90% confidence interval for the ratio of the geometric least 
square means for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0- for 
denosumab after first dose, conclusion will be drawn for Test Product-T vs. Reference 
Product-R. 
Bioequivalence of the test product with that of the reference product will be concluded, if 
90% confidence interval falls within the acceptance range of 80.00-125.00% for ln-
transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0- of denosumab after first 
dose.  
For EMA: 
Based on the statistical results of 90% confidence interval for the ratio of the geometric least 
square means for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0- for 
denosumab after first dose and 95% confidence interval for the ratio of the geometric least 
square means for ln-transformed pharmacodynamic parameters Emax and AUEC0-t for % 
reduction from baseline Serum C-terminal telopeptide (Serum CTX) after first dose, 
conclusion will be drawn for Test Product-T vs. Reference Product-R. 
Bioequivalence of the test product with that of the reference product will be concluded, if 
90% confidence interval falls within the acceptance range of 80.00-125.00% for ln-
transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0- of denosumab after first 
dose and 95% confidence interval falls within the acceptance range of 80.00-125.00% for 
ln-transformed pharmacodynamic parameters Emax and AUEC0-t of % reduction from 
baseline Serum C-terminal telopeptide (Serum CTX) after first dose.  
Efficacy/ Pharmacodynamic Analysis 
The primary endpoint is mean percentage change in bone mineral density (BMD) of lumbar 
spine from baseline to 12 months. A point estimate and a two-sided 95% confidence interval 
will be computed for the treatment groups and their differences. 95% CI will be calculated using 
ANCOVA considering baseline as a covariate. Descriptive statistics for mean percentage 
change in BMD at lumber spine from baseline to 12 months will be calculated. Independent t-
test will be used to evaluate the between-treatment comparison. 
Acceptance criteria: Therapeutic equivalence of the test with the reference treatment will be 
concluded if the 95% CI of the difference between test and reference for mean percentage 
change in BMD at lumber spine from baseline to 12 months is within the range of ± 1.45. 

 
 
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Note: Therapeutic equivalence of the test with the reference treatment will be claimed on ITT 
set for USFDA and on PP set for EMA.  
Secondary endpoints of the study will be analyzed as below: 
Descriptive statistics for mean percentage change in BMD of lumber spine from baseline to 06 
months and mean percentage change in BMD of femoral neck and total hip from baseline to 06 
and 12 months will be calculated presented. Independent t-test will be used to evaluate the 
between treatment comparison. 
Mean percentage reduction in serum N-terminal propeptide of type 1 collagen (P1NP) and in 
serum CTX concentrations from baseline to 06 and 12 months will be calculated and reported.  
Fracture incidence rate will be provided and compared. Incidence of anti-denosumab antibody 
at respective visits will be presented. 
Safety data collected after 12 months will be presented in separate tables and listings.  
Ethical Issues 
The trial will be conducted in accordance with this protocol and will comply with all 
requirements regarding the obligations of investigators and all other pertinent requirements of 
the ICH E6 (R2) Guideline on Good Clinical Practice; New Drugs & Clinical Trial Rules, 2019 
of Central Drugs Standard Control Organization (CDSCO); Declaration of Helsinki (Fortaleza, 
2013); as per any other applicable regulatory requirements. 
1.2. 
Schema 
 
 
 
Figure 1. Study Schema 
 
 
 
 
 
 
Eligible patients
Randomization
N=552
Denosumab-ref
n=276
PK~148
Denosumab-test
n=276
PK~148
1st dose
2nd dose
Endpoints for evaluation at 
the end of 6 month
First dose PK and PD 
parameters
Endpoints for evaluation at 
the end of 12 month
BMD
Denosumab-ref
n~68
(Considering ~20% 
dropouts/withdrawal in initial 12 
months phase)
Denosumab-test
n~68
(Considering ~20% dropouts/withdrawal in 
initial 12 months phase)
3rd dose
Endpoints for evaluation at the end 
of transition-extention period
• Immunogenicity
• PK and PD parameters (if 
applicable)
• Safety

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1.3. 
Schedule of Activities (SoA)  
Table 1. Schedule of Activities 
Phase 
Screening 
Treatment Period 
Transition-extension period* 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
(EOS) 
16 
17 
18 
19 
20 
(ET) 
End of Month 
- 
- 
- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
- 
- 
- 
- 
- 
Days 
-21 to -1 
1 
14 
31 
61 
91 
121 
151 
181 
211 
241 
271 
301 
331 
361 
Any 
day 
within 
21 
days 
after 
EOS 
visit 
Day 
31 
after 
last 
visit  
Day 
61 
after 
last 
visit 
Day 
91 
after 
last 
visit 
Day 
181 
after 
last 
visit 
Window period for visit (± 
days) 
0 
0 
0 
1 
3 
3 
3 
3 
14 
3 
3 
3 
3 
3 
3 
5 
5 
5 
5 
5 
General / administrative 
Informed consent (ICF)a  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteriab 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past treatment history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Instruction for daily vitamin D 
and calcium supplementation 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory Tests 
Hepatitis B and C, HIV  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Biochemistry 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
X 
Urine analysis 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
X 
Serum PTH 1-84 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin-adjusted calcium 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum FSH (if required) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
25 (OH) Vitamin D 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
X 
Serum pregnancy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Full physical examination 
X 
======================Targeted physical examination driven by signs and symptoms====================→ 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
Page 24 of 107 
 
Phase 
Screening 
Treatment Period 
Transition-extension period* 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
(EOS) 
16 
17 
18 
19 
20 
(ET) 
End of Month 
- 
- 
- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
- 
- 
- 
- 
- 
Days 
-21 to -1 
1 
14 
31 
61 
91 
121 
151 
181 
211 
241 
271 
301 
331 
361 
Any 
day 
within 
21 
days 
after 
EOS 
visit 
Day 
31 
after 
last 
visit  
Day 
61 
after 
last 
visit 
Day 
91 
after 
last 
visit 
Day 
181 
after 
last 
visit 
Window period for visit (± 
days) 
0 
0 
0 
1 
3 
3 
3 
3 
14 
3 
3 
3 
3 
3 
3 
5 
5 
5 
5 
5 
Periodontal examinationf 
X 
======================== At (a) EOS visit and (b) when clinically required =========================→ 
Height (At V1) and Weight 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
12-lead ECG 
X 
================================== when clinically required ==================================→ 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Lifestyle restrictions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-rayh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study specific assessments for efficacy 
DXA for BMD (Lumbar spine, 
total hip, femoral neck)i 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Thoracic and Lumbar Spine X-
rayj 
X 
====================At (a) EOS visit (B) ET visit and (c) when clinically required ======================→ 
Immunogenicityk 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Clinical Pharmacology Assessments (PK & PD sampling) 
Blood sample collection for PK 
& PD assessmentl 
 
======================================================================================→ 
Study IMP Administration 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
 
 
IMP Administration 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X* 
 
 
 
 
Injection site assessmentm 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X* 
 
 
 
 
Ongoing Participant Review 
AE 
 
X 
==================================================================================→ 
SAE 
 
X 
==================================================================================→ 
Concomitant medication 
 
X 
==================================================================================→ 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
Page 25 of 107 
 
Phase 
Screening 
Treatment Period 
Transition-extension period* 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
(EOS) 
16 
17 
18 
19 
20 
(ET) 
End of Month 
- 
- 
- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
- 
- 
- 
- 
- 
Days 
-21 to -1 
1 
14 
31 
61 
91 
121 
151 
181 
211 
241 
271 
301 
331 
361 
Any 
day 
within 
21 
days 
after 
EOS 
visit 
Day 
31 
after 
last 
visit  
Day 
61 
after 
last 
visit 
Day 
91 
after 
last 
visit 
Day 
181 
after 
last 
visit 
Window period for visit (± 
days) 
0 
0 
0 
1 
3 
3 
3 
3 
14 
3 
3 
3 
3 
3 
3 
5 
5 
5 
5 
5 
Footnotes:  
EOS: End-of-Study Visit; ET: End of transition extension period visit. 1 month is 30 days. 
*Only applicable for the study participants who (a) will be randomized in reference arm AND (b) have completed PK assessments during 12-month treatment period. Separate 
consent will not be taken for entering in to transition extension period, consent for the transition extension period will be taken at screening visit only. 
 
a. 
Must be signed before first study-related activity. 
b. Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Source Documentation in Appendix 10.1.8, Regulatory, Ethical, 
and Study Oversight Considerations. 
c. 
Recheck eligibility criteria as applicable at baseline. 
d. Medical history includes substance usage, smoking status, alcohol consumption, past history of fracture, history of hip fracture in parents.  
e. 
Data for patients must be frozen before initiating the transition-extension period randomization so to ensure blinding for initial 12-month study is not affected. 
Considering that all data entry needs to be completed before randomization for transition-extension period, patient can be randomized in the transition-extension period 
for up to 21 days after completion of EOS visit of double-blind period of the initial 12 months study. 
f. 
Periodontal examination to rule out risk factors for ONJ at screening and as clinically required during study including switching period as applicable. 
g. Pre-dose vitals: Within 1 hour prior to each dosing in clinical facility  
h. Chest X-ray (PA view), if not done in last 3 months. 
i. 
DXA scan performed in the past will not be considered during screening for eligibility assessment. Bone mineral density will be measured using DXA scan will be 
performed exclusively for screening and eligibility criteria assessment at the lumbar spine, total hip during screening period. Screening DXA will be used as baseline 
DXA. 
j. 
Additional lateral spine X-rays may be taken in cases of a suspected clinical vertebral fracture. 
k. Immunogenicity sampling at Pre-dose (baseline), at day 14, 31, 61, 91, 181*, 211, 241, 271 and 361. For switching period, additional samples will be collected at Pre- 
third dose (baseline), at day 2, 31, 61, 91 and 181 with respect to third dosing. 
Note: Blood sample for immunogenicity on day 181 and 361 will be collected prior to 2nd & 3rd dose administration. 
l. 
Serum C-terminal telopeptide for type I collagen [CTX] and  Serum N-terminal propeptide of type 1 collagen [P1NP] for bone resorption and serum denosumab for PK 
in hours at pre-dose (0.000 hour) and at 4.000, 12.000 (Day 1), 24.000 (Day 2), 48.000 (Day 3), 72.000 (Day 4), 96.000 (Day 5), 120.000 (Day 6), 168.000 (Day 8), 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
 
Confidential and Proprietary 
 
Page 26 of 107 
 
Phase 
Screening 
Treatment Period 
Transition-extension period* 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
(EOS) 
16 
17 
18 
19 
20 
(ET) 
End of Month 
- 
- 
- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
- 
- 
- 
- 
- 
Days 
-21 to -1 
1 
14 
31 
61 
91 
121 
151 
181 
211 
241 
271 
301 
331 
361 
Any 
day 
within 
21 
days 
after 
EOS 
visit 
Day 
31 
after 
last 
visit  
Day 
61 
after 
last 
visit 
Day 
91 
after 
last 
visit 
Day 
181 
after 
last 
visit 
Window period for visit (± 
days) 
0 
0 
0 
1 
3 
3 
3 
3 
14 
3 
3 
3 
3 
3 
3 
5 
5 
5 
5 
5 
216.000 (Day 10), 240.0000 (Day 11), 264.000 (Day 12), 312.000 (Day 14), 360.000 (Day 16), 408.000 (Day 18), 504.000 (Day 22), 624.000 (Day 27), 792.000 (Day 
34), 1008.000 (Day 43), 1344.000 (Day 57), 1680.000 (Day 71), 2016.000 (Day 85), 2352.000 (Day 99), 2688.000 (Day 113), 3024.000 (Day 127), 3360.000 (Day 141), 
3840.000 (Day 161), 4320.000 (Day 181) (before the second dose), and at 5040.000 (Day 211; Month 7), 5760.000 (Day 241; Month 8), 6480.000 (Day 271; Month 9), 
7200.000 (Day 301; Month 10), 7920.000 (Day 331; Month 11), and 8640.000 (Day 361; Month 12) hours after the first dose. The venous blood samples will be 
withdrawn at pre third dose, 24.000 (Day 2), 720.000 (Day 31), 1440.000 (Day 61), 2160.000 (Day 91), 2880.000 (Day 121), 3600.000 (Day 151) and 4320.000 (Day 
181) hours post dose following third dose administration. Post dose samples during the whole study will be collected on ambulatory basis. Only through PK sample will 
be collected along with immunogenicity sample. 
Note: Samples for PD evaluation [CTX and P1NP] should be collected in morning under fasting condition. 
m. Injection site assessment will be performed after every injection at 30 minutes (± 5 min) post dose. 
 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 27 of 107 
 
2. 
Introduction  
Denosumab of Intas is biosimilar denosumab candidate under development by Intas 
Pharmaceutical Limited (Biopharma Division). Denosumab of Intas is already approved by 
Indian drug licensing authority- Drug Controller General (India) for marketing in Indian 
population since 2018. 
2.1. 
Background 
Osteoporosis is characterized by low bone mass, microarchitectural disruption, and skeletal 
fragility, resulting in decreased bone strength and an increased risk of fracture. Decreased bone 
strength is related to many factors other than bone mineral density (BMD), including rates of 
bone formation and resorption (turnover), bone geometry (size and shape of bone), and 
microarchitecture. The World Health Organization (WHO) has defined diagnostic thresholds 
for low bone mass and osteoporosis based upon BMD measurements compared with a young 
adult reference population (T-score). 
The common therapeutic approach is to decrease bone loss with the use of antiresorptive agents 
such as estrogens, selective estrogen receptor modulators (SERMs) and bisphosphonates, 
anabolic agents like PTH (analogues)- teriparatide, abaloparatide; sclerostin inhibitor-
romosozumab; RANKL inhibitor- denosumab.  
Denosumab binds to RANKL, a transmembrane or soluble protein essential for the formation, 
function, and survival of osteoclasts, the cells responsible for bone resorption. Prolia prevents 
RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. 
Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and 
survival, thereby decreasing bone resorption and increasing bone mass and strength in both 
cortical and trabecular bone. 
For detailed information regarding denosumab of Intas, refer to the Investigator’s Brochure (IB) 
of denosumab of Intas. For detailed information regarding Prolia®, refer to the latest prescribing 
information / summary of product characteristics of Prolia. 
2.2. 
Study Rationale  
As per regulatory requirement, a comparative clinical study to establish Pharmacokinetic, 
Pharmacodynamic and Immunogenicity equivalence is required to conclude therapeutic 
equivalence to obtain marketing authorization of a biosimilar investigational product. This is a 
multicenter, randomized, double-blind, active-controlled study in approximately 552 
postmenopausal women with osteoporosis. FDA specifically requested for assessment of 
immunogenicity after switching from denosumab-ref. Hence the subset of patients who were 
included for PK, on denosumab-ref, will be shifted to denosumab-ref or denosumab, and then 
assessed for immunogenicity.  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of denosumab [denosumab and denosumab-ref] may be found in the 
Investigator’s Brochure for denosumab and Summary of Product Characteristics for 
denosumab-ref. Taking into account the measures taken to minimize risk to participants of this 
study, the potential risks identified in association with denosumab and denosumab-ref are 
justified by the anticipated benefits that may be afforded to participants with postmenopausal 
osteoporosis. 
 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
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Confidential and Proprietary 
 
Page 28 of 107 
 
3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
To compare the pharmacokinetic parameters 
of 
denosumab 
and 
denosumab-ref 
in 
postmenopausal women with osteoporosis. 
• Pharmacokinetics: Cmax, AUC0-t, and 
AUC0-∞ after first dose of denosumab and 
denosumab-ref 
To compare the pharmacodynamic effect of 
treatment with denosumab and denosumab-
ref on bone mineral density (BMD) and bone 
resorption marker in postmenopausal women 
with osteoporosis* 
• Mean percentage change in BMD at 
lumbar spine from baseline to 12 months 
between denosumab and denosumab-ref 
• Pharmacodynamics: Emax and AUEC0-t of 
% reduction from baseline serum C-
terminal telopeptide (CTX) after first dose 
of denosumab and denosumab-ref* 
*To be considered as secondary endpoint for 
USFDA submission. 
Secondary 
To compare the efficacy of treatment with 
denosumab and denosumab-ref in 
postmenopausal women with osteoporosis 
• Incidence of clinical fracture between 
denosumab and denosumab-ref over 12 
months. 
To compare the pharmacodynamic effects of 
the 
treatment 
with 
denosumab 
and 
denosumab-ref in postmenopausal women 
with osteoporosis 
• Mean percentage change in bone mineral 
density (BMD) of lumbar spine from 
baseline 
to 
06 
months 
between 
denosumab-test and denosumab-ref 
• Mean percentage change in BMD of 
femoral neck and total hip from baseline 
to 06 and 12 months between denosumab 
and denosumab-ref 
• Pharmacodynamics: Tmax of % reduction 
from 
baseline 
serum 
C-terminal 
telopeptide (CTX) after first dose of 
denosumab and denosumab-ref 
• Pharmacodynamics: Emax, AUEC0-t,Tmax 
of % reduction from baseline serum N-
terminal propeptide of type 1 collagen 
(P1NP) after first dose of denosumab and 
denosumab-ref 
• Mean percentage reduction in serum N-
terminal propeptide of type 1 collagen 
(P1NP) concentrations from baseline to 
06 and 12 months between denosumab 
and denosumab-ref 
• Mean percentage reduction in CTX 
serum concentrations from baseline to 06 
and 12 months between denosumab and 
denosumab-ref 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 29 of 107 
 
To 
compare 
the 
immunogenicity 
of 
denosumab 
and 
denosumab-ref 
in 
postmenopausal women with osteoporosis 
• Incidence of anti-denosumab antibody in 
denosumab and denosumab-ref arm over 
12 months.  
To compare the safety of treatment with 
denosumab 
and 
denosumab-ref 
in 
postmenopausal women with osteoporosis 
• Monitoring of adverse events and lab 
parameters 
in 
denosumab 
and 
denosumab-ref arm 
To evaluate the safety and immunogenicity 
of denosumab and denosumab-ref after 
single transition from denosumab-ref to 
denosumab 
and 
denosumab-ref 
in 
postmenopausal women with osteoporosis* 
*To be considered as secondary endpoint for 
USFDA submission. 
• Incidence of anti-denosumab antibody in 
denosumab and denosumab-ref arms 
after single transition from denosumab-
ref  
• Assesment for difference in PK or PD in 
patients 
who 
are 
found 
to 
be 
immunogenic 
• Monitoring of adverse events and lab 
parameters 
in 
denosumab 
and 
denosumab-ref arm arms after single 
transition from denosumab-ref 
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints. 
3.1. 
Hypothesis  
The primary clinical hypothesis is that in postmenopausal women with osteoporosis, the 
primary pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ after first dose of denosumab 
will be equivalent to denosumab-ref. Likewise, the primary pharmacodynamics parameter 
(Only for EMA) Emax and AUEC0-t of % reduction from baseline serum CTX after first dose of 
denosumab will be equivalent to that of those receiving denosumab-ref. It is further 
hypothesized that mean percentage change in BMD of lumbar spine from baseline to 12 months 
in participants receiving denosumab will be equivalent to that of those receiving denosumab-
ref. The safety hypothesis is that the safety profile of denosumab will be similar to denosumab-
ref in women with osteoporosis. 
 
 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 30 of 107 
 
4. 
Study Design  
4.1. 
Overall Design 
This is a randomized, double-blind, active-controlled, parallel-arm, multicenter study 
comparing the pharmacokinetics, pharmacodynamics, safety, immunogenicity, and clinical 
efficacy of denosumab of Intas (60 mg/ml) with Prolia in postmenopausal women with 
osteoporosis between the ages of 55 to 90 years. 
Approximately 552 participants will be randomized in a 1:1 ratio to receive denosumab or 
denosumab-ref, in a blinded fashion for the duration of the 12-month treatment period. All 
randomized patients will be undergoing efficacy (BMD and fracture incidence), safety and 
immunogenicity assessment at specified sampling schedule according to Section 8.  
All 552 patients (276 patients per arm) will be evaluated for BMD and immunogenicity 
assessment for initial 1-year treatment. 
Approximately 296 patients (148 patients per arm) per arm will be enrolled for the PK 
assessment and PD biomarker (CTX) assessment for initial 1-year treatment. 
136 patients (68 patients per arm) will be included in the immunogenicity assessment for 
extension 6-month phase of the study. 
For the transition-extension period (Single switch from denosumab-ref arm): 
This randomized, double-blind, transition-extension period is to investigate the safety, 
tolerability, immunogenicity, and efficacy (BMD and fracture incidence) of denosumab in 
participants with postmenopausal osteoporosis who transitioned from the denosumab-ref arm, 
compared with subjects who continue with denosumab-ref treatment after completion of 
double-blind period of the initial 12 months study. After completion of 12 months of treatment 
period, only participants who are (a) randomized in reference arm AND (b) have undergone PK 
assessments during double-blind period of the initial 12 months study will be re-randomized 
for transition-extension period. Data for patients must be frozen before initiating the transition-
extension period randomization so to ensure blinding for initial 12-month study is not affected. 
Considering that all data entry needs to be completed before randomization for transition-
extension period, patient can be randomized in the transition-extension period for up to 21 days 
after completion of EOS visit of double-blind period of the initial 12 months study. 
At Month 12, participant meeting criteria described above from the randomized, double-blind 
period of the initial 12 month study will be randomized again in a 1:1 ratio to either continue 
on denosumab-ref or be transitioned/switched to denosumab for additional 6 months (single 
dose of denosumab). Study participants will receive single-dose of denosumab 60 mg of either 
denosumab or denosumab-ref at Month-12. Subject safety and immunogenicity will be assessed 
in all subjects at Month 15 and 18; BMD will be assessed at Month 18. Assumption is 
approximately 120 patients in denosumab-ref arm who would have undergone PK assessments 
will be completing double-blind period of the initial 12 months study and will be randomized 
in the transition-extension period (~68 in denosumab-ref and ~68 in denosumab). The PK, PD 
samples collected in these patients will be assessed for impact of immunogenicity on PK and 
PD only if there is immunogenicity identified in a particular patient either clinically or by 
immunogenicity bioanalysis. 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 31 of 107 
 
Study participants who withdraw from the transition-extension period will be asked to return to 
the site for the ET Visit procedures to be performed. At the ET visit, participants will undergo 
all procedures they would have undergone at Month 18.  
A diagram of the study design is provided in Section 1.2, Schema. 
4.2. 
Scientific Rationale for Study Design 
4.2.1. 
Trial Design 
As per regulatory requirement, a comparative clinical study to establish Pharmacokinetic, 
Pharmacodynamic and Immunogenicity equivalence is required to conclude therapeutic 
equivalence to obtain marketing authorization of a biosimilar investigational product. This is a 
multicenter, randomized, double-blind, active-controlled study in approximately 552 
postmenopausal women with osteoporosis. The primary objective of study designed to prove 
the pharmacokinetics and pharmacodynamics equivalence of denosumab with denosumab-ref 
after the first dose. In addition, the study will assess the effect of treatment with denosumab 
compared with denosumab-ref on BMD of lumbar spine from baseline to 06 and 12 months.  
From screening to end of study (EOS visit) and during transition-extension period, study 
participants will be supplied with supplementary products containing at least 1000 mg calcium 
and at least 400 IU vitamin D (in containers with required number of tablets to suffice until next 
visit, including additional tablets for the window period) throughout the study at defined 
intervals. 
4.2.2. 
Selection of Endpoints 
Primary endpoints are Mean percentage change in bone mineral density (BMD) at lumbar spine 
from baseline to 12 months, pharmacokinetics (Cmax, AUC0-t, and AUC0-∞ of denosumab) and 
pharmacodynamics (AUEC0-t of % reduction from baseline serum CTX) after first dose of IMP. 
According to USFDA[1] and EMA guidelines[2] for biosimilars these endpoints are justified to 
compare and assess efficacy, PK and PD profile of denosumab. 
The co-primary endpoints mean percentage change in bone mineral density (BMD) of lumbar 
spine from baseline to 12 months which is also in line with the guideline on the evaluation of 
new medicinal products in the treatment of primary osteoporosis[3]. 
Incidence of anti-denosumab antibody in denosumab and denosumab-Ref arms at day 14, 31, 
61, 91, 181*, 211, 241, 271 and 361 in line with EMA guidelines and for switching period, 
additional samples will be collected at ), at day 2, 31, 61, 91 and 181 after third dosing is also 
in line with USFDA guidelines for biosimilars to compare the immunogenicity. 
4.2.3. 
Blinding, Control, Study Phase/Periods, IMP Groups 
An active control is used to determine the sensitivity of the pharmacodynamic, pharmacokinetic 
and surrogate endpoints in this study. Randomization will be used to minimize bias in the 
assignment of participants to IMP groups, to increase the likelihood that known and unknown 
participant attributes (e.g., demographic and baseline characteristics) are evenly balanced 
across IMP groups, and to enhance the validity of statistical comparisons across IMP groups. 
Blinded IMP will be used to reduce potential bias during data collection and evaluation of 
pharmacodynamic, pharmacokinetic and surrogate endpoints. 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
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Detailed information of blinded and unblinded study person have been mentioned in section 
6.3. 
4.2.4. 
Selection of the Trial Population 
At menopause, estrogen deficiency impairs the normal cycle by increasing osteoclastic 
resorption activity without a corresponding increase in osteoblastic activity and the amount of 
bone resorbed therefore is greater than the amount deposited leading to a net loss of bone. Study 
population chosen to be included in the current study will be in line with previous studies and 
approved indication of Prolia[4,5] as well as in general representative of population in real-world 
use in whom denosumab is prescribed by physician. Prolia® is indicated for the treatment of 
postmenopausal women with osteoporosis at high risk for fracture, defined as a history of 
osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are 
intolerant to other available osteoporosis therapy[5].  
The guidelines for prevention and treatment of osteoporosis in general indicate age, sex, low 
body mass index, previous fragility fracture, low BMD, parental history of hip fracture, 
glucocorticoid treatment, current smoking, alcohol intake of 3 or more units daily, and causes 
of secondary osteoporosis as major risk factors for osteoporotic fracture.[6]  
American Association of Clinical Endocrinologists/ American College of Endocrinology 
clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis— 
2020 update[7], defines patient with osteoporosis as “T-score of −2.5 or lower in the lumbar 
spine (antero-posterior), femoral neck, total hip, or 1/3 radius (33% radius), even in the 
absence of a prevalent fracture”. It also further defines patients with osteoporosis at high risk 
of fracture as following: “R23:Consider patients with a recent fracture (e.g., within the past 12 
months), fractures while on approved osteoporosis therapy, multiple fractures, fractures while 
on drugs causing skeletal harm (e.g., long-term glucocorticoids), very low T-score (e.g., less 
than −3.0), high risk for falls or history of injurious falls, and very high fracture probability by 
FRAX® (fracture risk assessment tool) (e.g., major osteoporosis fracture >30%, hip fracture 
>4.5%) or other validated fracture risk algorithm to be at very high fracture risk. Consider 
patients who have been diagnosed with osteoporosis but are not at very high fracture risk, as 
defined above, to be high risk.” Regarding need of pharmacotherapy it further states 
“Pharmacologic therapy is strongly recommended for patients with a T-score of −2.5 or lower 
in the spine, femoral neck, total hip, or 1/3 radius.” 
In registration study of denosumab for treatment of osteoporosis- FREEDOM trial, 
postmenopausal female aged 60-90 years with BMD T Score of at least -2.5 but not lower than 
-4.0 were included. Radiologic evidence of baseline vertebral fracture was not required (CDTL 
review of BLA 125,320/125,331 denosumab page no.16).[8] 
Considering above criteria, population planned for enrollment in our study represents high risk 
of osteoporosis (postmenopausal women, BMD T score of -2.5 to -4.0, aged 55-90 years with 
exclusion of patient with either 1 severe or 2 moderate vertebral fracture) and it is in line with 
innovator registration trial as well as current practice guidelines. 
4.2.5. 
Choice of Control Group 
Prolia is an approved biologic in the USA and EU for treatment of osteoporosis in 
postmenopausal women. denosumab is being developed as a biosimilar to Prolia.  

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 33 of 107 
 
4.2.6. 
Study-Specific Ethical Design Considerations 
Thorough scientific evaluation of any promising IMP before market authorization is an ethical 
requirement. In the continuing search for medications with improved efficacy and safety 
profiles, it is necessary to fully investigate and understand new products before public exposure. 
Potential participants will be fully informed of the risks and requirements of the study and, 
during the study, participants will be given any new information that may affect their decision 
to continue participation. They will be told that their consent to participate in the study is 
voluntary and may be withdrawn at any time with no reason given and without penalty or loss 
of benefits to which they would otherwise be entitled. Only participants who are fully able to 
understand the risks, benefits, and potential adverse events of the study, and provide their 
consent voluntarily will be enrolled. 
As with all clinical and PK studies, there are risks associated with venipuncture and multiple 
blood sample collection. To avoid multiple venipunctures, which cause additional discomfort 
and other potentially toxic effects, the use of intravenous indwelling catheters is permitted in 
this study. The blood sample collection scheme was designed to collect the minimum number 
of blood samples that accurately and completely describe the PK, PD and immunogenicity of 
the study IMP. This minimizes the number of venipunctures and the total volume of blood 
collected from each participant during the study. This is an acceptable amount of blood within 
physiological limits and to be collected over this time period from the population in this study 
based upon the standard of the ICMR guidelines.[9] 
4.2.7. 
Concomitant Medication  
The doses and overall treatment regimens for two of the concomitant medications used as 
non-investigational medicinal products during this trial, i.e. calcium and vitamin D products, 
are according to the recommendations in the respective products’ labelling for the indication of 
reference drug as well as in line with clinical practice guidelines. 
4.3. 
Justification for Dose 
Participants randomised in the study will be dosed according to the approved labelling of 
reference drug, Prolia. The recommended dose of Prolia is 60 mg administered as a 
subcutaneous injection once every 6 months into the thigh, abdomen or upper arm. During this 
study, total 2 doses of 60 mg/mL subcutaneous injections of denosumab will be administered. 
4.4. 
End of Study Definition 
Study Completion Definition 
A participant is considered to have completed the study if she has completed all assessment of 
the study at 12 months or 18 months as applicable. 
End of Study Definition 
The end of study is considered as the date of the last scheduled study assessment shown in the 
Schedule of Activities or for the last participant in the study globally. The final data from the 
study site will be sent to the sponsor (or designee) after completion of the final participant 
assessment at that study site, in the time frame specified in the Clinical Trial Agreement. 

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5. 
Study Population  
Screening for eligible participants will be performed within 21 days before administration of 
the study IMP. Refer to Section 5.4 for conditions under which the repeat of any screening 
procedures are allowed. 
The investigator agrees to complete a participant identification and enrollment log to permit 
easy identification of each participant during and after the study.  
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. These documents can be made available for review in 
redacted electronic forms. All reports and communications relating to the study will identify 
participants by participant identification and age at initial informed consent. In cases where the 
participant is not randomized into the study, the date seen and age at initial informed consent 
will be used. 
The inclusion and exclusion criteria for enrolling participants in this study are described below. 
If there is a question about these criteria, the investigator must consult with the medical monitor 
and resolve any issues before enrolling a participant in the study. Waivers are not allowed to be 
used. The Investigator will be authorized to randomize/enroll the participants upon review and 
approval of eligibility criteria by the study Medical Monitor. 
For a discussion of the statistical considerations of participant selection, refer to Section 9.1. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria are met: 
1. Participant must sign an ICF to participate in the study indicating that she understands 
the purpose of, and procedures required for the study as described in this protocol and 
is willing to and will be able to adhere to requirement of the protocol.  
2. Participant must be 55 to 90 years of age (both inclusive), at the time of signing the 
informed consent. 
3. Participants who are medically/clinically stable on the basis of physical examination, 
medical history, vital signs, chest x-ray PA view, 12-lead ECG and clinical laboratory 
parameters performed at screening. Any abnormalities or deviation from normal, must 
be consistent with the underlying illness in the study population and judged by 
investigator to be not clinically significant. This determination must be recorded in the 
participant's source documents and initialed by the investigator. 
4. Participants whose absolute bone mineral density T-score is ≤ -2.5 and ≥ -4.0 at the 
lumbar spine as measured by DXA (dual-energy x-ray absorptiometry), confirmed by 
the independent central imaging team  
5. At least two vertebrae in the L1-L4 region and at least one hip joint are evaluable by 
DXA, confirmed by the independent central imaging team 
6. Body weight between 50 kg and 90 kg (both inclusive) at screening. 
7. Postmenopausal ambulatory female and not considered to be of child-bearing potential 
if: 
a. Women are considered post-menopausal and not of child-bearing potential if,  

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i. They have had 12 months of natural (spontaneous) amenorrhea (no 
vaginal bleeding or spotting) with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) OR  
ii. Six months of spontaneous amenorrhea with serum FSH levels >40 
mIU/mL; OR  
iii. Have had surgical bilateral oophorectomy (with or without 
hysterectomy) at least six months ago. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment if she is considered 
not of child-bearing potential.  
5.2. 
Exclusion Criteria  
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study: 
1. Documented medical history of clinically significant cardiac, vascular, pulmonary, 
gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or 
metabolic disturbances 
2. Documented medical history of known allergies, hypersensitivity, or intolerance to   
denosumab or its excipients (refer to the IB) 
3. History of any prior use of denosumab 
4. Documented medical history of metabolic or bone disease (except osteoporosis) that 
may interfere with the interpretation of the results, such as Paget’s disease, 
osteomalacia, osteogenesis imperfecta, osteopetrosis, rheumatoid arthritis, ankylosing 
spondylitis or any other joint disease limiting mobility, Cushing’s disease, 
hyperprolactinemia, malabsorption syndrome  
5. Documented medical history of latex or dry natural rubber allergy 
6. Contraindications to the use of denosumab or Vitamin D and Calcium as per IB/local 
prescribing information at screening and/or baseline 
7. Documented medical history and/or current evidence of any of the following oral/dental 
conditions 
a) Prior history or current evidence of osteomyelitis or osteonecrosis of the jaw. 
b) Active dental or jaw condition which requires oral surgery. 
c) Planned invasive dental procedure expected during study period. 
d) Current evidence non-healed dental or oral surgery. 
e) Current evidence of poor oral hygiene 
f) Ill-fitting denture 
8. Current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium outside the 
normal range at screening. Serum calcium levels may be retested once in case of an 
elevated/low serum calcium level as assessed by the clinical laboratory. Final decision 
to include the patient based on the risk of hypocalcemia to be taken by the Investigator. 
9. History of frequent occurrence of hypocalcemia, history of severe hypocalcemia or 
presence of diseases that can precipitate hypocalcemia frequently (like malabsorption 
syndromes (for example celiac disease, history of excision of small intestine etc.) and 
severe renal impairment) 
10. Current, uncontrolled hyper- or hypoparathyroidism and history of hypoparathyroidism, 
per participant report or chart review. PTH outside the normal range (15-65 pg/mL) as 
assessed by central laboratory  
11. Current, uncontrolled hyper- or hypothyroidism, defined as thyroid stimulating 
hormone outside of the normal range (TSH-0.465 to 4.68 mIU/L) at screening.  

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12. 25 (OH) Vitamin D lower than 20 ng/mL as assessed by the central laboratory at 
Screening. Vitamin D repletion will be permitted, and participants may be rescreened 
once. 
13. History of external beam or implant radiation therapy involving the skeleton. 
14. History and /or presence of 1 severe fracture or 2 moderate vertebral fractures 
15. Patients with bone metastases or a history of malignancies affecting bones. 
16. Smokers or who have smoked within last 06 months prior to start of the study. 
17. Documented medical history of major surgery, (e.g. requiring general anesthesia) within 
12 weeks before screening, or will not have fully recovered from surgery, or has surgery 
planned during the time the participant is expected to participate in the study.  
Note: Participants with planned surgical procedures to be conducted under local 
anesthesia may participate. 
18. Documented medical history of hepatitis B surface antigen (HBsAg) or hepatitis C 
antibody (anti-HCV) positive, or other clinically active liver disease, or tests positive 
for HBsAg or anti-HCV at Screening. 
19. Documented medical history of human immunodeficiency virus (HIV) antibody 
positive, or tests positive for HIV at Screening. 
20. Documented medical history of drug or alcohol abuse according to Diagnostic and 
Statistical Manual of Mental Disorders (5th edition) (DSM-V) criteria within 1 year 
before Screening 
21. Lymphoma, leukemia, or any malignancy (current or suspected) within the past 5 years 
except for basal cell or squamous epithelial carcinomas of the skin that have been 
resected with no evidence of metastatic disease for 3 years; carcinoma in situ of the 
cervix; or malignancy, which is considered cured with minimal risk of recurrence 
22. QTc interval >470 msec or QT interval >480 msec in participants with bundle branch 
block.  
Note: The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB). It is either machine-read or manually over-read.  
23. Administration of bisphosphonate as follows: - 
c) IV Bisphosphonate in the past 3 years  
d) Oral bisphosphonates treatment for osteoporosis  
i. 
More than 3 years of cumulative use  
ii. 
Any dose received within 6 months prior to randomization 
iii. 
More than 1 month of cumulative use between 6 and 12 months prior to 
randomization 
24. Teriparatide or any PTH analogs treatment received within 12 months prior to 
randomization. 
25. Systemic oral or transdermal estrogen, SERMs, or calcitonin treatment of more than 1 
month of cumulative use within 6 months prior to randomization. 
26. Androgen deprivation or hormonal ablation therapy of more than 1 month of cumulative 
use within 6 months prior to randomization. 
27. Tibolone or cinacalcet treatment received within 3 months prior to randomization 
28. Systemic glucocorticoids: ≥ 5 mg prednisone equivalent per day for more than 10 days 
within 3 months prior to randomization. 
29. Abnormal laboratory values 
a. General: Any laboratory abnormality which, in the opinion of the Investigator, 
will prevent the patient from completing the study or interfere with the 
interpretation of the study results. 
b. Liver transaminases: 

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i. 
Serum aspartate aminotransferase (AST) ≥3.0 × upper limit of normal 
(ULN) 
ii. 
Serum alanine aminotransferase (ALT) ≥3.0 × ULN 
c. Alkaline phosphatase and bilirubin ≥1.5 × ULN 
d. Creatinine clearance estimated using Cockcroft Gault formula is <30 mL/min 
30. Taken any prohibited therapies as noted in Section 6.8, Concomitant Therapy before the 
planned first dose of study IMP 
31. Received any investigational IMP 30 days or 5 half-lives (whichever is longer) before 
the signing the consent or is currently enrolled in an investigational study 
32. Unstable liver or biliary disease per investigator assessment defined by the presence of 
ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric 
varices, persistent jaundice, or cirrhosis. This includes but is not limited to hepatitis 
virus infections, drug- or alcohol-related liver disease, non-alcoholic steatohepatitis, 
autoimmune hepatitis, hemochromatosis, Wilson’s disease, α-1 antitrypsin deficiency, 
primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease 
considered clinically significant by the investigator.  
Note: Stable chronic liver disease (including Gilbert’s syndrome, asymptomatic 
gallstones) is acceptable if the participant otherwise meets entry criteria. 
33. Any other clinical/social/ psychiatric condition for which, in the opinion of the 
investigator, participation would not be in the best interest of the participant (eg, 
compromise the well-being) or that could prevent, limit, or confound the protocol-
specified assessments 
34. Employee of the investigator or study site, with direct involvement in the proposed study 
or other studies under the direction of that investigator or study site 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a participant's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study IMP is given such 
that he or she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. 
5.3. 
Lifestyle Considerations  
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study to be eligible for participation: 
• 
Refer to Section 6.8 for details regarding prohibited and restricted therapy during the 
study. 
5.3.1. 
Alcohol and Tobacco 
• 
Alcohol-containing products are not permitted throughout the study period. 
• 
Use of tobacco products/smoking will not be allowed from 6 months before screening 
until after EOS. Participants will be instructed to abstain from the same. 
These details will be captured based on patient history. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study IMP/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 

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includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Retesting 
At the Screening Visit, the results of the required laboratory tests must be within the limits 
specified in the inclusion criteria. Exceptional and limited retesting of abnormal screening 
values that lead to exclusion are allowed only once using an unscheduled visit during the 
screening period (to reassess eligibility). The investigator may consider the participant eligible 
if the previously abnormal laboratory test result is within acceptable range as per 
inclusion/exclusion criteria, on a repeat testing. Informed consent obtained at the beginning of 
the screening period also covers the partial rescreening for allowed parameters; therefore, 
reconsenting is not required. 
If the results of clinical laboratory tests are outside the normal reference ranges, the participant 
may be included only if the Investigator judges the abnormalities or deviations from normal to 
be not clinically significant or to be appropriate and reasonable for the population under study. 
This determination must be recorded in the participant's source documents and initialed by the 
Investigator. 
Rescreening 
If a participant does not meet all inclusion and exclusion criteria (is a screen failure) but at some 
point in the future is expected to meet the participant eligibility criteria (in the opinion of the 
investigator the reason for the initial screen failure has been resolved or is not applicable 
anymore), the participant may be rescreened once only. Another 21-day rescreening period will 
start from date that new ICF is signed. Participants who are rescreened will be assigned a new 
participant number. During full rescreening, all screening procedures have to be performed as 
defined in SoA. Participants who fail to meet the serum 25 (OH) Vitamin D criterion during the 
full rescreening may still enter the retesting.  

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6. 
Study IMP and Concomitant Therapy  
Study IMP is defined as any investigational IMP(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant according to the study protocol. 
6.1. 
Study IMP Administered  
The study IMP denosumab, 60 mg, will be provided as pre-filled syringe for subcutaneous 
injection. Participants will be injected with study IMP at site as defined in SoA. 
Table 2. IMP details 
ARM Name 
denosumab 
denosumab-ref 
Study IMP Name 
Denosumab 
Prolia®  
Manufacturer 
Intas Pharmaceuticals Ltd., 
India 
Amgen Europe B.V. (EU-
licensed product) 
Dose Formulation 
Solution for injection in single-
use prefilled syringe  
Solution for injection in single-
use prefilled syringe  
Unit Dose 
Strength(s) 
60 mg/mL 
60 mg/mL 
Dosage Level(s) 
60 mg once every 6 months 
60 mg once every 6 months 
Route of 
Administration 
Subcutaneous injection 
Subcutaneous injection 
Use 
Experimental drug 
Active comparator 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Study IMP administration must be captured in the source documents and the case report form 
(CRF).  
denosumab will be manufactured and provided under the responsibility of the sponsor. Refer to 
the IB for a list of excipients. 
Other Protocol-Required Therapies 
All other protocol-required drugs (ie, vitamin D and calcium supplements) that are 
commercially available will be provided by the Sponsor. The investigator will be responsible 
for obtaining supplies of these drugs. 
From screening to end of study, participants will receive daily calcium and vitamin D 
supplementation that at a minimum should be in the range of at least 1000 mg calcium and at 
least 400 IU vitamin D. In addition, participants with a serum 25 (OH) Vitamin D level of < 20 
ng/mL at screening will be repeated and retested during screening.  
Where available, vitamin D3 preparations should be used; if vitamin D3 is not available, use of 
vitamin D2 preparations is acceptable. 

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If a participant develops hypercalcemia over the course of the study, the principal investigator 
may use his/her medical judgment and reduce the calcium and/or vitamin D supplementation 
to maintain serum calcium concentration within the normal range. If a participant develops 
hypocalcemia over the course of the study, appropriate additional supplementation should be 
instituted as deemed acceptable by local guidelines, to maintain serum calcium concentration 
within the normal range. If a participant is unable to tolerate the daily calcium or vitamin D 
supplementation, the formulation may be changed, or the dose lowered. The intolerance as well 
as the resolution (i.e., change in formulation or dosage) should be documented in the source 
documents.  
6.2. 
Preparation/Handling/Storage/Accountability 
6.2.1. 
Investigational Medicinal Product Receipt and Storage 
The Sponsor shall supply adequate units of investigational products for dose administration 
purpose. The received investigational products at CRO pharmacy will be verified for the sealed 
condition of packs and adequacy of label as per applicable regulatory and other requirements.  
Enough quantities of labels will be provided along with the IMP shipment for affixing on the 
IMP. The labels will be designed to capture all the relevant information as required by the 
regulatory agency/study. 
CRO pharmacy custodian or designated study personnel will ship sufficient quantity of IMP 
for conduct of the study to respective sites. The shipment of inventory log will be maintained 
at CRO site. 
Preparation/Handling/Storage 
All study IMP must be stored at controlled temperatures ranging from 2°C to 8°C (36°F to 46°F). 
Prior to administration, study IMP may be allowed to reach room temperature (up to 25°C/77°F) 
in the original packaging. Once removed from the refrigerator, study IMP must not be exposed 
to temperatures above 25°C/77°F. It should not be frozen or exposed to direct light. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study IMP received and any discrepancies are reported and 
resolved before use of the study IMP. 
Refer to the most recent version of IMP manual for additional guidance on study IMP preparation, 
handling, and storage. 
Accountability 
The investigator is responsible for ensuring that all study IMP received at the site is inventoried 
and accounted for throughout the study. The study IMP administered to the participant must be 
documented on the IMP accountability form. All study IMP will be stored and disposed of 
according to the Sponsor's instructions. Study-site personnel must not combine contents of the 
study IMP containers. 
Only participants enrolled in the study may receive study IMP and only authorized site staff 
will administer study IMP. All study IMP must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  

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Potentially hazardous materials containing hazardous liquids such as used PFS should be 
disposed of immediately in a safe manner and therefore will not be retained for IMP 
accountability purposes.  
Study IMP will not be relabeled or reassigned for use by other participants. The investigator 
agrees neither to dispense the study IMP from, nor store it at, any site other than the study sites 
agreed upon with the Sponsor. Further guidance and information for the final disposition of 
unused study IMPs are provided in the most recent version pharmacy manual/study site 
operational manual. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study IMP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
6.2.2. 
Retention Samples 
IMP samples will be retained in required amount and at required places as per applicable 
regulatory guidelines. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Procedures for Screening and Randomization 
At the Screening visit, patients enrolling into the study will be assigned a unique screening 
number. This number will be serially allocated as per the chronological sequence of entering 
into the trial at each site and will also incorporate the site identity. The specimen of screening 
number will be combination of Site number like 101, 102, 103…….., Project number: 0774-19 
and followed by serial number like 01, 02, 03, etc. as per the chronological order of entering of 
patient at each site. Hence, specimen of screening number will be like 101-0774-19-01, 101-
0774-19-02……and so on. 
All patients enrolled must be identifiable throughout the study. The randomization numbers 
will be generated using the following procedure to ensure that treatment assignment is unbiased 
and concealed from patients and investigator staff. 
Dynamic central randomization will be implemented in conducting this study. At the 
randomization visit after ensuring that a patient meets all eligibility criteria, participants will be 
assigned to 1 of 2 IMP groups based on an algorithm implemented in the interactive web 
response system (IWRS) before the study. Dynamic central randomization minimizes the 
imbalance in the distribution of the number of participants across IMP groups within the levels 
of each individual stratification factor: age (≥65, <65) and prior osteoporosis treatment status 
(present, absent). Based on the algorithm, the IWRS will assign a unique IMP code, which will 
dictate the IMP assignment and matching study IMP kit for the participant.  
Before the study is initiated, the log in information & directions for the IWRS will be provided 
to each site. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list or equivalent mechanism will be 
produced by or under the responsibility of Lambda Clinical Trial Supply Management using a 
validated system. The assigned patient number will be recorded in the CRF of the patient. The 
identification of patient will be based on the kit number. 

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After completion of 1-year study participants (who are randomized for Reference arm and 
involved in PK analysis) will be re-randomized on either Test or Reference arm using IWRS 
for further six month immunogenicity and safety evaluation. 
Central randomization schedule will be generated using SAS® Version 9.4 or higher (SAS 
Institute Inc., USA) or equivalent software before the commencement of the study by the 
biostatistician who is not involved in the conduct of the study. In case randomization schedule 
will be prepared by vendor or third party, then same will be generated as per their SOPs.  
Unblinded study staff involved in dispensing of study drug and verification of dispensed study 
drugs will be accountable for ensuring compliance to randomization schedule. 
Every attempt should be made for participants to receive their first injection of IP on the day of 
randomization. If this is not possible, participants must receive the first injection of IP within 
72 hours of randomization. A participant will be considered enrolled once a randomization 
number is assigned. It is therefore very important randomization only after the participant’s 
eligibility and willingness to participate has been confirmed, as the participant cannot be 
‘unenrolled’. 
6.3.2. 
Procedures of blinding 
Instructions provided in this section are overarching description of operational procedures. 
Investigators are instructed to always refer to latest version of respective study plans/manuals 
for detailed and latest information. 
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct and interpretation of the clinical study. The essential aim of masking, therefore, is to 
prevent identification of the treatments by the Investigator, subject, and others associated with 
the conduct of the study until all such opportunities for bias have passed. 
Participant, investigator staff, persons performing the assessments and all other study personnel 
who could have an impact on the outcome of the study will be blinded to the identity of the 
treatment from the time of randomization until final database lock after efficacy assessment. 
All members (except dosing nurse and pharmacist at site) of the site team will be blinded to 
treatment assignments while the study is in progress. All roles for each study staff member 
should be clearly documented on the Site Delegation Log. The Delegation Log should be signed 
by the Principal Investigator. In case a site is experiencing unexpected extreme situations, the 
Medical Monitor’s permission might be granted to switch the study staff member from the 
blinded to the unblinded.  
Dosing nurse and pharmacist at site (unblinded to the treatment assignment): A qualified nurse 
and pharmacist at site who will be performing all the subcutaneous injections (denosumab) to 
study participants during the study duration; must not perform any study assessments; will not 
complete eCRFs and must not be involved in any other aspect of the study or communicate 
details of the treatment to anyone. The treating nurse should, however, assess subject safety 
immediately following injection (ie, they will perform the post-injection assessment; the 
blinded physician/site personnel should not perform this assessment) and record the findings in 
the source documents. There should not be mentioned of allocation. The treating nurse must be 
the same throughout the study. 
At CRO, there will be separate group of blinded and unblinded study personnel will be created 
and their role will be clearly defined in project management plan. In brief, there will be clear 

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separation of roles and responsibilities for blinded and unblinded personnel throughout the 
study. Personnel who have access to treatment codes (eg, personnel directly involved with 
bioanalysis of serum samples, unblinded monitors performing IP accountability and logistics, 
and clinical supplies personnel, etc.) will not divulge the codes to subjects, Investigators, site 
staff, clinical trial management (CTM), medical monitor, central reading personnel. CRA, 
personal involved in PK analysis and biostatistician, project manager, CDM team who are 
directly involved in the conduct of the study will remain blinded to treatment assignments while 
the study is in progress.  If necessary, the sponsor/CRO pharmacovigilance and/or Safety 
Review Team may be required to unblind a subject if an adverse event (AE) meets criteria of a 
suspected unexpected serious adverse reaction (SUSAR) in order to fulfill expedited regulatory 
reporting requirements. In this event, the Sponsor/CRO PV and/or Safety Review Team will 
not divulge the treatment code to any other personnel involved in reporting, obtaining, and/or 
reviewing the clinical evaluations. Once the designated masked vs. unmasked roles are 
delineated and the site study staff have started to perform them, the roles cannot be switched or 
reversed at any time during the conduct of the study. Refer to project management plan for 
detailed and current blinding procedures. 
Data 
that 
may 
potentially 
unmask 
the 
IMP 
assignment 
(i.e., 
study 
IMP 
preparation/accountability data, IMP allocation, biomarker or other specific laboratory data) 
will be handled with special care to ensure that the integrity of the masking is maintained and 
the potential for bias is minimized. Unmasking will only occur in the case of participant 
emergencies (see section 6.3.2.1) and at the conclusion of the study.  
Drug dispensing logs, drug accountability forms and other papers identifying treatment 
allocation are kept in a separate binder in a locked cupboard to which the investigator does not 
have access. The subject will during the informed consent process be informed, both verbally 
and in writing, to not disclose her treatment allocation to the investigator. Trial staff is provided 
training in the importance of maintaining masking, and trial medication delegates/trial 
coordinators are also helped to set up systems at the clinic. 
The sponsor clinical trial team (i.e. data manager, statistician, trial manager, trial coordinator, 
medical writer, safety monitor and sponsor’s responsible medical officer) will be blinded to 
treatment allocation until breaking of the blinding. The blinding will be broken when the trial 
database is declared clean and locked. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study IMP records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
There is a risk of unblinding for those patients who were part of PK assessment on denosumab-
ref who will be subsequently stratified to either denosumab or denosumab-ref. Every effort will 
be made to ensure blinding. The key endpoints BMD, CTX, PK and PD are all objective 
assessments.  
6.3.2.1. Emergency unblinding of treatment assignment 
As both arms contain the same treatment (denosumab injection), there is very limited possibility 
of emergency unblinding of treatment assignment. Most often, study drug discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study participant who 
presents with an emergency condition. The IWRS will be programmed with blinding-breaking 
instructions. While the responsibility to break the IMP code in emergency situations resides 
solely with the investigator, it is recommended that the investigator contact the sponsor or its 

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designee/study medical monitor if possible to discuss the particular situation, before breaking 
the blinding unless this could delay emergency treatment of the participant. Telephone contact 
with the sponsor or its designee will be available 24 hours per day, 7 days per week. If a 
participant’s IMP assignment is unblinded, the sponsor must be notified within 24 hours after 
breaking the blinding.  
The investigator will inform the participant how to contact his/her backup in cases of emergency 
when he/she is unavailable. The investigator will provide protocol number, study drug name if 
available, participant number, and instructions for contacting the sponsor (or any entity to which 
it has delegated responsibility for emergency code breaks) to the participant in case emergency 
unblinding is required at a time when the investigator and backup are unavailable.  
The modalities for opening the blind of the treatment after the data transferred to biostatistics 
for statistical analysis will be described in statistical analysis plan (SAP). Individual sealed 
envelope containing participant treatment details will be provided to investigator to break the 
treatment information in case of emergency. Unblinding at the study site for any other reason 
will be considered a protocol deviation. Refer to the site operational manual for instructions on 
process of unblinding. The principal investigator is strongly encouraged to contact the medical 
monitor before unblinding any participant’s treatment assignment but must do so within 1 
working day after the event. 
An assessment will be done by the appropriate site personnel and the Study Lead after an 
emergency unblinding to assess whether or not study drug should be discontinued for a given 
participant.  
6.4. 
Study IMP Compliance 
Study IMP will be administered as a subcutaneous injection by qualified study-site personnel. 
The date and time of each dose administered in the clinic will be recorded in the source 
documents and recorded in the CRF. The dose of study IMP and study participant identification 
will be confirmed at the time of dosing by a member of the study site personnel other than the 
person administering the study IMP.  
Study-site personnel will maintain a log of all study IMP administered. Study IMP supplies for 
each participant will be inventoried and accounted for. 
6.5. 
Dose Modification 
Dose modification is not allowed during the participation of the study. 
All efforts should be made to administer study IMP within the defined study visit windows 
(refer to SoA). If study IMP cannot be administered within the target visit date, the dose has to 
be considered missed.  
If a dose of study IMP is missed, IMP administration will be done only after discussion with 
medical monitor/sponsor. However, no modification must be done for schedule of assessments 
and efficacy measurement should be done according to Day 1 of the study. 
6.6. 
Continued Access to Study IMP after the End of the Study 
The Sponsor will evaluate the appropriateness of continuing to provide denosumab to 
participants randomized to study IMP after evaluating the primary efficacy outcome measures 
and safety data gathered in the study. These analyses may be conducted prior to completion of 

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the study. Post-trial access will be provided in line with requirement of local regulations and 
guidelines. 
6.7. 
Treatment of Overdose 
For this study, any dose of denosumab greater than 60 mg per dose or dose more frequently 
than prescribed frequency (with consideration of allowed window period as per protocol) will 
be considered an overdose.  
Overdose with denosumab has not been reported. Neither the effects of overdose of denosumab 
nor an antidote to overdose are known. Sponsor does not recommend specific treatment for an 
overdose.  
As a general guidance in the event of an overdose, the investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities based on 
pharmacodynamics of study IMP until 5 half-life of IMP. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding drug discontinuation or withdrawal of participant with overdose will be 
made by the investigator in consultation with the Medical Monitor based on the clinical 
evaluation of the participant. 
6.8. 
Concomitant Therapy  
Concomitant therapies must be recorded throughout the study beginning with start of the first 
dose of study IMP to last study visit. Concomitant therapies should also be recorded beyond 
last study visit only in conjunction with serious adverse events that meet the criteria outlined in 
Serious Adverse Events in Section 8.6.1. 
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, 
herbal supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, 
special diets, exercise regimens, or other specific categories of interest) different from the study 
IMP must be recorded in the CRF. Recorded information will include a description of the type 
of therapy, duration of use including start and stop dates, dosing regimen, route of 
administration, and indication/reason for use. Modification of an effective preexisting therapy 
should not be made for the explicit purpose of entering a participant into the study. 
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. The Medical Monitor should be contacted if there 
are any questions regarding concomitant or prior therapy. 
Table 3. Prohibited medication 
Medications listed below will be prohibited during the study, including the use of other 
investigational products and medications known or suspected to affect bone metabolism 
(except calcium and vitamin D).  
Drugs affecting bone 
metabolism 
• Strontium (including strontium ranelate and over-the-counter 
strontium preparations)  
• Fluoride (for treatment of osteoporosis)  

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• Vitamin K and vitamin K analogues (for treatment of 
osteoporosis)  
• Activated 
vitamin 
D 
(1,25-dihydroxyvitamin 
D 
or 
1-
hydroxyvitamin D)  
• IV bisphosphonates  
• Oral bisphosphonates (cumulative dosing regimens of ≤ 1 month 
are acceptable)  
• Denosumab (other than study drugs) 
• Teriparatide or any PTH analogs  
• Systemic oral or transdermal estrogen (cumulative dosing 
regimens of ≤ 1 month are acceptable, vaginal preparations and 
estrogen creams will be allowed at any time)  
• SERMs (cumulative dosing regimens of ≤ 1 month are 
acceptable)  
• Calcitonin (cumulative dosing regimens of ≤ 1 month are 
acceptable)  
• Tibolone (cumulative dosing regimens of ≤ 1 month are 
acceptable)  
• Cinacalcet 
• Androgen deprivation/hormone ablation therapy or hormone 
replacement therapy 
• Prolonged (i.e., >1 months) oral glucocorticoid therapy at a 
prednisone 
equivalent 
dose 
of 
≥5.0 
mg/day 
(tapering 
glucocorticoid courses of < 1 month duration are permitted 
regardless of dose; inhaled or topical glucocorticoids are 
permitted) 
• Any cathepsin K inhibitor 
• Any other investigational treatment targeting bone turnover 
If a participant receives any prohibited therapy(ies) while being on-study, further IMP 
administration must be discontinued. However, every effort should be made to have the 
participant continue participation in the study and complete all activities defined in SoA.  
If a participant discontinues IP and begins an approved alternative osteoporosis therapy, every 
effort should be made to have the participant continue participation in the study and complete 
all activities defined in SoA. 

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7. 
Discontinuation of Study IMP and Participant 
Discontinuation/Withdrawal 
Participant can discontinue study treatment and/or be withdrawn from the study because of the 
appearance of a new health condition suspected to require appropriate care, unacceptable AEs, 
refusal to continue treatment, or at the investigator’s discretion based on his or her clinical 
judgment if he/she believes that continuation would be detrimental to the participant’s well-
being. 
7.1. 
Discontinuation of Study IMP 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study IMP. If a participant discontinues study IMP for any reason before the 
end of the study, scheduled assessments off study IMP should be continued. 
Subjects meeting the following criteria will be withdrawn from the study treatment. All 
withdrawn subjects from the study treatment will be followed up till the end of study as per 
schedule of activities. 
• The participant withdraws consent to receive study IMP 
• The investigator believes that for safety reasons or tolerability reasons (eg, adverse 
event) it is in the best interest of the participant to discontinue study IMP 
• Concomitant medications: Consumption of co-medication / requirement to consume co-
medication that can affect the safety of the participant continuing in the trial as per the 
investigator; Consumption of prohibited medication as mentioned in section 6.8 
If a participant discontinues study IMP definitely for any reason before the end of the study 
visit but is still willing to collaborate in providing further data by continuing on study, the 
participant will remain in the study to be evaluated for further collection of information on 
primary endpoint as well as immunogenicity. These participants to be provided Standard of 
Care as per investigator and participant agreement.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
Investigator must determine the primary reason for a participant’s premature withdrawal from 
the study and record this information on the eCRF and in the source document. If premature 
withdrawal from the study occurs for any reason, if possible, End of Study visit as described in 
Section 1.3 (SoA) should be conducted. If the reason for withdrawal from the study is 
withdrawal of consent, then no additional assessments are allowed. 
A participant will be withdrawn from the study for any of the following reasons: 
• 
Consent is withdrawn: Subjects have the right to withdraw from the trial at any time for 
any reason. If withdrawal occurs, the subject will be requested to come for a complete 
follow-up examination. 

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• 
Non-compliance: The subject may be withdrawn from the trial at the discretion of the 
Investigator if it is judged that participant is non-compliant to study assessment and 
schedule and it can cause safety concerns.  
• 
Protocol deviation:  
➢ Participant entered in the study in violation of the protocol and there is safety concern.  
➢ Any deviations from the protocol-prescribed dose regimen and/or dose delay for the 
study drug. 
➢ Participant can be withdrawn from trial after consultation with the sponsor, if 
participant’s continued participation in trial affects his/her safety due to protocol 
deviation   
• 
Pregnancy: A female participant with pregnancy will be withdrawn from the trial. 
• 
Lost to follow-up  
• 
Death 
If the participant withdraws consent for disclosure of future information, the sponsor can retain 
and continue to use any data collected before such a withdrawal of consent. 
The Investigator will discuss the appropriate therapy with each participant who withdraws early 
from this study. Determination of the appropriate follow-up therapy will be left to the discretion 
of the Investigator. 
Sponsor or CRO will train the investigators to ensure that there will be no or minimal drop-out 
of subjects in the trial with in the 12 months of treatment period. Importance of extension of 
study for the participants who are only randomized in reference arm during 12 months study 
and involved in PK along with PD assessment, will be communicated and explained to the 
investigator. The relevance of the generated scientific data will be explained. 
7.3. 
Lost to Follow up 
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization 
attempts should be made to obtain contact information from each participant, eg, home, work, 
and mobile telephone numbers and email addresses for both the participant as well as 
appropriate family members. 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed 
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the 
participant are deemed futile.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee must 
make every reasonable effort to regain contact with the participant (where possible, at 
least 3 telephone calls, e-mails, fax, and, if necessary, a certified letter to the 
participant’s last known mailing address, or local equivalent methods). There should 
be time interval of at least 4 weeks (or justified) between each contact attempt. These 
contact attempts should be documented in the participant’s medical records. 

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• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
• 
Should a study site close, eg, for operational, financial, or other reasons, and the 
investigator cannot reach the participant to inform them, their contact information will 
be transferred to another study site. Discontinuation of specific sites or of the study as 
a whole are handled as part of Appendix 10.1. 
Investigator should follow-up with all procedures as per GCP to ensure that there is minimal 
subject drop-out with in the initial 12 months of treatment. If there is drop-out, every effort 
should be made to get the patient back in the trial. The effort made by the investigator should 
be discussed with sponsor and documented. Investigator is expected to ensure 100% follow-up 
of patients who are re randomized further for 6-month study period. Reasons for missing data, 
if any, will have to be documented. While consenting, the importance of compliance with the 
study procedure should be explained to the patients.  
 

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8. 
Study Assessments and Procedures 
Overview 
The Schedule of Activities (SoA) summarizes the frequency and timing of efficacy, PK, 
immunogenicity, PD, and safety measurements applicable to this study. 
• 
Study assessments and procedures will be performed only after written informed 
consent is obtained.  
• 
Study assessments and procedures will be captured in detail in study site operation 
manual. 
• 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the medical monitor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study IMP. (Note: Investigator should assess and intervene immediately 
for any safety related issues without prior discussion with the medical monitor, 
however the medical monitor should be updated as soon as possible.) 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record reasons 
for screening failure, as applicable. 
• 
IP administration must be the last procedure after all other study visit procedures have 
been completed. 
 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Refer to the Schedule of Activities for the timing and frequency of all sample 
collections. Instructions for the collection, handling, storage, and shipment of samples are found 
in the laboratory manual that will be provided.  
 
Collection, handling, storage, and shipment of samples must be under the specified, and where 
applicable, controlled temperature conditions as indicated in the laboratory manual. 
The total blood volume for the study is approximately 407 + 10 mL or 544 + 10 mL as 
applicable. 
Table 4. Volume of blood to be collected from each participant 
Type of Sample 
Volume 
per 
Sample 
(mL) 
No. of 
Samples per 
Participant 
No. of Samples 
per following 
up Participant 
(entered in 
Transition-
extension 
period) 
Approximate  
Total Volume 
of Blood 
(mL)[a] 
Approximate  
Total Volume 
of Blood for 
following up 
Participant 
(mL)[a] 
(entered in 
Transition-
extension 
period) 
Safety (including screening 
and post-IMP assessments) 
 
Hematology 
2 
5 
7 
10 
14 
Serum chemistry  
6 
5 
7 
30 
42 

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Serology 
2 
1 
1 
2 
2 
Serum -hCG pregnancy 
tests 
2 
1 
1 
2 
2 
Albumin-adjusted calcium 
2 
14 
19 
28 
38 
25 (OH) Vitamin D 
2 
5 
7 
10 
14 
Efficacy 
 
Pharmacokinetic samples 
3.5 
34 
42 
119c 
147c 
Pharmacodynamic samples 
3.5 
34 
42 
119d 
147d 
Immunogenicity 
8.5 
10 
16 
85 
136 
Loss by use of indwelling 
intravenous cannula 
0.5 
4 
4 
2 
2 
Approximate Total[b] 
 
 
407e 
544 e 
a. Calculated as number of samples multiplied by amount of blood per sample. 
b. Repeat or additional unscheduled samples may be taken for additional analysis for safety reasons or 
technical issues with the samples. 
c. Only applicable to those participants who are going for assessment of PK. 
d. Only applicable to those participants who are going for assessment of PD. 
e. Total blood loss will be applicable according to participation of patient in PK and PD assessment 
(Transition-extension period). 
Note: An indwelling intravenous cannula may be used for blood sample collection. 
8.1. 
Study Procedure 
All study procedures and the timing when they must be performed are detailed in the Section 
1.3 (SoA). All data obtained for these assessments must be supported in the participants' source 
documentation. Investigators are instructed to always follow latest version of study plans/ 
manual for detailed information. 
Prior to undergoing any study specific procedures participants must read and sign the consent 
form. All study procedures and the timing when they must be performed are detailed in the 
Section 1.3. All data obtained for these assessments must be supported in the participants' 
source documentation. 
This study will be initiated only after getting required permission from regulatory authority and 
Institutional/Independent Ethics Committees and after registration with the Clinical Trial 
Registry, India. Prior to study initiation, all the investigators will be made familiar with the 
requirements and obligations of Good Clinical Practices (GCP). Investigators and other site 
personnels will undergo study-specific training before the initiation of trial. The study will be 
carried out according to the protocol in accordance with declaration of Helsinki and CDSCO 
“Good Clinical Practice” guidelines after approval from IEC/IRB. 
Written informed consent will be obtained from each participant prior to screening for the study. 
If the participant is unable to read/write, an impartial witness should be present during the entire 
informed consent process, which must provide his/her signature in consent form. 
The screening date is defined as the date the ICF is signed. The enrollment date is defined as 
the date of randomization. Day 1 is defined as the day the first dose of study IMP is administered. 
All on-study (post Day 1) visits are to be calculated from the Day 1 visit. If a participant’s visit 
is delayed, their subsequent visit date is not to be shifted, and is always to be calculated from 
the Day 1 visit. Study procedures for a specific visit may be completed on multiple days as long 
as all the procedures are completed within the visit window. 
8.2. 
Hospitalization 
Hospitalization is a not a requirement of protocol. Considering that PK and PD are co-primary 
endpoints, it is important that investigators adhere to the timepoint described for PK and PD 

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samples. If investigator consider 24-48 hours housing to ensure the adherence to the PK and 
PD sampling schedule due to logistic or administrative issues, this hospitalization will not be 
considered an SAE. 
8.3. 
Unscheduled Visits 
During the trial, in case of need, the participant can visit the study center and/or contact the 
investigator on any day apart from the scheduled day of visit. If required, the participant will 
be investigated and treated as per the Investigator’s discretion. All relevant details of such 
unscheduled visits/contacts will be documented in the eCRF. 
8.4. 
Efficacy Assessments  
8.4.1. 
Evaluations 
8.4.1.1. 
Dual-energy X-ray Absorptiometry  
Bone density measurements will be performed by DXA. The same DXA machine must be used 
for all study procedures for a particular participant for the duration of the study. Eligibility will 
be determined by a central DXA reading. All on-study DXA scans will be submitted to and 
analyzed by the central imaging vendor. A separate procedure manual provided by the central 
imaging vendor will give specific instructions for acquisition of scans as well as performance 
of Instrument Quality Control. 
DXA scan performed in the past will not be considered during screening. Bone mineral density 
will be measured using DXA scan will be performed exclusively for screening and eligibility 
criteria assessment at the lumbar spine, total hip during screening period. Lumbar spine scans 
must include L1 through L4. Detailed instructions for scan acquisition can be found in the 
separate manual provided by the central imaging vendor. 
For total hip, femoral neck DXA scans, the left side should be used for all scans at all study 
visits. If the right side must be used (eg, due to implants) or is inadvertently used at baseline, 
then it must be used consistently throughout the study. If a subject fracture the hip that has been 
scanned during the study up to the time of fracture, no further scans will be obtained. 
All DXA scan data will be submitted electronically to the central imaging vendor for analysis. 
Sites unable to submit data electronically can submit on compact disc or other media as 
specified in the DXA Procedural Manual, but electronic submission is preferred.  
After analysis by the central imaging vendor, the study site may be asked to re-acquire a scan 
due to mispositioning or other technical reasons. The study site must comply with the requests 
from the central imaging vendor. Repeat scans must be performed as soon as possible after the 
request is received. 
The results from the central imaging vendor will be used as the final data for statistical analysis.  
8.4.1.1.1. Screening BMD Assessment  
To determine eligibility based on BMD T-score, lumbar spine DXA scans will be analyzed by 
the central imaging vendor. To facilitate subject scheduling, the Day 1/baseline lumbar spine 
DXA scan may be taken with the lumbar spine DXA scan performed during screening. Lumbar 
spine vertebrae with artifacts or conditions (visible on the DXA scan) affecting the accuracy of 
the analysis may be excluded from the DXA analysis in order to determine eligibility. To be 

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eligible for the study, subjects must have at least two evaluable lumbar vertebrae on the DXA 
scan and the BMD must meet the criteria outlined in Section 5.1.  
8.4.1.2. 
Lateral Spine X-ray Assessments  
For assessment of prevalent vertebral fractures at screening/baseline, which will be performed 
by a radiologist at the central imaging center, a visual semiquantitative grading scale will be 
used[10]: 
• 
SQ grade 0 (SQ0) = no fracture  
• 
SQ grade 1 (SQ1) = mild fracture, 20% to 25% reduction in vertebral height (anterior, 
middle, or posterior)  
• 
SQ grade 2 (SQ2) = moderate fracture, 25% to 40% reduction in height  
• 
SQ grade 3 (SQ3) = severe fracture, greater than 40% reduction in height 
Details and specific requirement of X-ray will be mentioned in imaging manual. 
For assessment of incident vertebral fracture, x-rays will be scored blinded to treatment but not 
to sequence. The semiquantitative grading scale will be used. New vertebral fractures are 
defined as fractures in previously undeformed vertebrae. Worsening of pre-existing vertebral 
fractures will also be assessed. Worsening is defined as an increase of at least 1 grade on the 
semiquantitative scale. Investigators will be alerted by the central imaging vendor when a new 
or worsening vertebral fracture is identified.  
If a subject presents with acute back pain likely related to a new vertebral fracture at a time 
point other than when a scheduled lateral spine x-ray is obtained during the primary analysis 
period, and occurrence of a vertebral fracture is suspected, unscheduled lateral spinal x-rays 
will be obtained for submission to the central imaging facility for evaluation. The central 
imaging vendor will inform the sites if a new or worsening vertebral fracture is identified; 
however, these x-rays may also be read locally if necessary, to support the subject’s medical 
care. Only fractures confirmed by the central imaging vendor will be included for the analyses. 
8.4.1.3. 
Clinical Fracture Recording  
Information on suspected clinical vertebral fractures will be recorded and will include date of 
fracture, anatomical site(s) of fracture(s), degree of trauma involved and treatment. 
8.4.1.3.1. Suspected Clinical Vertebral Fractures  
If a participant reports back pain that is considered by the investigator to be possibly due to a 
new or worsening vertebral fracture, a confirmatory lateral spine x-ray will be taken and the 
back pain (but not a vertebral fracture) will be recorded as an adverse event. The lateral spine 
x-rays as well as copies of other diagnostic images (computerized tomography or magnetic 
resonance imaging) and/or radiology report, surgical report, or discharge summary will be 
submitted to the central imaging vendor for confirmation of fracture. To confirm a clinical 
vertebral fracture, at least one new or one worsening (ie, change by at least 1 SQ grade) vertebral 
fracture have to be identified by the central imaging vendor on lateral spine x-rays. The central 
imaging vendor will inform the sites of any new or worsening vertebral fractures; however, x-
rays taken upon reporting of back pain may also be read locally if necessary, to support subject 
medical care. Only clinical vertebral fractures confirmed by the central imaging vendor will be 
included for the statistical analysis. 
8.4.1.3.2. Nonvertebral Fractures  
Information about any nonvertebral fractures and level of trauma causing the fracture while on 
study will be recorded. A copy of radiographs or other diagnostic images such as computerized 
tomography or magnetic resonance imaging confirming the fracture, and/or a copy of the 

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radiology report, surgical report, or discharge summary should be obtained and included in the 
subject’s study records. Copies of the radiographs, diagnostic images and/or radiology report, 
surgical report, clinical notes, or discharge summary will be submitted to the central imaging 
vendor for confirmation of fracture. If the radiograph or diagnostic image is not available, then, 
at minimum, a copy of the radiology report, surgical report, clinical notes, or discharge 
summary should be submitted to the central imaging vendor. Additional information about 
nonvertebral fractures will be entered into the eCRF, eg, details regarding the type of fracture 
and other pertinent data.  
8.4.1.4. 
Pharmacodynamics 
Venous blood samples of approximately 3.5 mL will be collected for measurement of serum 
CTX and PINP at time points specified. Please refer to section 1.3 for further information. 
8.5. 
Safety Assessments  
• 
Adverse events will be reported and followed by the investigator as specified in 
Section 8.6 and Appendix 10.3. 
• 
Any clinically relevant changes occurring during the study must be recorded on the 
Adverse Event section of the CRF. 
• 
Any clinically significant abnormalities persisting at the end of the study/early 
withdrawal will be followed by the investigator until resolution or until a clinically 
stable condition is reached.  
• 
The study will include the following evaluations of safety and tolerability according 
to the time points provided in the Schedule of Activities. 
8.5.1. 
Demographic Characteristics 
Demographic data will include age, sex, and self-reported race/ethnicity. 
8.5.2. 
Medical History 
The Principal Investigator, or a licensed physician who has been delegated by the Principal 
Investigator, will obtain a detailed medical history and complete a physical examination at 
predefined time points. 
Medical history includes clinically significant diseases, including chronic and ongoing 
conditions (e.g., trauma, cancer, cardiovascular, and ophthalmic history); surgeries; cancer 
history; reproductive status including years since menopause; previous ECGs. History of 
fractures will also be obtained, and will include date of fracture, anatomical site(s) of 
fracture(s), and degree of trauma involved. The investigator or designee will collect information 
about the prior and/or current use of tobacco and alcohol and substance use. All findings are to 
be recorded on the CRF. 
8.5.3. 
Medication History 
Pre-study therapies for treatment of osteoporosis and other therapies affecting bone metabolism 
administered up to 3 years before first dose of study IMP must be recorded at screening as 
defined in eligibility criteria. The therapy name, indication, dose, unit, frequency, start date and 
stop date will be recorded. 
Information on other prior medications (e.g., prescription drugs, over-the-counter drugs, herbal 
or homeopathic remedies, nutritional supplements) used by the participant within 30 days prior 
to Day 1 will be recorded on the eCRF. The therapy name, indication, start date and stop date 
will be recorded. 

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Concomitant medications administered from screening to randomization will be recorded as a 
medication history on the eCRF. 
8.5.4. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the general 
examination and cardiovascular, respiratory, gastrointestinal, neurological systems. A pelvic, 
breast, or rectal examination will not be required for the screening or on-study physical 
examinations unless specific evaluation is deemed necessary by the principal investigator. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Height (using a stadiometer, to be measured without shoes) and body weight (to the nearest 0.1 
kilogram [kg] in indoor clothing, but without shoes or jacket) will also be measured and 
recorded at SoA defined timepoints. 
Throughout the study, targeted physical examination will be conducted at each visit as per signs 
and symptoms of participant as per standard care. 
8.5.5. 
Vital Signs 
Vital signs will include temperature, blood pressure and pulse obtained in the sitting position 
after the subject has sat quietly for at least 5 minutes.  
8.5.6. 
Electrocardiograms 
During the collection of ECGs, participants should be in a quiet setting. Participants should rest 
in a supine position for at least 5 minutes before ECG collection and should refrain from talking 
or moving arms or legs. If blood sampling (for safety measures) or vital sign measurement is 
scheduled for the same time point as ECG recording, the procedures should be performed in 
the following order: ECG(s), vital signs, blood draw (for safety measures). 12-lead ECG will 
be obtained at timepoints outlined in the SoA using an ECG machine and heart rate and various 
intervals such as PR, QRS, QT, and corrected QT (QTc) by Bazett's formula will be calculated. 
Investigator must document his/her review of the ECG in source documents. 
8.5.7. 
Clinical Safety Laboratory Assessments 
All protocol-required laboratory tests, as defined in Appendix 10.2, must be conducted in 
accordance with the laboratory manual and the SoA (Section 1.3). 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline or are 
no longer considered clinically significant by the investigator. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified, and the sponsor be notified. 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (e.g., SAE or AE or dose modification), then the results 
must be recorded in the CRF. 
8.5.8. 
Pregnancy Testing 
• 
Refer to Section 5.1 for pregnancy testing entry criteria. 

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• 
Pregnancy testing (serum) should be conducted at screening visit. Additional 
pregnancy tests can be performed at any visit during the study period as per 
investigator’s discretion. 
8.5.9. 
Periodontal Examination 
• 
Periodontal examination will be done to rule out risk factors for ONJ at screening and 
at EOS. Periodontal examination will be done at any visit during study as per 
investigator’s discretion. 
8.5.10. 
Injection site assessment 
• 
Injection site assessment will be performed after every injection at 30 minutes (± 5 
min) post dose. If any abnormalities observed than it will be documented. 
8.6. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of participants, investigators, and the sponsor, and are 
mandated by regulatory agencies worldwide. The sponsor has established Standard Operating 
Procedures in conformity with regulatory requirements worldwide to ensure appropriate 
reporting of safety information; all clinical studies conducted by the sponsor or its affiliates will 
be conducted in accordance with those procedures. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative) for the duration of the study. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study IMP or study procedures, or that caused 
the participant to discontinue the study IMP (see Section 7). 
8.6.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and special reporting situations, whether serious or non-serious, will be collected from 
the start of IMP until end-of-study visit or at end-of-switching period as applicable at the time 
points specified in the SoA (Section 1.3). 
Medical occurrences that begin before the start of study IMP but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the case 
report form (CRF) and not in the AE section. 
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel immediately after their knowledge of the event, and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Information regarding serious adverse events will be transmitted to the sponsor using the 
Serious Adverse Event Form and Safety Report Form of the CRF, which must be completed 
and reviewed by a physician from the study site and transmitted to the sponsor within 24 hours. 
The initial and follow-up reports of a serious adverse event should be transmitted electronically 
or by facsimile (fax). 

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Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study IMP or study participation, the investigator must promptly notify 
the sponsor. 
8.6.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. A consistent 
methodology of open-ended, non-directive/non-leading verbal questioning should be adopted 
for eliciting adverse event information at all participant evaluation timepoints. Examples of 
non-directive questions include the following:  
• 
"How have you felt since your last clinic visit?"  
• 
"Have you had any new or changed health problems since you were last here?"  
8.6.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in 
Section 8.6.9), will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is provided in Appendix 10.3. All the ongoing adverse events at EOS visit will 
be followed up till resolution/ stabilization/ 30 days (whichever is earlier). Adverse/ medical 
events occurring before starting study treatment but after signing the informed consent form 
will be recorded on the medical history/ current medical conditions of case report form. 
8.6.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor, local regulatory authority and Ethics 
committee of a SAE is essential so that legal obligations and ethical responsibilities towards 
the safety of participants and the safety of a study IMP under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority, other 
regulatory agencies and any other authority as per the local regulations about the safety of a 
study IMP under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators. 
For all studies, investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
The sponsor or its designee will also report to the investigator (and the head of the 
investigational institute where required) all suspected unexpected serious adverse reactions 
(SUSARs). The investigator (or sponsor where required) must report SUSARs to the 
appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) that 
approved the protocol unless otherwise required and documented by the IEC/IRB. A SUSAR 
will be reported to regulatory authorities unblinded. Participating investigators and IEC/IRB 
will receive a blinded SUSAR summary, unless otherwise specified. 

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8.6.5. 
Pregnancy 
Current protocol is planning to enroll post-menopausal women without any child-bearing 
potential as defined in eligibility criteria. Following is a general guideline for pregnancy 
reporting if required: 
• 
Details of all pregnancies in female participants if any, will be collected after the start 
of study IMP and until end-of-study visit. 
• 
If a pregnancy is reported, the investigator should inform the sponsor immediately of 
learning of the pregnancy using the appropriate pregnancy notification form(s) and 
should follow the procedures outlined in Appendix 10.3. 
• 
Any participant who becomes pregnant during the study must be promptly withdrawn 
from the study and discontinue further study IMP.  
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 8 weeks beyond the estimated delivery date. Any termination 
of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or abnormal outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) or elective termination of a pregnancy for 
medical reasons will be reported as a SAE.  
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring 
at >22 weeks gestational age) is always considered to be an SAE and will be reported 
as such.  
• 
Any post-study pregnancy related SAE considered reasonably related to the study IMP 
by the investigator will be reported to the sponsor as described in Section 8.6.4. While 
the investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
8.6.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs 
For the purposes of this study, the fractures (serious or non-serious) will be considered 
anticipated disease-related event due to underlying disease. Because these events are typically 
associated with the disease under study or disease progression, they will not be reported 
according to the standard process for expedited reporting of SAEs even though the event may 
meet the definition of a SAE. These events will be recorded on the disease-related event page 
in the participant’s CRF.  
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an AE or a SAE (instead of a DRE): 
• 
The event is, in the investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant. 
AND/OR 
• 
The investigator considers that the clinical signs or symptoms of progression and the 
possibility that the study treatment is enhancing disease progression  
AND/OR 
• 
The investigator considers that there is a reasonable possibility that the event was 
more likely related to study IMP than underlying disease. 

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8.6.7. 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result should 
be reported as an adverse event if it meets any of the following criteria:  
• 
Is accompanied by clinical symptoms  
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)  
• 
Results in a medical IMP (e.g., potassium supplementation for hypokalemia)  
• 
Is clinically significant in the investigator’s judgment  
• 
Requiring a change in concomitant therapy (i.e. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
It is the responsibility of the investigator to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory abnormality 
should be classified as an adverse event. The investigator must review the laboratory report, 
document this review, and record any clinically relevant changes occurring during the study in 
the AE section of the eCRF. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 × ULN associated with cholecystitis), only the diagnosis (i.e., 
cholecystitis) should be recorded on the adverse event eCRF.  
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the adverse event eCRF, along with a descriptor 
indicating if the test result is above or below the normal range (e.g., "elevated potassium," as 
opposed to "abnormal potassium").  
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the adverse event eCRF, unless the etiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens. 
For each laboratory abnormality reported as an AE, the following laboratory values should be 
reported in the laboratory section of the eCRF: the value indicative of the onset of each toxicity 
grade; the most abnormal value observed during the AE, and the value supporting recovery to 
Grade ≤1 or to baseline values. 
8.6.8. 
Abnormal Vital Sign Values  
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be 
reported as an adverse event if it meets any of the following criteria:  
• 
Is accompanied by clinical symptoms  
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)  
• 
Results in a medical IMP (e.g., potassium supplementation for hypokalemia)  
• 
Is clinically significant in the investigator’s judgment  
• 
Requiring a change in concomitant therapy (i.e. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 

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It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an adverse event.  
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event 
eCRF.  
Observations of the same clinically significant vital sign abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF, unless the etiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens. 
8.6.9. 
Adverse Events of Special Interest  
In order to fully evaluate certain events of interest during the study, following adverse events 
of clinical interest, based on nonclinical studies conducted with denosumab, will be collected:  
• 
Potential osteonecrosis of the jaw events 
• 
Hypocalcemia (defined as per below table) 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Corrected serum 
calcium of 
<LLN - 8.0 
mg/dL: <LLN - 
2.0mmol/L; 
Ionized calcium 
<LLN -1.0 
mmol/L 
Corrected serum 
calcium of <8.0 - 
7.0 mg/dL: <2.0 -
1.75 mmol/L; 
Ionized calcium 
<1.0 -0.9 
mmol/L; 
Symptomatic 
Corrected serum 
calcium of <7- 6.0 
mg/dL: <1.75 – 
1.5mmol/L; Ionized 
calcium <0.9 -0.9 
mmol/L; 
Hospitalization 
indicated 
Corrected serum 
calcium of < 6.0 
mg/dL: <1.5 
mmol/L; Ionized 
calcium <0.8 
mmol/L; Life-
threatening 
consequences  
Death  
• 
Potential atypical femoral fracture events 
• 
Injection site reaction 
• 
Serious infection leading to hospitalization 
• 
Hypersensitivity reaction including dermatologic reactions 
 
All AESI should be notified to sponsor or its designee as early as possible and preferably within 
24 hours of occurrence. If any AESI meets criteria for seriousness, then it will be notified to 
EC and regulatory agencies as per SAE reporting timelines captures in section 8.6.1. 
8.7. 
Pharmacokinetics  
Blood samples will be collected only in prespecified number of patients as defined in section 
9.1 for pharmacokinetics assessment of denosumab and denosumab-ref. 
8.7.1. 
Evaluations 
Venous blood samples of approximately 3.5 mL will be collected for measurement of 
concentrations of denosumab and denosumab-ref as specified in the SoA. 
Samples collected for analyses of denosumab and denosumab-ref concentration may 
additionally be used to evaluate safety or efficacy aspects that address concerns arising during 
or after the study period or for the evaluation of relevant biomarkers.  

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Sample collection after first dose and prior to second dose: 
The venous blood samples will be withdrawn at pre-dose (0.00 hour) and at 4.000, 12.000 (Day 
1), 24.000 (Day 2), 48.000 (Day 3), 72.000 (Day 4), 96.000 (Day 5), 120.000 (Day 6), 168.000 
(Day 8), 216.000 (Day 10), 240.000(Day 11), 264.000 (Day 12), 312.000 (Day 14), 
360.000(Day 16), 408.000 (Day 18), 504.000 (Day 22), 624.000 (Day 27), 792.000 (Day 34), 
1008.000 (Day 43), 1344.000 (Day 57), 1680.000 (Day 71), 2016.000 (Day 85), 2352.000 (Day 
99), 2688.000 (Day 113), 3024.000 (Day 127), 3360.000 (Day 141), 3840.000 (Day 161), 
4320.000 (Day 181) hours post dose following first dose administration.  
The venous blood samples will be withdrawn at 5040.000 (Day 211; Month 7), 5760.000 (Day 
241; Month 8), 6480.000 (Day 271; Month 9), 7200.000 (Day 301; Month 10), 7920.000 (Day 
331; Month 11), and 8640.000 (Day 361; Month 12) hours post dose following first dose 
administration. The venous blood samples will be withdrawn at Pre third dose, 24.000 (Day 2), 
720.000 (Day 31), 1440.000 (Day 61), 2160.000 (Day 91), 2880.000 (Day 121), 3600.000 (Day 
151) and 4320.000 (Day 181) hours post dose following third dose administration. 
*Note: Blood sample for immunogenicity on day 181 will be collected prior to 2nd dose administration 
and day 361 before 3rd dose administration respectively. 
Window period for Sampling of PK and PD analysis 
The pre-dose blood samples for first dose will be collected within a period of 60 minutes before 
dosing. Post-dose sample at 4.000 hours will be collected within ± 30 minutes from schedule 
time. Post-dose samples at 12.000 (Day 1) and 24.000 (Day 2), will be collected within ± 1 
hours from schedule time. Post-dose samples from 48.000 hours (Day 3) to 408.000 (Day 18) 
hours will be collected within ± 4 hours from schedule time. Sample from 504.000 (Day 22) to 
792.000 (Day 34) will be collected within ± 1 day from schedule time. Samples from 1008.000 
(Day 43) to 3840.000 (Day 161) will be collected within ± 3 day from schedule time. However, 
4320.000 (Day 181) hours post-dose sample will be collected prior to second-dose 
administration. 
Sample from 5040.000 (Day 211) to 8640.000 (Day 361) through Day 541 will be collected 
within ± 3 day from schedule time. However, the pre-dose blood samples for third dose will be 
collected within a period of 60 minutes before dosing. Post dose samples not collected within 
this time frame from scheduled time will be documented as sampling deviations. 
All, post dose samples during the whole study will be collected on ambulatory basis. 
Note: Blood sample collection (PK assessment) will be collected first if other activities are 
coinciding. At visits during which serum samples for the determination of multiple aspects of 
denosumab and denosumab-ref will be taken, one sample of sufficient volume can be used. 
Genetic analyses will not be performed on these serum samples. Participant confidentiality will 
be maintained. 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
A maximum of 2 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. The timing of sampling 
may be altered during the course of the study based on newly available data (e.g., to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 

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The actual date and time (24-hour clock time) of each sample will be recorded. Additional 
information about the collection, handling, and shipment of biological samples can be found in 
the laboratory manual. 
8.7.2. 
Blood Sample Handling for PK, PD and Immunogenicity Analysis 
An instruction manual will be prepared with detailed information on blood sample collection, 
separation, storage and shipment of bioanalytical samples for PK, PD and Immunogenicity 
estimation. 
8.7.3. 
Analytical Procedures  
8.7.3.1. 
Bioanalytical Plan 
Bioanalytical study plan for Pharmacokinetic measurement will be prepared before study 
sample analysis. The analysts concerned will not have access to the randomization schedule till 
the completion of bioanalytical phase. All collected samples will be analyzed. If any participant 
is dropped out after dosing and no post dose samples are collected, then pre-dose sample of 
such participant will not be analyzed. In the extension phase of study, PK blood collection will 
be done for all ongoing trial patients but, PK measurement will be done for only anti-drug 
antibody positive patients. 
8.7.3.2. 
Pharmacokinetics measurements 
Serum samples of participants will be assayed for denosumab using ELISA based method at 
Lambda Therapeutic Research, Limited, Ahmedabad which is validated according to the 
international guidelines. The analysis of participant samples will be done using a calibration 
curve with quality control samples. The details for the preparation of the calibration curve and 
quality control samples, analytical run organization and the analytical run acceptance criteria 
as discussed in the respective in-house procedure or bioanalytical study plan will be followed 
during analysis. The criteria for repeat analysis, as defined in the respective in-house procedure, 
will be followed. Incurred sample reproducibility will be performed to confirm the reliability 
of the study data. Sample selection will be based on the procedure and acceptance of the results 
will be as per the in-house SOP. The results will be presented in the bioanalytical report. 
Primary aliquot used for study sample analysis will be discarded after completion of analysis. 
Any missing samples will be reported as `M’ and non-reportable concentration values due to 
insufficient volume or any other reason as per in-house procedure will be reported as ‘NR’. 
8.7.4. 
Pharmacokinetic Parameters and Evaluations 
8.7.4.1. 
Parameters 
The following pharmacokinetic parameters will be computed for denosumab, using non-
compartmental model of Phoenix® WinNonlin® Version 8.1 or higher (Certara L.P.) 
• 
Primary PK Parameters: Cmax, AUC0-t, and AUC0-∞ of denosumab after first-dose 
• 
Secondary PK Parameters: Tmax, AUC_%Extrap_obs, λz, Vd/F, Cl/F, and t1/2 of 
denosumab after first dose; Tmax, Cmax, AUC0-t, AUC0-∞, λz, and t1/2 of denosumab after 
second and individual patient’s PK parameters after  third dose 
Pharmacokinetic Parameters: 
Cmax 
: 
Maximum measured concentration. 

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Pharmacokinetic Parameters: 
AUC0-t 
: 
Area under the concentration versus time curve from time zero to the last 
measurable concentration as calculated by linear trapezoidal method 
AUC0- 
: 
Area under the 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 of the maximum measured concentration.  
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 concentration values. 
t1/2 
: 
The terminal half-life will be calculated as ln(2)/z. 
AUC_%Extrap_obs 
: 
The residual area in percentage will be determined by the formula,  
[(AUC0- - AUC0-t)/AUC0-] x 100 
Cl/F 
: 
Total body clearance will be calculated using the formula, [Dose/AUC0-]. 
Vd/F 
: 
Volume of distribution based on terminal phase will be calculated using the 
formula, [Dose/(λz x AUC0-)].  
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, Cl/F, 
Vd/F or t1/2 will be reported for cases that do not exhibit a terminal log-linear phase in the 
concentration versus time profile. 
8.7.4.2. 
Pharmacokinetic analysis 
Pharmacokinetic analysis will be performed on the available concentration data of all the 
eligible patients. Criteria for exclusion of pharmacokinetic parameters (for first dose only) will 
be as follows:  
• 
Three consecutive missing or non-reportable samples in before actual Tmax may 
significantly influence all pharmacokinetic parameter estimations. Inclusion of parameters 
in the statistical analysis may mislead the final outcome. Hence, all pharmacokinetic 
parameters will be excluded. 
• 
Three consecutive missing or non-reportable samples in elimination phase (i.e. after Tmax) 
may significantly influence the AUC0-t and elimination phase dependent parameters 
(AUC0-∞, t1/2, λz, AUC_%Extrap_obs, Vd, Cl). Inclusion of such parameters in the 
statistical analysis may mislead the final outcome. Hence, AUC0-t and elimination phase 
dependent parameters (AUC0-∞, t1/2, λz, AUC_%Extrap_obs, Vd, Cl) will be excluded. 
• 
Patient having pre-dose value >5% of Cmax. [Note: statistical analysis with including the 
same will be provided for additional information]. 
• 
Patients without measurable concentrations or who have only very low concentrations from 
the reference medicinal product will be excluded from the pharmacokinetic and statistical 
analyses for the PK comparison of test product with reference product. According to EMA 

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Guidance (Doc. Ref. CPMP/QWP/EWP/1401/98 Rev.1/Corr**), a patient is considered to 
have very low concentrations if his/her AUC0-t is less than 5% of reference medicinal 
product geometric mean AUC0-t, calculated without inclusion of data from the outlying 
patient. [Note: statistical analysis with including the same will be provided for additional 
information, this criterion will be applicable for analysis of EMA only.] 
8.8. 
Genetics and/or Pharmacogenomics 
Pharmacogenomics are not evaluated in this study. 
8.9. 
Pharmacodynamics  
Serum CTX and serum P1NP as biomarkers for bone resorption are being evaluated in this 
study. Other samples may be used for research to develop methods, assays related to this study. 
8.9.1. 
Evaluation 
Venous blood samples of approximately 3.5 mL will be collected for measurement Serum CTX 
and serum P1NP as biomarkers for bone resorption of denosumab and denosumab-ref from all 
participant prespecified for PK assessment in each arm as specified in the Schedule of Activities 
(SoA) . 
Blood samples for PD analysis will be collected in all participants who will be undergoing PK 
assessment. 
, same window period will be applicable as described in PK section. 
Note: Samples for PD evaluation [CTX and P1NP] should be collected in morning under 
fasting condition. 
Sample collection after first dose and prior to second dose: 
The venous blood samples will be withdrawn at pre-dose (0.000 hour) and at 4.000, 12.000 (Day 1), 
24.000 (Day 2), 48.000 (Day 3), 72.000 (Day 4), 96.000 (Day 5), 120.000 (Day 6), 168.000 (Day 8), 
216.000 (Day 10), 240.000 (Day 11), 264.000 (Day 12), 312.000 (Day 14), 360.000 (Day 16), 408.000 
(Day 18), 504.000 (Day 22), 624.000 (Day 27), 792.000 (Day 34), 1008.000 (Day 43), 1344.000 (Day 
57), 1680.000 (Day 71), 2016.000 (Day 85), 2352.000 (Day 99), 2688.000 (Day 113), 3024.000 (Day 
127), 3360.000 (Day 141), 3840.000 (Day 161), 4320.000 (Day 181) hours post dose following first 
dose administration.  
The venous blood samples will be withdrawn at 5040.000 (Day 211; Month 7), 5760.000 (Day 241; 
Month 8), 6480.000 (Day 271; Month 9), 7200.000 (Day 301; Month 10), 7920.000 (Day 331; Month 
11), and 8640.000 (Day 361; Month 12) hours post dose following first dose administration.  
The venous blood samples will be withdrawn at pre third dose, 24.000 (Day 2), 720.000 (Day 31), 
1440.000 (Day 61), 2160.000 (Day 91), 2880.000 (Day 121), 3600.000 (Day 151) and 4320.000 (Day 
181) hours post dose following third dose administration.  
*Note: Blood sample for immunogenicity on day 181 will be collected prior to 2nd dose administration 
and day 361 before 3rd dose administration respectively. 
Window period will be applicable as mentioned in section 8.8.1. 

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8.9.2. 
Analytical procedure 
8.9.2.1. 
Pharmacodynamic measurement 
Bioanalytical study plan for Pharmacodynamic analysis will be prepared before study sample 
analysis. The analysts concerned will not have access to the randomization schedule till the 
completion of bioanalytical phase. All collected samples will be analyzed. If any participant is 
dropped out after dosing and no post dose samples are collected, then pre-dose sample of such 
participant will not be analyzed. In the extension phase of study, PD blood collection will be 
done for all ongoing trial patients but, PD analysis will be done for only anti-drug antibody 
positive patients.  
Serum samples will be analyzed for CTX and P1NP by using validated methods at Lambda 
Therapeutic Research Ltd., Ahmedabad. The details for the analytical run organization, 
analytical run acceptance criteria and criteria for repeat analysis as mentioned in the respective 
in-house procedure or respective bioanalytical study plan will be followed during analysis. 
Incurred sample reproducibility will be performed to confirm the reliability of the study data. 
Sample selection will be based on the procedure and acceptance of the results will be as per the 
in-house SOP. The results will be presented in the bioanalytical report. 
Primary aliquot used for study sample analysis will be discarded after completion of analysis. 
Any missing samples will be reported as `M’ and non-reportable concentration values due to 
insufficient volume or any other reason as per in-house procedure will be reported as ‘NR’. 
8.9.3. 
Pharmacodynamic parameters & analysis 
8.9.3.1. 
Parameters 
Pharmacodynamic effect for Serum C-terminal telopeptide (CTX) and Serum N-terminal 
propeptide of type 1 collagen (P1NP) will be assessed as % reduction from baseline. The 
following pharmacodynamic parameter will be computed for denosumab Serum C-terminal 
telopeptide (CTX) and Serum N-terminal propeptide of type 1 collagen (P1NP) using non-
compartmental model of Phoenix® WinNonlin® Version 8.1 or higher (Certara L.P.) 
For Serum C-terminal telopeptide (CTX): 
• 
Primary PD Parameters: Emax and AUEC0-t after first dose (These will be primary 
parameters for EMA Submission only) 
• 
Secondary PD Parameters: Tmax after first dose; Tmax, Emax and AUEC0-t after second 
and individual patient’s PD parameters after third-dose. 
For Serum N-terminal propeptide of type 1 collagen (P1NP): 
• 
Secondary PD Parameters: Tmax, Emax and AUEC0-t after first, second and individual 
patient’s PD parameters after third-dose. 
Note: Pharmacodynamic effect for Serum C-terminal telopeptide (CTX) and Serum N-terminal 
propeptide of type 1 collagen (P1NP) will be assessed as decrease from the baseline. 
Pharmacodynamic Parameters: 
Emax 
: 
Maximum % reduction from baseline. 
AUEC0-t 
: 
Area under the % reduction from baseline versus time curve from time zero to 
the last measurable concentration as calculated by linear trapezoidal method 
Tmax 
: 
Time of the maximum % reduction from baseline.  

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8.9.3.2. 
Pharmacodynamic analysis  
Pharmacodynamic analysis will be performed on the available concentration data of all the 
eligible patients of the study. Criteria for exclusion of Pharmacodynamic parameters (for first 
dose only) will be as follows:  
• 
Three consecutive missing or non-reportable samples before actual Tmax may significantly 
influence all Pharmacodynamic parameter estimations. Hence, all Pharmacodynamic 
parameters will be excluded. 
• 
Three consecutive missing or non-reportable samples in terminal phase (i.e. after Tmax) may 
significantly influence the AUEC0-t. Hence, AUEC0-t will be excluded. 
8.10. 
Immunogenicity Assessments  
8.10.1. 
Sampling Schedule for Immunogenicity evaluation 
8.5 ml of blood will be withdrawn for estimation of Immunogenicity parameters at Pre-dose 
(baseline), at day 14, 31, 61, 91, 181*, 211, 241, 271 and 361 with respect to first dosing. 8.5 
ml of blood will be withdrawn for estimation of Immunogenicity parameters at Pre- third dose 
(baseline), at day 2*, 31, 61, 91 and 181 with respect to third dosing. 
*Note: Blood sample for immunogenicity on day 181 will be collected prior to 2nd dose 
administration. 
Blood sample for immunogenicity on day 361 will be collected prior to 3rd dose administration 
Additionally, serum samples should also be collected at the final visit from participants who 
discontinued study IMP or were withdrawn from the study. These samples will be tested by the 
sponsor or sponsor's designee. 
Window period for immunogenicity samples collection will be according to window period for 
visit as mentioned in SoA. 
Serum samples will be screened for antibodies binding to denosumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to denosumab further characterize the immunogenicity of denosumab. 
Samples collected for immunogenicity analyses may additionally be used to evaluate safety or 
efficacy aspects that address concerns arising during or after the study period. Genetic analyses 
will not be performed on these serum samples. Participant confidentiality will be maintained. 
Predose sample may be used for establishing in study cut point or for method validation 
purposes. 
8.10.2. 
Analytical Procedures  
The detection and characterization of antibodies to denosumab will be performed using 
validated assay methods. Antibodies may be further characterized and/or evaluated for their 
ability to neutralize the activity of the study IMP(s).  
Bioanalytical study plan for Immunogenicity assessment will be prepared before study sample 
analysis. The analysts concerned will not have access to the randomization schedule till the 
completion of bioanalytical phase. All collected samples will be analyzed. If any participant is 
dropped out after dosing and no post dose samples are collected, then pre-dose sample of such 

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participant will not be analyzed. All samples collected in the extension phase of the study will 
be analyzed. 
The serum samples for assessment of Immunogenicity will be analyzed by three-tiered 
approach at Lambda Therapeutic Research Limited, Ahmedabad. The anti-denosumab 
antibodies will be detected using a validated ELISA based screening assay. All samples deemed 
positive by the screening assay shall be re-assessed using ELISA based validated confirmatory 
assay and confirmed positive samples will be submitted for validated ELISA based titer assay 
and validated ligand binding based neutralizing antibody (NAb) assay. Respective positive and 
negative controls will be included in each assay. The details for the preparation of positive 
controls, negative controls, analytical run organization, analytical run acceptance criteria, 
determination of run specific cut points and criteria for repeat analysis as mentioned in the 
respective in-house procedure or respective bioanalytical study plan will be followed during 
analysis. 
Primary aliquot used for study sample analysis will be discarded after completion of analysis. 
Any missing samples will be reported as `M’ and non-reportable concentration values due to 
insufficient volume or any other reason as per in-house procedure will be reported as ‘NR’.  
Bioanalytical data including PK, PD and Immunogenicity will be transferred to 
Pharmacokinetics and Statistics team for further analysis. 
8.11. 
Medical Resource Utilization and Health Economics  
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 

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9. 
Statistical Considerations  
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is 
outlined below. Specific details will be provided in the Statistical Analysis Plan (SAP).  
9.1. 
Sample Size Determination  
Pharmacokinetic endpoint 
Based on in-house data, total CV was found to be ~47% for AUC0-t of denosumab. Hence, the 
sample size has been calculated considering the same using SAS with following estimates.  
• 
T/R ratio = 95.0-105.0% 
• 
CV% = 47% (AUC0-t) 
• 
alpha = 5% 
• 
Power = 90% 
• 
90% CI = 80.00-125.00%  
Based on above estimates, 117 completers per arm will be required. Considering~20% 
dropouts/withdrawals and 1:1 treatment allocation ratio, 296 patients (148 patients per arm) 
will be required. 
Pharmacodynamic endpoint 
Based on the literature[11], back calculated inter subject CV was found to be ~13% for AUEC0-
t in healthy volunteers for reduction from baseline for serum CTX. Hence, the sample size has 
been calculated considering the same using SAS with following estimates.  
• 
T/R ratio = 95.0-105.0% 
• 
CV% = 13% (AUEC0-t) 
• 
alpha = 2.5% 
• 
Power = 90% 
• 
95% CI = 80.00-125.00%  
Based on above estimates, 26 completers (13 completers per arm) will be required. 
Considering ~20% dropouts/withdrawals and 1:1 treatment allocation ratio, 34 patients (17 
patients per arm) will be required. 
Immunogenicity assessment 
A sample size of 54 completers per group would ensure that the upper bound of the 95% CI of 
ADA incidence will not be larger than 10% assuming no more than one patient per group is 
observed to be positive for ADA at the end of treatment duration and using a Clopper-Pearson 
exact method to calculate the 95% CI for a sample proportion. Considering ~20% dropouts/ 
withdrawals, 136 patients (68 patients per arm) will be required for immunogenicity 
assessment. 
BMD assessments 
An equivalence test of means using two one-sided equal-variance t-tests with sample sizes of 
220 completers in each treatment group achieves 90% power at a 2.5% significance level when 
the equivalence limits are -1.45 and 1.45, the actual difference between the means is 0.0, and 

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the standard deviation is assumed as 4.20 in each group. Total 440 completers (220 in each 
treatment group) will be required to prove therapeutic equivalence between test and reference. 
Considering above all approaches, ~20% dropouts/withdrawals and 1:1 treatment allocation 
ratio, 552 patients (276 patients per arm) will be enrolled for BMD assessment. 
9.2. 
Populations for Analyses  
Analysis populations are defined as below.  
• Safety set: The safety set is defined as all randomized patients who will receive at least 
one dose of study medication. 
• Pharmacokinetic (PK) set: The PK set is defined as all patients who will complete the 
study and has no major protocol deviation which can significantly influence the 
pharmacokinetic parameter estimation. 
• Pharmacodynamic (PD) set: The PD set is defined as all patients who will complete the 
study and has no major protocol deviation which can significantly influence the 
pharmacodynamic parameter estimation. 
• Intent-To-Treat (ITT) set: The ITT set is defined as all randomized patients who will 
receive at least one dose of study medication. 
Sensitivity analysis will be performed on patients in ITT set for primary endpoint mean 
percentage change in bone mineral density (BMD) of lumbar spine from baseline to 12 
months. For this analysis, missing values of individual BMD of lumbar spine at 12 
months will be imputed with value as baseline value ± 0.73 (i.e. half of equivalence 
limit 1.45 considered in the study). Imputation will be done with value as (baseline value 
- 0.73) for test and (baseline value + 0.73) for reference product.[12]Additionally, 
imputation will be done with value as (baseline value + 0.73) for test and (baseline value - 0.73) 
for reference product. 
• Modified Intent-To-Treat (mITT) set: The mITT set is defined as all randomized 
patients who will receive at least one dose of study medication and will undergo at least 
one post-dose efficacy evaluation. Missing data will be imputed using last observation 
carried forward (LOCF) technique. 
• Per-protocol (PP) set: The PP set is defined as all randomized patients who will 
complete the study with no major protocol deviations. 
Safety set will be used for the safety and immunogenicity analysis, PK set will be used for 
pharmacokinetic analysis and PD set will be used for pharmacodynamic analysis. Patients 
included in ITT, mITT and PP set will be used for the evaluation of the efficacy end points. 
9.3. 
Statistical Analyses  
The statistical analysis plan will be finalized prior to un-blinding and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 

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All the statistical analysis will be performed using SAS Version 9.4 or higher (SAS Institute 
Inc., USA).  
9.3.1. 
PK and PD data 
Descriptive statistics and statistical analysis will be performed on patients in PK set and PD set. 
Analysis of Variance (ANOVA) 
• For USFDA: 
The ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of denosumab after 
first dose, ln-transformed pharmacodynamic parameters Emax and AUEC0-t of % reduction from 
baseline Serum C-terminal telopeptide (Serum CTX) and % reduction from baseline Serum N-
terminal propeptide of type 1 collagen (P1NP) after first dose will be subjected to Analysis of 
Variance (ANOVA). 
ANOVA model will include the term Centre, Centre*Formulation and Formulation as fixed 
effect.  
If the Centre*Formulation interaction term is not statistically significant at a 5% level of 
significance, then the interaction term will be dropped from the model and the statistical analysis 
will be re-performed excluding the interaction term.  
Each ANOVA will include calculation of LSMs, the difference between adjusted formulation 
means and the standard error associated with this difference. This statistical analysis will be 
performed using PROC MIXED of SAS procedure.  
An F-test will be performed to determine the statistical significance of the effects involved in 
the model at a significance level of 5 % (alpha = 0.05). 
Note: In case there is a centre with less than five patients, then that data will be pooled with the 
subsequent centre. 
• For EMA: 
The ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of denosumab after 
first dose, ln-transformed pharmacodynamic parameters Emax and AUEC0-t of % reduction from 
baseline Serum C-terminal telopeptide (Serum CTX) and % reduction from baseline Serum N-
terminal propeptide of type 1 collagen (P1NP) after first dose will be subjected to Analysis of 
Variance (ANOVA). 
ANOVA model will include the term Centre and Formulation as fixed effect.  
Each ANOVA will include calculation of LSMs, the difference between adjusted formulation 
means and the standard error associated with this difference. This statistical analysis will be 
performed using PROC GLM of SAS procedure.  
An F-test will be performed to determine the statistical significance of the effects involved in 
the model at a significance level of 5 % (alpha = 0.05). 
Note: In case there is a centre with less than five patients, then that data will be pooled with the 
subsequent centre. 

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90%/95% confidence intervals 
90% confidence intervals for the ratio of geometric least squares means of test and reference 
formulations will be calculated and reported for ln-transformed pharmacokinetic parameters 
Cmax, AUC0-t and AUC0-∞ of denosumab after first dose. 
90% and 95% confidence intervals will be calculated and reported for ln-transformed 
pharmacodynamic parameters Emax and AUEC0-t of % reduction from baseline serum C-
terminal telopeptide (Serum CTX) and % reduction from baseline Serum N-terminal propeptide 
of type 1 collagen (P1NP) after first dose.  
Power 
The power of the study will be computed and reported for ln-transformed pharmacokinetic 
parameters Cmax, AUC0-t and AUC0-∞ of denosumab after first dose and ln-transformed 
pharmacodynamic parameters Emax and AUEC0-t of % reduction from baseline Serum C-
terminal telopeptide (Serum CTX) and % reduction from baseline Serum N-terminal propeptide 
of type 1 collagen (P1NP) after first dose. 
Ratio Analysis 
Ratio of geometric least square means of test and reference formulations will be computed and 
reported for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of 
denosumab after first dose and ln-transformed pharmacodynamic parameters Emax and    
AUEC0-t of % reduction from baseline Serum C-terminal telopeptide (Serum CTX) and % 
reduction from baseline Serum N-terminal propeptide of type 1 collagen (P1NP) after first dose. 
Inter-Patient Variability 
Inter-patient variability will be computed and reported for ln-transformed pharmacokinetic 
parameters Cmax, AUC0-t and AUC0-∞ of denosumab after first dose and ln-transformed 
pharmacodynamic parameters Emax and AUEC0-t of % reduction from baseline Serum C-
terminal telopeptide (Serum CTX) and % reduction from baseline Serum N-terminal propeptide 
of type 1 collagen (P1NP) after first dose. 
Missing and Non-Reportable Values 
Any missing samples (M) or not reportable concentration values (NR) will not be included in 
the pharmacokinetic, pharmacodynamic and statistical analysis. 
Bioequivalence criteria 
For USFDA: 
Based on the statistical results of 90% confidence interval for the ratio of the geometric least 
square means for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0- for 
denosumab after first dose, conclusion will be drawn for Test Product-T vs. Reference Product-
R. 
Bioequivalence of the test product with that of the reference product will be concluded, if 90% 
confidence interval falls within the acceptance range of 80.00-125.00% for ln-transformed 
pharmacokinetic parameters Cmax, AUC0-t and AUC0- of denosumab after first dose.  
 
 

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For EMA: 
Based on the statistical results of 90% confidence interval for the ratio of the geometric least 
square means for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0- for 
denosumab after first dose and 95% confidence interval for the ratio of the geometric least 
square means for ln-transformed pharmacodynamic parameters Emax and AUEC0-t for % 
reduction from baseline Serum C-terminal telopeptide (Serum CTX) after first dose, conclusion 
will be drawn for Test Product-T vs. Reference Product-R. 
Bioequivalence of the test product with that of the reference product will be concluded, if 90% 
confidence interval falls within the acceptance range of 80.00-125.00% for ln-transformed 
pharmacokinetic parameters Cmax, AUC0-t and AUC0- of denosumab after first dose and 95% 
confidence interval falls within the acceptance range of 80.00-125.00% for ln-transformed 
pharmacodynamic parameter Emax and AUEC0-t of % reduction from baseline Serum C-terminal 
telopeptide (Serum CTX) after first dose. 
9.3.2. 
Baseline and Demographic Characteristics 
Baseline and demographic characteristics will be summarized using descriptive statistics by 
treatment.  
9.3.3. 
Efficacy / Pharmacodynamic Data 
Categorical variable will be summarized with frequency distribution. Continuous variables will 
be summarized with mean, standard deviation, median, minimum and maximum. 
The primary endpoint is mean percentage change in bone mineral density (BMD) of lumbar 
spine from baseline to 12 months. 
A point estimate and a two-sided 95% confidence interval will be computed for the treatment 
groups and their differences. 95% CI will be calculated using ANCOVA considering baseline 
as a covariate.  
Descriptive statistics for mean percentage change in BMD at lumber spine from baseline to 12 
months will be calculated. Independent t-test will be used to evaluate the between treatment 
comparison. 
The study conclusion will be based on the primary endpoint (PK & BMD/PD), which are 
independent from each other.  Hence, multiplicity adjustment to control the study-wise overall 
Type I error rate would not be applicable.  
Acceptance criteria: Therapeutic equivalence of the test with the reference treatment will be 
concluded if the 95% CI of the difference between test and reference for mean percentage 
change in BMD at lumber spine from baseline to 12 months is within the range of ± 1.45. 
Note: Therapeutic equivalence of the test with the reference treatment will be claimed on ITT 
set for USFDA and on PP set for EMA.  
Secondary endpoints of the study will be as below: 
• Mean percentage change in bone mineral density (BMD) of lumbar spine from baseline to 
06 months between denosumab and denosumab-ref 

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• Mean percentage change in BMD of femoral neck and total hip from baseline to 06 and 12 
months between denosumab and denosumab-ref 
• Mean percentage reduction in serum N-terminal propeptide of type 1 collagen (P1NP) 
concentrations from baseline to 06 and 12 months between denosumab and denosumab-ref 
• Mean percentage reduction in CTX serum concentrations from baseline to 06 and 12 
months between denosumab and denosumab-ref 
Descriptive statistics for mean percentage change in BMD of lumber spine from baseline to 06 
months and mean percentage change in BMD of femoral neck and total hip from baseline to 06 
and 12 months will be calculated presented. Independent t-test will be used to evaluate the 
between treatment comparison. 
Mean percentage reduction in serum N-terminal propeptide of type 1 collagen (P1NP) and in 
serum CTX concentrations from baseline to 06 and 12 months will be calculated and reported.  
Fracture incidence rate will be provided and compared. 
9.3.4. 
Immunogenicity Data 
Incidence of anti-denosumab antibody at respective visits will be presented. The data post-
switching will be presented separately as an amendment to the main report. In those patients 
who show clinical concerns or analytical concerns of immunogenicity, specific patients PK and 
PD will be assessed for interpreting the impact of immunogenicity on PK and PD. 
9.3.5. 
Safety Data 
All patients who have received at least one dose of the study medicine will be included in the 
safety evaluation. Result obtained when evaluating safety and tolerability (adverse events, vital 
signs, clinical laboratory tests that are out of the range) will be listed and evaluated by 
descriptive statistics. 
Safety data collected after 12 months will be presented in separate tables and listings.  
 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Current ICH Good Clinical Practice (GCP) Guidelines 
• 
Good Clinical Practices Guidelines for conduct of clinical studies in India, formulated 
by the Central Drugs Standard Control Organisation and adopted by the Drugs 
Technical Advisory Board 
• 
New Drugs & Clinical Trial Rules, 2019 of Central Drugs Standard Control 
Organization (CDSCO) 
• 
Applicable local country-specific laws, guidelines and regulations 
10.1.1.1. Investigator Responsibilities 
The investigator is responsible for ensuring that: (a) the study is performed in accordance with 
the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable 
regulatory and country-specific requirements; (b) providing oversight of the conduct of the 
study at the site and adherence to requirements of 21 CFR; ICH guidelines; the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable); New Drugs and Clinical Trial 
Rules, 2019; and all other applicable local regulations; (c) providing written summaries of the 
status of the study to the IRB/IEC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/IEC and regulatory authority; (d) 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human 
participants. Compliance with this standard provides public assurance that the rights, safety, 
and well-being of study participants are protected, consistent with the principles that originated 
in the Declaration of Helsinki, and that the study data are credible.  
10.1.1.2. Protocol Amendments 
Neither the investigator nor the sponsor or its designee will modify this protocol without a 
formal amendment by the sponsor. All protocol amendments must be issued by the sponsor or 
its designee and signed and dated by the investigator. Protocol amendments, if become 
necessary before initiation or during the course of a clinical trial, all such amendments should 
be submitted to the appropriate regulatory authority in writing along with the approval by the 
ethics committee, if available, which has granted the approval for the study. No deviations from 
or changes to the protocol should be implemented without prior written approval of the ethics 
committee and appropriate regulatory authority except when it is necessary to eliminate 
immediate hazards to the trial subject or when change involves only logistic or administrative 
or minor aspects of the trial. All such exceptions must be immediately notified to the ethics 
committee as well as to the appropriate regulatory authority. Administrative or logistic changes 
or minor amendments in the protocol should be notified to the appropriate regulatory authority 

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within thirty days. Documentation of amendment approval by the investigator and IEC/IRB 
must be provided to the sponsor or its designee.  
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing 
any departure from the protocol. In all cases, contact with the sponsor or its designee must be 
made as soon as possible to discuss the situation and agree on an appropriate course of action. 
The data recorded in the CRF and source documents will reflect any departure from the 
protocol, and the source documents will describe this departure and the circumstances requiring 
it. 
10.1.1.3. Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. The protocol, protocol amendments, ICF, Investigator 
Brochure, and other relevant documents (e.g., advertisements) must be submitted to an IRB/IEC 
by the investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
Status of enrolment of the trial subjects shall be submitted to the appropriate regulatory 
authority on quarterly basis or as appropriate as per the duration of treatment in accordance 
with the approved clinical trial protocol, whichever is earlier. Further, status report of each 
clinical trial, as to whether it is ongoing, completed or terminated, will be submitted to 
appropriate regulatory authority and ethic committee as per local regulations. In case of studies 
prematurely discontinued for any reason including lack of commercial interest in pursuing the 
new drug application, the detailed reasons for such termination shall be communicated to the 
appropriate regulatory authority within thirty working days of such termination and a summary 
report should be submitted within 3 months to IRB/IEC and appropriate regulatory authority. 
10.1.1.4. Required Prestudy Documentation 
The following documents must be provided to the sponsor or its designee before shipment of 
study intervention to the study site: 
• 
Protocol and amendment(s), if any, signed and dated by the principal investigator 
• 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee. 
• 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or 
a member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study. 
• 
Regulatory authority approval or notification, if applicable 
• 
Signed and dated statement of investigator (eg, Form FDA 1572) or letter of undertaking 
by investigator, as applicable 

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• 
Documentation of investigator qualifications (eg, curriculum vitae) 
• 
Completed investigator financial disclosure form from the principal investigator, where 
required 
• 
Signed and dated clinical trial agreement, which includes the financial agreement 
• 
Any other documentation required by local regulations 
The following documents must be provided to the sponsor or its designee before enrollment of 
the first participant: 
• 
Completed investigator financial disclosure forms from all sub-investigators 
• 
Documentation of sub-investigator qualifications (eg, curriculum vitae) 
• 
Name and address of any local laboratory conducting tests for the study, and a dated copy 
of current laboratory normal ranges for these tests, if applicable 
• 
Local laboratory documentation demonstrating competence and test reliability 
(eg, accreditation/license), if applicable 
10.1.1.5. Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or sponsor or its designee where required) will 
provide the IRB/IEC with current and complete copies of the following documents (as required 
by local regulations): 
• 
Final protocol and, if applicable, amendments 
• 
Sponsor or its designee approved ICF (and any other written materials to be provided to 
the participants) 
• 
IB (or equivalent information) and amendments/addenda 
• 
Sponsor or its designee approved participant recruiting materials 
• 
Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable 
• 
Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IRB/IEC) 
• 
Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for participants 
• 
Any other documents that the IRB/IEC requests to fulfill its obligation 
This study will be undertaken only after the IRB/IEC has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct, unless required locally), the ICF, 
applicable recruiting materials, and participant compensation programs, and the sponsor or its 
designee has received a copy of this approval. This approval letter must be dated and must 
clearly identify the IEC/IRB and the documents being approved. 
During the study the investigator (or sponsor or its designee where required) will send the 
following documents and updates to the IRB/IEC for their review and approval, where 
appropriate: 
• 
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct) 

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Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
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• 
Revision(s) to ICF and any other written materials to be provided to participants 
• 
If applicable, new or revised participant recruiting materials approved by the sponsor or its 
designee 
• 
Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable 
• 
New edition(s) of the IB and amendments/addenda 
• 
Summaries of the status of the study at intervals stipulated in guidelines (quarterly basis or 
as appropriate as per the duration of treatment in accordance with the approved clinical 
trial protocol, whichever is earlier) 
• 
Reports of SAE, unlisted/unexpected, and associated with the study intervention 
• 
New information that may adversely affect the safety of the participants or the conduct of 
the study 
• 
Deviations from or changes to the protocol to eliminate immediate hazards to the 
participants 
• 
Report of deaths of participants under the investigator's care 
• 
Notification if a new investigator is responsible for the study at the site 
• 
Development Safety Update Report and Line Listings, where applicable 
• 
Any other requirements of the IRB/IEC 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF 
revisions must be submitted promptly to the IRB/IEC for review and approval before 
implementation of the change(s). 
At least once a year, the IRB/IEC will be asked to review and reapprove this study, where 
required. 
At the end of the study, the investigator (or sponsor or its designee, where required) will notify 
the IEC/IRB about the study completion. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study. 
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure. 
10.1.3. 
Informed Consent Process 
Each participant must freely give informed, written consent according to local requirements 
after the nature of the study has been fully explained. The ICF(s) must be signed before 
performance of any study-related activity. The ICF(s) and patient information sheet that is/are 
used must be approved by the sponsor or its designee; by the reviewing IEC/IRB and 
appropriate regulatory authority and be in a language that the participant can read and 
understand. Any changes in the informed consent documents should be approved by the ethics 
committee and submitted to the appropriate regulatory authority before such changes are 
implemented. The informed consent should be in accordance with principles that originated in 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 78 of 107 
 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.  
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participants the aims, methods, reasonably anticipated 
benefits, and potential hazards of the study, and any discomfort participation in the study may 
entail in language potential participant may understand and comfortable with. Participants will 
be informed that their participation is voluntary and that they may withdraw consent to 
participate at any time. They will be informed that choosing not to participate will not affect 
the care the participant will receive for the treatment of her disease. Participants will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a 
participant identification register for the purposes of long-term follow up if needed and that 
their records may be accessed by health authorities and authorized sponsor personnel without 
violating the confidentiality of the participant, to the extent permitted by the applicable law(s) 
or regulations. By signing the ICF the participant or legally acceptable representative is 
authorizing such access, which includes permission to obtain information about her survival 
status. It also denotes that the participant agrees to allow her study physician to recontact the 
participant for the purpose of obtaining consent for additional safety evaluations, and 
subsequent disease-related treatments, if needed.  
The participant will be given sufficient time to read the ICF and the opportunity to ask 
questions. After this explanation and before entry into the study, participants will be required 
to sign and date a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements  where applicable, and the IRB/IEC or study center.  
After having obtained the consent, a copy of the ICF must be given to the participant. The 
medical record must include a statement that written informed consent was obtained before the 
participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. Participants must be 
re-consented to the most current version of the ICF(s) during their participation in the study.  
Participants who are rescreened are required to sign a new ICF. 
If the participant is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the participant is obtained. 
The consent will mention that if participant discontinue before 12 months, follow-up for safety 
will be needed for up to 12 months, for scientific value.  The consent will clearly mention that 
the subject is expected to follow-up for an additional period of 6 months after the initial 12 
months treatment for assessment of safety and immunogenicity, if the investigators requests. It 
will be mentioned clearly the scientific importance of the follow-up information. 
10.1.4. 
Data Protection 
10.1.4.1. Privacy of Personal Data 
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. Participants will be 
assigned a unique identifier by the sponsor or its designee. Any participant records or datasets 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 79 of 107 
 
that are transferred to the sponsor or its designee will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable local and global data privacy protection laws and regulations. 
Appropriate technical and organizational measures to protect the personal data against 
unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss or 
alteration must be put in place. Sponsor personnel whose responsibilities require access to 
personal data agree to keep the identity of participants confidential. 
The informed consent obtained from the participant includes explicit consent for the processing 
of personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, independent auditor 
appointed by sponsor under confidentiality agreements, appropriate IRB/IEC members, and 
inspectors from regulatory authorities. This consent also addresses the transfer of the data to 
other entities and to other countries. 
The participant has the right to request through the investigator access to his or her personal 
data and the right to request rectification of any data that are not correct or complete. Reasonable 
steps will be taken to respond to such a request, taking into consideration the nature of the 
request, the conditions of the study, and the applicable laws and regulations. 
PK, PD and immunogenicity research is not conducted under standards appropriate for the 
return of data to participants. In addition, the sponsor or its designee cannot make decisions as 
to the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to participants or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will 
be protected by the same standards applicable to all other clinical data. 
10.1.5. 
Publication Policy / Dissemination of Clinical Study Data 
All information, including but not limited to information regarding denosumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, 
prior clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including biomarker research data, generated as a result of 
this study, are considered confidential and remain the sole property of the sponsor. The 
investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study and will not use it for other purposes without the sponsor's prior written 
consent. 
For all the publications related to this study, the Sponsor Publication Policy will be followed.  
10.1.6. 
Data Quality Assurance 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator 
and study-site personnel before the study, and periodic monitoring visits by the sponsor, and 
direct transmission of clinical laboratory data from a central laboratory, imaging data to central 
imaging vendor into the sponsor's data base. Written instructions will be provided for collection, 
handling, storage, and shipment of samples.  

Product: Denosumab 
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Clinical Study Protocol: 0774-19; Version No.: 2.0 
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Confidential and Proprietary 
 
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The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) will be provided in the 
monitoring plans and/or contracts. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator as per CTA after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
10.1.7. 
Case Report Form Completion 
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in CRF. Guidelines for CRF completion 
will be provided and reviewed with study-site personnel before the start of the study. All CRF 
entries, corrections, and alterations must be made by the investigator or authorized study-site 
personnel. The investigator must verify that all data entries in the CRF are accurate and correct. 
A CRF must be completed for each participant enrolled in the study. Completed CRFs are the 
sole property of Intas Pharmaceutical Limited (Biopharma Division) and may not be made 
available in any form to third parties without written permission, except for authorized 
representatives of Intas Pharmaceutical Limited (Biopharma Division) and appropriate 
regulatory authorities. 
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor. 

Product: Denosumab 
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Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
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Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered 
into CRF in English. The CRF must be completed as soon as possible after a participant visit 
and the forms should be available for review at the next scheduled monitoring visit. 
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways: 
• 
Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool). 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel. 
Data management 
CDM will set up the study as specified in Data Management Plan. Data Validation including 
DCF (Data clarification Form, if applicable) / Query generation and resolution, medical coding, 
reconciliation of external data etc. will be done as per Data Management Plan (DMP). Detailed 
scope of Clinical Data Management will be described in the DMP. Medical coding will be done 
by using standard medical dictionaries such as MedDRA and/or WHODD. 
10.1.8. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the 
following: participant identification, eligibility, and study identification; study discussion and 
date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; IMP receipt/dispensing/return records; study IMP administration 
information; and date of study completion and reason for early discontinuation of study IMP or 
withdrawal from the study, if applicable.  
The author of an entry in the source documents should be identifiable. 
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document). 
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as 
follows: 
• 
Referral letter from treating physician or 
• 
Complete history of medical notes at the site 

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Clinical Study Protocol: 0774-19; Version No.: 2.0 
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Confidential and Proprietary 
 
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• 
Discharge summaries 
• 
Diagnostic reports and summaries 
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents. 
10.1.9. 
Study and Site Start and Closure 
10.1.9.1. First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
10.1.9.2. Study/site Termination 
The sponsor or its designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• 
Discontinuation of further study IMP development 
For site termination: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The Investigator shall promptly inform the participant 
and the participant should be seen as soon as possible for the assessments described in Section 
8 for a discontinued or withdrawn participant. The investigator will be responsible to assure 
appropriate participant therapy and/or follow-up.  
10.1.10. 
Monitoring 
The sponsor will use a combination of monitoring techniques: central, remote, or on-site 
monitoring to monitor this study. 

Product: Denosumab 
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Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
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The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRF with the source documents (eg, 
hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
CRF are known to the sponsor and study-site personnel and are accessible for verification by 
the sponsor study-site contact. If electronic records are maintained at the study site, the method 
of verification must be discussed with the study-site personnel.  
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. The sponsor expects 
that, during monitoring visits, the relevant study-site personnel will be available, the source 
documents will be accessible, and a suitable environment will be provided for review of study-
related documents. The monitor will meet with the investigator on a regular basis during the 
study to provide feedback on the study conduct. 
The monitor will review and verify: the diagnosis, medical history, inclusion/exclusion criteria, 
physical exams and vital signs, efficacy evaluations; safety and laboratory evaluations/tests, 
AEs and SAEs, concomitant medications and procedures, and the use of study IMP. Specific 
items required as source documents will be reviewed with the Investigator prior to the study. 
In addition, the monitor will verify that standards of GCP were followed. This includes, but is 
not limited to: completion of regulatory documents (e.g., FDA Form 1572, financial disclosure, 
Institutional Review Board [IRB]/Independent Ethics Committee [IEC] approvals, submitting 
safety/progress reports, etc.) ensuring Informed Consent was adequately performed and 
documented, that study IMP dispensation and accountability was handled properly, SAEs were 
reported to the Sponsor and IRB/IEC in a timely manner, that the protocol was followed and 
that the rights and welfare of participants were protected. 
Findings from the review of CRFs/eCRFs, source documents, and study conduct will be 
discussed with the Investigator. The dates of the monitoring visits will be recorded by the 
monitor in a sign-in log to be kept at the site.  
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the 
progress of the study at the site. 
Medical monitoring plan will be prepared according to standard procedure and followed during 
the study. 
Central monitoring will take place for data identified by the sponsor as requiring central review. 
10.1.11. 
On-Site Audits 
Representatives of the sponsor's clinical quality assurance department or independent auditors 
appointed by sponsor may visit the study site at any time during or after completion of the study 
to conduct an audit of the study in compliance with regulatory guidelines and company policy. 
These audits will require access to all study records, including source documents, for inspection. 
Participant privacy must, however, be respected. The investigator and study-site personnel are 
responsible for being present and available for consultation during routinely scheduled study-
site audit visits conducted by the sponsor or its designees.  

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 84 of 107 
 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of 
a regulatory submission. The investigator should immediately notify the sponsor or its designee 
if he or she has been contacted by a regulatory agency concerning an upcoming inspection. 
10.1.12. 
Record Retention 
In compliance with the ICH/GCP guidelines and/or clinical trial agreements/contracts as 
applicable, the investigator/institution will maintain all CRF and all source documents that 
support the data collected from each participant, as well as all study documents. The 
investigator/institution will take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents must be retained for period defined in clinical trial agreements/contract 
based on regulatory submission and requirement. These documents will be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the 
sponsor or its designee. It is the responsibility of the sponsor or its designee to inform the 
investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor or its designee must be notified in writing of the name 
and address of the new custodian. Under no circumstance shall the investigator relocate or 
dispose of any study documents before having obtained written approval from the sponsor or 
its designee. 
If it becomes necessary for the sponsor or its designee or the appropriate regulatory authority 
to review any documentation relating to this study, the investigator/institution must permit 
access to such reports. 
10.1.13. 
Insurance 
Intas Pharmaceutical Limited (Biopharma Division) is the sponsor of this study and will finance 
this study. 
Lambda Therapeutic Research Limited, Ahmedabad on behalf of the sponsor/designee will take 
out reasonable third-party liability insurance cover in accordance with all local legal 
requirements. The civil liability of the investigator, the persons instructed by him/her and the 
hospital, practice or institute in which they are employed and the liability of the Sponsor in 
respect of financial loss due to personal injury and other damage which may arise as a result of 
the carrying out of this study are governed by the applicable local law. As a precautionary 
measure, the investigator, the persons instructed by him/her and the hospital, practice or 
institute may be included in such cover in respect of work done by them in carrying out this 
study to the extent that the claims are not covered by their own professional indemnity 
insurance. 
Lambda Therapeutic Research Limited, Ahmedabad on behalf of the Sponsor will arrange for 
participants participating in this study to be insured against financial loss due to personal injury 
caused by the pharmaceutical products being tested or by medical steps taken in the course of 
the study. 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 85 of 107 
 
10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 5 will be performed by the clinical laboratory. Further details can be 
found in laboratory manual. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 
5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Table 5. Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
(Local lab) 
Platelet Count  
Red blood cell 
(RBC) Count 
Hemoglobin 
Hematocrit 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
Total WBC count 
with differential in 
%: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Note: A WBC evaluation may include any abnormal cells, which will then 
be reported by the laboratory. A RBC evaluation may include abnormalities 
in the RBC count, RBC parameters, or RBC morphology, which will then 
be reported by the laboratory. In addition, any other abnormal cells in a 
blood smear will also be reported. 
Clinical 
Chemistry 
(Central 
lab) 
Blood urea 
nitrogen 
(BUN), 
Uric acid, 
Lactate 
dehydrogenase 
Sodium, 
Potassium, 
Chloride 
Phosphate 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
Creatinine 
Serum PTH 1-
84 
Serum TSH 
25 (OH) 
Vitamin D 
Albumin-
adjusted  
Calcium$, 
 
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-
Pyruvic 
Transaminase 
(SGPT) 
Total Protein, 
Albumin, 
Globulin, 
A/G ratio, 
Gamma-glutamyl 
transferase (GGT) 
Non-fasting 
random 
Glucose  
 
Alkaline 
phosphatase 
 
Routine 
Urinalysis 
(Central 
lab) 
• Specific gravity,  
• pH, glucose, protein, blood, 
ketones, urobilinogen, nitrite 
• Microscopic examination  
• Red blood cells, White blood cells, 
epithelial cells, crystals, casts 
Note: In the microscopic examination, observations other than the presence 
of WBC, RBC and casts may also be reported by the laboratory. 

Product: Denosumab 
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Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
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Virology 
(Central 
lab) 
• Human Immunodeficiency Virus (HIV-1 and HIV-2 Antibody and 
Antigen (p24) Evaluation) 
• Hepatitis B surface antigen (HBsAg)  
• Hepatitis C virus (HCV RNA or Hepatitis C Antibody Test) 
Other 
Screening 
Tests 
(Central 
lab) 
• Follicle-stimulating hormone (as needed) 
• Highly sensitive Serum human chorionic gonadotropin (hCG) 
pregnancy test 
$ Albumin adjusted calcium will be performed at local lab. 
Investigators must document their review of each laboratory safety report in source documents 
and record in CRF. 
 
 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
An AE is any untoward medical occurrence in a clinical study participant administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily have 
a causal relationship with the study intervention. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH] E2A). 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study IMP administration even though it 
may have been present before the start of the study. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE.  
• AEs not previously observed in the participant that emerge during the protocol-
specified AE reporting period 
• Complications that occur as a result of protocol-mandated IMPs (e.g., invasive 
procedures such as vitreous hemorrhage). AEs that occur prior to assignment of study 
treatment that are related to a protocol-mandated IMP (e.g., invasive procedures). 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study IMP 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE 
unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Such overdoses should be reported regardless of sequelae. All adverse events 
associated with an overdose or incorrect administration of study IMP should be 
recorded on the Adverse Event eCRF. If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 

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• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. An elective surgery/procedure scheduled to occur 
during a study will not be considered an adverse event if the surgery/procedure is 
being performed for a pre-existing condition and the surgery/procedure has been pre-
planned prior to study entry. However, if the pre-existing condition deteriorates 
unexpectedly during the study (e.g., surgery performed earlier than planned), then the 
deterioration of the condition for which the elective surgery/procedure is being done 
will be considered an adverse event. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
a. Results in death 
• Only the AE leading to death should be documented as SAE with an outcome of 
death. Stop date should be the date of death. Other events ongoing at the time of death 
should be recorded as outcome unknown. 
b. Is life-threatening 
• The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event 
is serious. When in doubt as to whether “hospitalization” occurred or was necessary, 
the AE should be considered serious. 
• Hospitalization does not include the following:  
o rehabilitation facilities;  
o hospice facilities;  
o respite care (e.g, caregiver relief);  
o skilled nursing facilities;  
o same-day surgeries (as outpatient/same-day/ambulatory procedures),  
o planned hospitalization required by the protocol (e.g., for study treatment 
administration and intensive PK sampling), 

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o Hospitalization for a preexisting condition, provided that all of the following 
criteria are met: The hospitalization was planned prior to the study or was 
scheduled during the study when elective surgery became necessary because 
of the expected normal progression of the disease. The participant has not 
suffered an AE. 
• An event that leads to hospitalization under the following circumstances is not 
considered to be a SAE, but should be reported as an AE instead:  
o Hospitalization for an AE that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available. 
• Hospitalization or prolongation of hospitalization in the absence of a precipitating 
clinical AE is not in itself an SAE. Hospitalization for elective treatment of a pre-
existing condition that did not worsen from baseline is not considered an AE. Hospital 
admissions for transfusion sessions, anti-cancer therapy, social admission (e.g, 
subject has no place to sleep), administrative admission (e.g, for yearly physical 
examination), protocol-specified admission during a study (e.g, for a procedure 
required by the study protocol), hospitalization for observation without a medical AE, 
and/or surgeries planned before or during a study are not considered SAEs if the 
illness or disease existed before the participant was enrolled in the study, provided 
that it did not deteriorate in an unexpected way during the study. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
• An anomaly detected at or after birth, or any anomaly that results in fetal loss 
f. 
Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical IMP to prevent one of 
the other outcomes listed in the above definition. These events should usually be 
considered serious. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development 
of drug dependency or drug abuse. Additionally, any elective or spontaneous 
abortion or stillbirth is considered an important medical event. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(as in mild, moderate, or severe pain); the event itself may be of relatively minor medical 
significance (such as severe headache). “Serious” is a regulatory definition and is based on 
participant or event outcome or action criteria usually associated with events that pose a threat 
to a participant’s life or vital functions. Seriousness (not severity) serves as the guide for 

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defining regulatory reporting obligations. Severity and seriousness should be independently 
assessed when recording AEs and SAEs on the eCRF. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the participant’s 
medical records, in accordance with the investigator’s normal clinical practice and on 
the appropriate form of the CRF. 
• 
All AEs should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study intervention dosage 
adjusted/temporarily interrupted; study intervention permanently discontinued due to 
this AE; concomitant medication given; non-drug therapy given; participant 
hospitalized/participant’s hospitalization prolonged. The action taken to treat the AE 
should be recorded on the appropriate form of the CRF. 
• 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the participant is lost to follow-
up, or the participant withdraws consent. Every effort should be made to follow all SAEs 
considered to be related to study intervention or trial-related procedures until a final 
outcome can be reported. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records in lieu of completion of the /AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested 
by sponsor or its designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission. 
• 
During the study period, resolution of AEs to baseline grade or better (with dates) should 
be documented on the appropriate form of CRF and in the participant’s medical record 
to facilitate source data verification. If, after follow-up, return to baseline status or 
stabilization cannot be established, an explanation should be recorded on the AE section 
of eCRF. 
• 
A diagnosis (if known) should be recorded on the rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded. If a diagnosis is subsequently established, all 
previously reported AEs based on signs and symptoms should be nullified and replaced 
by one AE report based on the single diagnosis, with a starting date that corresponds to 
the starting date of the first symptom of the eventual diagnosis. 
• 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. However, medically significant AEs occurring secondary to 
an initiating event that are separated in time should be recorded as independent events 
on the AE section of CRF. For example:  

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− 
If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be reported on the CRF.  
− 
If vomiting results in severe dehydration, both events should be reported separately 
on the CRF.  
− 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the CRF.  
− 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the CRF.  
− 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the CRF.  
All AEs should be recorded separately on the AE section of CRF if it is unclear as to 
whether the events are associated. 
• 
A persistent AE is one that extends continuously, without resolution, between participant 
evaluation timepoints. Such events should only be recorded once on the AE section of 
CRF. The initial severity of the event will be recorded at the time the event is first 
reported. If a persistent AE becomes more severe, the most extreme severity should also 
be recorded. Details regarding any increases in severity will be captured on the source 
note. If the event becomes serious, it should be reported to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning that the event became serious; 
see Section for reporting instructions). The CRF should be updated by changing the 
event from "non-serious" to "serious," providing the date that the event became serious, 
and completing all data fields related to SAEs.  
• 
A recurrent AE is one that resolves between participant evaluation timepoints and 
subsequently recurs. Each recurrence of an AE should be recorded as a separate event 
on CRF. 
• 
Please refer to section 8.6.7 for abnormal laboratory values and 8.6.8 for abnormal vital 
sign values. 
• 
If the SAE was due to a hospitalization of the participant, a copy of the discharge 
summary should be made available to the Sponsor or its designee, upon request. In 
addition, a letter from the Investigator that summarizes the events related to the case as 
well as results of any relevant laboratory tests may also be requested. Further, depending 
upon the nature of the SAE, Sponsor or its designee may request copies of applicable 
portions of the participant's medical records. In either case, all participant identifiers, 
with the exception of the participant number, will be redacted on the copies of the 
medical records before submission to sponsor or its designee. 
• 
All deaths that occur during the protocol-specified AE reporting period, regardless of 
relationship to study intervention, must be recorded on the appropriate form of CRF and 
immediately reported to the Sponsor or its designee. Death should be considered an 
outcome and not a distinct event. The event or condition that caused or contributed to 
the fatal outcome should be recorded as the single medical concept on the appropriate 
form of the CRF. Generally, only one such event should be reported. The term "sudden 
death" should be used only for the occurrence of an abrupt and unexpected death due to 
presumed cardiac causes in a participant with or without preexisting heart disease, within 
1 hour after the onset of acute symptoms or, in the case of an unwitnessed death, within 
24 hours after the participant was last seen alive and stable. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, "unexplained death" should 

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be recorded on the appropriate form of the CRF. If the cause of death later becomes 
available (e.g., after autopsy), "unexplained death" should be replaced by the established 
cause of death. 
• 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the Medical History/Current Medical Conditions 
of CRF. 
• 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the AE section of CRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”). 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
o Mild: An event that subject is aware of but is easily tolerated, causing minimal 
discomfort and not interfering with everyday activities. 
o Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
o Severe: An event that is incapacitating and results in the subject's inability to work or 
engage in their usual activities.  
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements. 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. The 
investigator must use clinical judgment to determine the relationship. The investigator must 
also consult the Investigator’s Brochure (IB) and/or Product Information and /or reference 
safety information material provided by sponsor, as applicable, in his/her assessment. 
The following components are to be used to assess the relationship between the test drug and 
the AE; the greater the correlation with the components and their respective elements (in 
number and/or intensity), the more likely the test drug caused the adverse experience (AE). 
The investigator will use clinical judgment to determine the relationship. 
• Exposure: Is there evidence that the participant was actually exposed to the test drug 
such as: reliable history, acceptable compliance assessment (pill count, diary, etc.), 
expected pharmacologic effect, or measurement of drug/metabolite in bodily 
specimen? 
• Temporal relationship of event onset to the initiation of study intervention: Did 
the AE follow in a reasonable temporal sequence from administration of the test drug? 
Is the time of onset of the AE compatible with a drug-induced effect? 

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• Likely cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors? 
• Dechallenge: Was the dose of test drug discontinued or reduced?  
o If yes, did the AE resolve or improve partially or completely, within a 
reasonable time from medication discontinuation? If yes, this is a positive 
dechallenge.  
o If no, this is a negative dechallenge.  
(Note:  This criterion is not applicable if: (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of 
the test drug; or (3) the study is a single-dose drug study.) 
• Rechallenge: Was the participant re-exposed to the test drug in this study?  
o If yes, did the AE recur or worsen? If yes, this is a positive rechallenge.  
o If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study.) 
NOTE: If a rechallenge is planned for an adverse event which was serious and 
which may have been caused by the test drug, or if re-exposure to the test drug 
poses additional potential significant risk to the participant, then the 
rechallenge must be approved in advance by the medical monitor as per dose 
modification guidelines in the protocol. 
• Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the test drug or 
drug class pharmacology or toxicology? The investigator will also consult the 
Investigator’s Brochure (IB) and/or Product Information, for marketed products, in 
his/her assessment. 
• Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event. 
• Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
Causal Attribution Guidance for relationship with drug 
• Yes, there is a reasonable possibility of drug relationship: There is a plausible 
temporal relationship between the onset of the adverse event and administration of 
the study intervention, the adverse event cannot be readily explained by the 
participant's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study intervention; and/or 
the adverse event abates or resolves upon discontinuation of the study intervention 
and, if applicable, reappears upon re-challenge. 
Depending on data collection method employed, drug relationship may be further 
graded as follows: 
o 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)  

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▪ Event definitive pharmacologically or phenomenologically (i.e. an 
objective 
and 
specific 
medical 
disorder 
or 
a 
recognised 
pharmacological phenomenon)  
▪ Rechallenge satisfactory, if necessary 
▪ Key Features: Temporal relationship, no other cause, withdrawal 
response plausible (dechallenge), rechallenge “definitive”  
o 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 (if performed) clinically reasonable  
▪ Rechallenge not required 
▪ Key Features: Temporal relationship, other cause unlikely, positive 
dechallenge 
o POSSIBLE:  
▪ Event or laboratory test abnormality, with reasonable time relationship 
to drug intake  
▪ Could also be explained by another equally likely cause e.g. disease or 
other drugs  
▪ Information on drug withdrawal may be lacking or unclear  
▪ Key features: Temporal relationship, other causes possible 
• No, there is not a reasonable possibility of drug relationship: Study participant 
did not receive the test drug OR temporal sequence of the AE onset relative to 
administration of the test drug is not reasonable OR evidence exists that the adverse 
event has an etiology other than the study intervention (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication). 
Depending on data collection method employed, drug relationship may be further 
graded as follows: 
o 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 more plausible explanations  
▪ Key Features: Poor timing, other causes more likely 
o CONDITIONAL/UNCLASSIFIED 
▪ Additional data under examination 
▪ A clinical event, including laboratory test abnormality, reported as an 
adverse reaction, about which more data is essential for a proper 
assessment or the additional data is under examination. 
▪ Key features: Can’t assess with the information available 
o UNASSESSABLE/UNCLASSIFIABLE:  
▪ A report suggesting an adverse reaction which cannot be judged 
because information is insufficient or contradictory, and which cannot 
be supplemented or verified. 
▪ Key features: Data elements concerning the event are inadequate and 
will not be available. 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality along with medical 
justification. 

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There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to sponsor or its designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to sponsor or its designee. 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
Assessment of Expectedness 
An “unexpected” AE is an AE that is not listed in the reference safety information or is not 
listed at the specificity or severity that has been observed. For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the reference safety information 
referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism 
and cerebral vasculitis would be “unexpected” (by virtue of greater specificity) if the 
reference safety information listed only cerebral vascular accidents. "Unexpected" also refers 
to AEs that are mentioned in the reference safety information as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the study drug under investigation. 
Sponsor or its designee will be responsible for determining whether an AE is expected or 
unexpected.  
For denosumab, the Investigator's Brochure will be considered reference safety information. 
For Prolia®, the Summary of Product Characteristics (EMA) or Prescribing Information (US-
FDA) as applicable will be considered reference safety information. 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor 
or its designee to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details and outcome 
information (e.g., from hospital discharge summaries, consultant reports, autopsy 
reports) in order to perform an independent medical assessment of the reported case. 
• If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide sponsor with a copy of any post-mortem 
findings including histopathology, if available. 
• New or updated information will be recorded in the originally completed CRF 
• The investigator will submit any updated SAE data to sponsor receipt of the 
information. 
• The report of the SAE, after due analysis, shall be forwarded by the investigator to 
the appropriate regulatory authority, the chairperson of the ethics committee and the 
head of the institution where the trial has been conducted within fourteen days of the 
occurrence of the SAE.  

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• The sponsor or its representative and the investigator shall forward their reports on 
SAE of death after due analysis to the appropriate regulatory authority and the head 
of the institution where the clinical trial or bioavailability or bioequivalence study has 
been conducted within fourteen days of the knowledge of occurrence of SAE of death. 
10.3.4. 
Reporting of SAEs 
SAE Reporting to sponsor or its designee 
• Electronic mail or facsimile transmission from investigator containing appropriately 
filled SAE form along with required deidentified details of participant is the preferred 
method of SAE reporting to sponsor or its designee. 
• In rare circumstances and in the absence of computer or facsimile equipment, 
notification by telephone is acceptable with a copy of the SAE data collection tool 
sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE form within the designated reporting time frames. 

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10.4. 
Appendix 4: CENTRAL LABORATORY REFERENCE 
INTERVALS 
BIOCHEMISTRY 
Parameter 
Reference Interval 
Units 
A/G Ratio 
1.2 – 2.2 
- 
Albumin 
3.9 – 5.2 
g/dL 
Alkaline Phosphatase 
55.0 – 137.0 
U/L 
ALT [SGPT] 
10.0 – 56.0@ 
U/L 
AST [SGOT] 
15.0 – 46.0@ 
U/L 
Bilirubin Total  
0.2 – 1.5@ 
mg/dL 
BUN [Blood Urea Nitrogen] 
7.0 – 17.0# 
mg/dL 
Calcium 
8.7 - 10.2 
mg/dL 
Chloride 
97.3-107.0@ 
mmol/L 
Creatinine,Serum  
0.5 – 0.9@ 
mg/dL 
GGT [gamma glutamyl transferase] 
12.0 – 43.0# 
U/L 
Globulin 
2.5 – 3.8# 
g/dL 
Plasma Random(casual) Glucose 
AMERICAN DIABETES 
ASSOCIATION €  
DIABETES*: >200  
mg/dL 
Potassium, Serum 
3.8-5.4@ 
mmol/L 
Sodium 
135.6-145.9@ 
mmol/L 
Total Protein 
6.9 – 8.6 
g/dL 
Urea 
15.0 – 36.0# 
mg/dL 
Uric Acid 
2.4-6.7# 
mg/dL 
HEMATOLOGY #  
Parameter 
Reference Interval 
Units 
WBC (total) 
4.2-11.5 
X 103/µL 
Neutrophils % 
40 – 80 
% 
Lymphocytes % 
20 – 40 
% 
Eosinophils % 
1 – 6 
% 
Monocytes % 
2 – 10  
% 
Basophils % 
0 – 2 
% 
Neutrophils (abs) 
2 – 7 
X 103/ µL 
Lymphocytes (abs) 
1– 3 
X 103/ µL 
Eosinophils (abs) 
0.02 – 0.5 
X 103/ µL 
Monocytes (abs) 
0.2 – 1 
X 103/ µL 
Basophils (abs) 
0.02 – 0.1 
X 103/ µL 
RBC count 
3.8 – 4.8  
X 106/ µL 
Haemoglobin[Hb] 
10.0 – 14.4@ 
g/dL 
HCT 
36.0 – 46.0  
% 
MCV 
83.0 – 101.0 
fL 
MCH 
27.0 – 32.0 
pg 
MCHC 
31.5 – 34.5 
g/dL 
RDW SD 
39.0 – 46.0 
fl 
RDW CV 
11.6 – 14.0 
% 
Reticulocyte % 
0.5-2.5 
% 
Reticulocyte (abs) 
0.05-0.1 
X 106/ µL 

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Platelet count 
150 – 410 
X 103/µL 
URINANALYSIS # 
Parameter 
Reference Interval 
Chemical Analysis 
Specific Gravity 
1.005 - 1.020 
pH 
5.0 – 8.0 
Glucose 
Negative 
Protein 
Negative 
Bilirubin 
Negative 
Ketone 
Negative 
Urobilinogen 
Negative 
Erythrocytes 
Negative 
Leucocytes 
Negative 
Nitrite 
Negative 
Microscopic Examination 
Epithelial cell 
0-10 / hpf (Females) & 0-2 / hpf (male) 
Pus cells  
<5 hpf ¥ 
RBCs 
<5 hpf ¥ 
Casts 
Absent 1¥ 
Crystal 
Absent2¥ 
Trichomonas 
Absent 
Yeast cells 
Absent 
Bacteria 
Absent 
Amorphous 
Absent3¥ 
Urine Pregnancy Test  (For 
Female) 
Negative 
Urine Microalbumin 
Absent(< 20 mg/L) 
MICROBIOLOGY AND SEROLOGY 
Parameter 
Reference Interval 
Anti HIV AB (I & II) 
Non-Reactive 
Western Blot for HIV-I 
Negative 
HbsAg 
Non-Reactive  
Anti HAV IgM 
Non-Reactive  
Anti HCV 
Non-Reactive  
Anti HbcIgM 
Non-Reactive 
IMMUNOLOGY # 
Parameter 
Reference Interval 
Units 
TSH 
Vitros EciQ                                   
Cobase411 
0.465 to 4.68                                  0.270-4.2 
mIU/L 
IMMUNOLOGY # 
Parameter 
Reference Interval 
Units 
iPTH 
15-65 
pg/mL 
*ND = Not detectable 
Source of reference interval is available from respective parameter SOP/procedure manual as   
applicable. 

Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 99 of 107 
 
# Textbook reference interval except -hCG test for postmenopausal female on Vitros EciQ. 
  @ Establish range established by LTR Facility 
  € In the absence of unequivocal hyperglycaemia, results should be confirmed by repeat 
testing. 
Reference: Standards of Medical Care In Diabetes-2018 in Diabetes Care (The Journal of 
Clinical & Applied Research & Education,Vol 41,suppl 1,Jan 2018) American Diabetes 
Association 
  ¥ Colour Atlas of the Urinary Sediment, CAP, 2010, ISBN: 978-0-930304-87-4. 
1¥ Hyaline and Granular cast may be found in urine of normal individuals. 
2¥ Calcium oxalate and triple phosphate can be seen in healthy individuals. 
3¥ Amorphous phosphate can be seen in healthy individuals.

 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 100 of 107 
 
10.5. 
Appendix 5: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located directly before the Table of Contents (TOC). 
Summary of major changes in Amendment number 2.0 dated 14 Sep 2020 
Sr. 
No. 
Location in 
protocol 
Description 
Protocol (Version 1.0; Dated 26 Mar 2020) 
Change in the Text 
(List of Changes in version 2.0; Dated 14 Sep 2020) 
Reason for the 
Change 
1 
List of Facilities 
Bioanalytical services: 
• 
For Pharmacodynamic Services: Lambda Therapeutic 
Research Limited, Ahmedabad. 
• 
For Pharmacokinetic and Immunogenicity Services: 
Address : 
Lambda Therapeutic Research 
Inc. 
460 Comstock Road, Toronto, 
Ontario, M1L 4S4, Canada 
Tel. No. : 
+1-416-752-3636 
Fax. 
: 
+1-416-752-7610 
Bioanalytical services (Pharmacodynamic, Pharmacokinetic 
and Immunogenicity assessments). 
Address 
: 
Lambda Therapeutic Research 
Limited, Ahmedabad 
Lambda House, Plot No. 38, 
Survey No. 388, Near Silver Oak 
Club, S. G. Highway, Gota, 
Ahmedabad – 382481. Gujarat, 
India 
Tel. No. 
: 
+91-79-4020 2020 
Fax No. 
: 
+91-79-4020 2021/22 
 
All bio analytical 
services kept at 
Ahmedabad facility  
2 
Sponsor’s 
Medical 
Monitor 
Name 
: 
Dr Inderjeet Singh 
Tel. No. : 
02717-660948 
Fax No : 
02717-660105 
E-Mail:  : 
inderjeet_singh@intaspharma.com 
 
Name 
: 
Dr. Dharma Rao Uppada 
Tel. No. 
: 
02717-660948 
Fax No 
: 
02717-660105 
E-Mail:   
: 
Dharma_Uppada@intaspharma.com 
 
Administrative 
change 
3 
Synopsis: and 
section 3.0 
Objectives and 
Endpoints: 
(….) 
(…) 
Below secondary endpoint has been added  
• 
Assessment for difference in PK or PD in patients who 
are found to be immunogenic 
Regulatory advice 
related strategy 
change 
4 
Synopsis and 
section 4.1: 
Overall Design 
(….) 
 
(….) 
The PK, PD samples collected in these patients will be 
assessed for impact of immunogenicity on PK and PD only 
Regulatory advice 
related strategy 
change 

 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 101 of 107 
 
Sr. 
No. 
Location in 
protocol 
Description 
Protocol (Version 1.0; Dated 26 Mar 2020) 
Change in the Text 
(List of Changes in version 2.0; Dated 14 Sep 2020) 
Reason for the 
Change 
 
 
 
 
 
 
if there is immunogenicity identified in a particular patient 
either clinically or by immunogenicity analysis. 
5 
Other Protocol-
Required 
Therapies 
(…) 
From screening to end of study, participants will receive 
daily calcium and vitamin D supplementation that at a 
minimum should be in the range of at least 600 mg calcium 
and at least 400 IU vitamin D. 
(…) 
(…) 
From screening to end of study, participants will receive daily 
calcium and vitamin D supplementation that at a minimum 
should be in the range of at least 1000 mg calcium and at least 
400 IU vitamin D. 
(…) 
Update 
6 
Synopsis and 
Section 5.1 
(…) 
1. Participant must be 55 to 75 years of age (both 
inclusive), at the time of signing the informed 
consent. 
(…) 
(…) 
1. Participant must be 55 to 90 years of age (both inclusive), at 
the time of signing the informed consent. 
(…) 
Regulatory advice 
related strategy 
change 
7 
Synopsis and 
Section 5.2 
(…) 
11. Current, uncontrolled hyper- or hypothyroidism, defined 
as thyroid stimulating hormone outside of the normal range 
(Total T3-1.49 to 2.60 nmol/L, Total T4-5.53-11.0 µg/dL, 
TSH-0.465 to 4.68 mIU/L) at screening 
(…) 
(…) 
11. Current, uncontrolled hyper- or hypothyroidism, defined 
as thyroid stimulating hormone outside of the normal range 
(TSH-0.465 to 4.68 mIU/L) at screening. 
(…) 
Update 

 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 102 of 107 
 
Sr. 
No. 
Location in 
protocol 
Description 
Protocol (Version 1.0; Dated 26 Mar 2020) 
Change in the Text 
(List of Changes in version 2.0; Dated 14 Sep 2020) 
Reason for the 
Change 
8 
Synopsis: 
Section 8.7, 8.9: 
Sampling 
Schedule for PK 
and PD 
evaluation 
(…) 
Sample collection after second dose: The venous blood 
samples will be withdrawn at 4704.00 (Day 211; Month 7), 
5376.00 (Day 241; Month 8), 6048.00 (Day 271; Month 9), 
6720.00 (Day 301; Month 10), 7392.00 (Day 331; Month 
11), and 8064.00 (Day 361; Month 12) hours post dose 
following first dose administration. 
(…)  
Sample collection after second dose: The venous blood 
samples will be withdrawn at 5040.000 (Day 211; Month 7), 
5760.000 (Day 241; Month 8), 6480.000 (Day 271; Month 9), 
7200.000 (Day 301; Month 10), 7920.000 (Day 331; Month 
11), and 8640.000 (Day 361; Month 12) hours post dose 
following first dose administration.  
Sample collection after third dose: The venous blood 
samples will be withdrawn at pre third dose, 24.000 (Day 
2), 720.000 (Day 31), 1440.000 (Day 61), 2160.000 (Day 91), 
2880.000 (Day 121), 3600.000 (Day 151) and 4320.000 (Day 
181) hours post dose following third dose administration. 
Regulatory advice 
related strategy 
change 
9 
Synopsis: 
Section 8.10: 
Sampling 
Schedule for 
Immunogenicity 
evaluation 
8.5 ml of blood will be withdrawn for estimation of 
Immunogenicity parameters at Pre-dose (baseline), at day 
14, 31, 61, 91, 181*, 211, 241, 271 and 361 with respect to 
dosing. 
*Note: Blood sample for immunogenicity on day 181 will be 
collected prior to 2nd dose administration. 
8.5 ml of blood will be withdrawn for estimation of 
Immunogenicity parameters at Pre-dose (baseline), at day 14, 
31, 61, 91, 181*, 211, 241, 271 and 361 with respect to first 
dosing. 
8.5 ml of blood will be withdrawn for estimation of 
Immunogenicity parameters at Pre- third dose (baseline), 
at day 2, 31, 61, 91 and 181 with respect to third 
dosing.*Note: Blood sample for immunogenicity on day 181 
will be collected prior to 2nd dose administration and day 361 
before 3rd dose administration respectively. 
Regulatory advice 
related strategy 
change 

 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 103 of 107 
 
Sr. 
No. 
Location in 
protocol 
Description 
Protocol (Version 1.0; Dated 26 Mar 2020) 
Change in the Text 
(List of Changes in version 2.0; Dated 14 Sep 2020) 
Reason for the 
Change 
10 
4.1. 
Overall 
Design 
(…) 
Assumption is approximately 120 patients in denosumab-ref 
arm who would have undergone PK assessments will be 
completing double-blind period of the initial 12 months 
study and will be randomized in the transition-extension 
period (~60 in denosumab-ref and ~60 in denosumab). 
(…) 
Assumption is approximately 120 patients in denosumab-ref 
arm who would have undergone PK assessments will be 
completing double-blind period of the initial 12 months study 
and will be randomized in the transition-extension period (~68 
in denosumab-ref and ~68 in denosumab). The PK, PD 
samples collected in these patients will be assessed for impact 
of immunogenicity on PK and PD only if there is 
immunogenicity identified in a particular patient either 
clinically or by immunogenicity bioanalysis. 
Regulatory advice 
related strategy 
change 
11 
8. 
Study 
Assessments 
and Procedures 
The total blood volume for the study is approximately 407 
+ 10 mL or 456 + 10 mL as applicable. 
The total blood volume for the study is approximately 407 + 
10 mL or 544 + 10 mL as applicable. 
Update according to 
changes in sampling 
schedules 
12 
9.1. 
Sample 
Size 
Determination 
(…) 
 
(…) 
Immunogenicity assessment 
A sample size of 54 completers per group would ensure that 
the upper bound of the 95% CI of ADA incidence will not 
be larger than 10% assuming no more than one patient per 
group is observed to be positive for ADA at the end of 
treatment duration and using a Clopper-Pearson exact 
method to calculate the 95% CI for a sample proportion. 
Considering ~20% dropouts/ withdrawals, 136 patients (68 
Regulatory advice 
related strategy 
change 

 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 104 of 107 
 
Sr. 
No. 
Location in 
protocol 
Description 
Protocol (Version 1.0; Dated 26 Mar 2020) 
Change in the Text 
(List of Changes in version 2.0; Dated 14 Sep 2020) 
Reason for the 
Change 
patients per arm) will be required for immunogenicity 
assessment. 
13 
Section 9.2: 
Populations for 
Analyses 
(….) 
Modified Intent-To-Treat (mITT) set: The mITT set is 
defined as all randomized patients who will receive at least 
one dose of study medication and will undergo at least one 
post-dose efficacy evaluation. 
(…) 
(…) 
• 
Intent-To-Treat (ITT) set: The ITT set is defined as all 
randomized patients who will receive at least one dose 
of study medication. 
Sensitivity analysis will be performed on patients in ITT set for 
primary endpoint mean percentage change in bone mineral 
density (BMD) of lumbar spine from baseline to 12 months. 
For this analysis, missing values of individual BMD of lumbar 
spine at 12 months will be imputed with value as baseline value 
± 0.73 (i.e. half of equivalence limit 1.45 considered in the 
study). Imputation will be done with value as (baseline value - 
0.73) for test and (baseline value + 0.73) for reference product. 
• 
Modified Intent-To-Treat (mITT) set: The mITT set is 
defined as all randomized patients who will receive at 
least one dose of study medication and will undergo at 
least one post-dose efficacy evaluation. Missing data 
will be imputed using last observation carried 
forward (LOCF) technique. 
Regulatory advice 
related strategy 
change 
Note: The above-mentioned changes are universal changes applicable to all respective sections of protocol.

 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 105 of 107 
 
References 
1.  Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference 
Product: Guidance for Industry [Internet]. Available from: 
https://www.fda.gov/media/88622/download 
2.  Committee for Medicinal Products for Human Use. Guideline on similar biological 
medicinal products containing biotechnology-derived proteins as active substance: quality 
issues (revision 1) [Internet]. London, UK: European Medicines Agency; 2014 [cited 
2019 Dec 10]. Available from: https://www.ema.europa.eu/documents/scientific-
guideline/guideline-similar-biological-medicinal-products-containing-biotechnology-
derived-proteins-active_en-0.pdf 
3.  Committee for Medicinal Products for Human Use. Guideline on the evaluation of new 
medicinal products in the treatment of primary osteoporosis [Internet]. London, UK: 
European Medicines Agency; 2006 [cited 2019 Dec 11]. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-
medicinal-products-treatment-primary-osteoporosis_en.pdf 
4.  PROLIA® (denosumab) 60 mg solution for injection [Summary of Product 
Characteristics] [Internet]. The Netherlands: Amgen Europe B.V.; 2019 [cited 2019 Sep 
8]. Available from: https://www.ema.europa.eu/en/documents/product-information/prolia-
epar-product-information_en.pdf 
5.  PROLIA® (denosumab) injection [Prescribing information] [Internet]. Thousand Oaks, 
California: Amgen Inc; 2019 [cited 2019 Aug 8]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125320s198lbl.pdf 
6.  Kanis JA. European guidance for the diagnosis and management of osteoporosis in 
postmenopausal women. Osteoporos Int 2019;42.  
7.  Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical 
Endocrinologists/ American College of Endocrinology clinical practice guidelines for the 
diagnosis and treatment of postmenopausal osteoporosis-2020 update [Internet]. [cited 
2020 Sep 14];Available from: https://www.aace.com/sites/default/files/2020-
05/Vol%2026%20Supplement%201%20%28May%202020%29%20GL-2019-0524.pdf 
8.  Center for Biologics Evaluation and Research. Cross Discipline Team Leader Review for 
Approval Package for: BLA 125320/000 [Internet]. [cited 2020 Sep 14];Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125320s000MedR.pdf 
9.  Indian Council of Medical Research. National Ethical Guidelines for Biomedical 
Research Involving Children [Internet]. New Delhi: Indian Council of Medical Research; 
2017 [cited 2019 Aug 26]. Available from: 
https://icmr.nic.in/sites/default/files/guidelines/National_Ethical_Guidelines_for_BioMed
ical_Research_Involving_Children_0.pdf 
10.  Genant HK, Wu CY, Kuijk C van, Nevitt MC. Vertebral fracture assessment using a 
semiquantitative technique. J Bone Miner Res 1993;8(9):1137–48.  

 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
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11.  CENTER FOR DRUG EVALUATION AND RESEARCH. APPLICATION NUMBER: 
BLA 125320/S-007 [Internet]. 2010 [cited 2020 Jan 1];Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/review/2018/125320Orig1s007.pdf 
12.  Koch GG. Comments on “Current issues in non-inferiority trials” by Thomas R. Fleming, 
Statistics in Medicine, DOI: 10.1002/sim.2855. Stat Med 2008;27(3):333–42.  
 
 
 

 
Product: Denosumab 
Sponsor: Intas Pharmaceutical Limited (Biopharma Division) 
Clinical Study Protocol: 0774-19; Version No.: 2.0 
Status: Final; Release Date: 14 September 2020 
 
Confidential and Proprietary 
 
Page 107 of 107 
 
Investigator Agreement 
Protocol Title: A Randomized, Double-Blind, Active-Controlled, Parallel Arm, Multicenter 
Study Comparing Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Denosumab 
of Intas Pharmaceutical Limited (60 mg/mL) with Prolia® in Postmenopausal Women with 
Osteoporosis. 
Protocol Number: 0774-19 
I, the undersigned, have read this protocol and agree that it contains all necessary details for 
carrying out this study. I will conduct the study as outlined herein and will complete the study 
within the time designated. I agree to conduct the study in accordance with this protocol and to 
comply with all requirements regarding the obligations of investigators and all other pertinent 
requirements of ICH E6 (R2) Guideline on Good Clinical Practice; New Drugs & Clinical Trial 
Rules, 2019 of CDSCO; Declaration of Helsinki (Fortaleza, 2013); as per any other applicable 
regulatory requirements. 
I will provide copies of the protocol and all pertinent information to all individuals responsible 
to me who assist in the conduct of this study. I will discuss this material with them to ensure 
that they are fully informed regarding the study IMP, the conduct of the study, and the 
obligations of confidentiality. 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature:  
Date:  
 
 
 
(DD-MMM-YYYY) 
Notes:  
• 
If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be 
required. 
• 
Please retain original page of the Investigator’s declaration at the site and send a copy of this page to 
Lambda Therapeutic Research Limited, Ahmedabad.