A Randomized, Double-Blind, Multicenter, Parallel-Arm Phase 3 Study to Compare the Efficacy, Pharmacodynamics, Safety, and Immunogenicity Between Bmab 1000 and Prolia® in Postmenopausal Women With Osteoporosis
Phase: PHASE3
Conditions: Postmenopausal Women With Osteoporosis
Sponsor: Biocon Biologics UK Ltd

CLINICAL STUDY PROTOCOL
 
A Randomized, Double-Blind, Multicenter, Parallel-Arm Phase 3 Study to 
Compare the Efficacy, Pharmacodynamics, Safety, and Immunogenicity 
Between Bmab 1000 and Prolia in Postmenopausal Women with 
Osteoporosis 
(DEVOTE: DEnosumab biosimilar Versus Prolia for post-menopausal 
Osteoporosis: A randomized, double-blind, multicenter, Two-arm phase 3 study 
comparing Efficacy, safety, and immunogenicity)
Page 1 of 140

Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Randomized, 
Double-Blind, Multicenter, Parallel-Arm Phase 3 Study to Compare the Efficacy, 
Pharmacodynamics, Safety, and Immunogenicity Between Bmab 1000 and Prolia in 
Postmenopausal Women with Osteoporosis”. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 3.0, dated 31-Aug-2022, the International 
Council for Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice 
and all applicable government regulations. I will not make changes to the protocol before 
consulting with Biocon Biologics UK Limited or implement protocol changes without 
independent ethics committee approval except to eliminate an immediate risk to patients. I 
agree to administer study treatment only to patients under my personal supervision or the 
supervision of a sub investigator. 
I will not supply the investigational product to any person not authorized to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Biocon Biologics UK Limited. 
Signature of Principal Investigator
Date
Printed Name of Principal Investigator
Page 5 of 140

Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
Protocol Amendment Summary of Changes 
Protocol Version History
Protocol Version
Date
Amendment 2 
31-Aug-2022 
Amendment 1 
13-Apr-2022 
Original Protocol
06-Jan-2022
Amendment 2 (31-Aug-2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC and Article 2(13) of Regulation (EU) No 536/2014 of the European 
Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
Major changes from Amendment 1 (13-Apr-2022) to Amendment 2 (31-Aug-2022) are 
summarized in the following table. Additional minor changes to the protocol and changes to 
the synopsis are not listed but were applied, as applicable. Minor editorial or formatting 
changes are not included in this summary table. 
Section # and Name 
Description of Change 
Brief Rationale 
Title page, Signature page, 
Protocol Amendment 
Summary of Changes, 
Header, and Appendix 13.3 
with protocol amendment 
history 
Updated the protocol version and 
date. 
Reflect the new version and date. 
Synopsis – 
Pharmacodynamic 
Assessments  
Section 13.1 Appendix: 
Schedule of Events 
Added visit in double-blind active-
controlled period (Part 1) at Week 
23 (Day 162) for blood sample 
collection for PD testing and other 
relevant assessments including PK 
Based on the EMA 
recommendation.  
Section 5.8.1 Prohibited 
Concomitant Medications 
It has been clarified that the use of 
COVID-19 vaccine is encouraged, 
although, at the discretion of PI, an 
interval of 7 days is advised 
between the COVID-19 vaccine 
and study drug administration due 
to putative adverse drug reactions.  
Clarification 
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Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2.1.1.1 Adverse 
Events 
Clarified that AE does not include 
pre-existing diseases or conditions 
present or detected prior to signing 
the ICF that does not worsen. 
Clarification 
Section 6.2.2 Clinical 
Safety Laboratory 
Assessments 
deleted the following texts “only if 
urinalysis dipstick results are 
abnormal”.  
Clarification 
Section 6.2.3 
Section 7.6.8.4 Physical 
Examinations 
Clarified that significant findings 
and illnesses to be reported after 
signing the ICF. 
Clarification
Section 7.6.2 (Table 7-3) 
Summary of Statistical 
Methods, Including 
Sensitivity Analyses  
Section 7.6.3.4 Sensitivity 
Analysis for  
Estimand 1a EMA (Co-
Primary Efficacy) 
Updated text for sensitivity 
analysis of estimand 1a EMA (co-
primary efficacy) to reflect missing 
data imputed under MI MAR 
approach, penalties and Rubin’s 
method used for results.  
Removed sensitivity analysis for 
Estimand 1a (US FDA) as it is not 
required since sensitivity included 
in other estimands that are 
explored. 
Based on the US FDA 
recommendation.
Section 7.6.2 (Table 7-3) 
Summary of Statistical 
Methods, Including 
Sensitivity Analyses  
Section 7.6.3.1  
Main Estimation of 
Estimand 1a US FDA 
(Efficacy) 
Section 7.6.3.5 Multiple 
Imputation Model Under 
Missing at Random 
Section 7.6.3.5.1 Penalties 
for Non-Inferiority and 
Non-Superiority  
Section 7.7 Handling of 
Missing Data 
Added missing data imputed under 
MI MAR approach, penalties to 
reflect non-inferiority and non-
superiority nulls, and results 
pooled using Rubin’s method and 
two one-sided tests. 
Clarified that sensitivity analysis is 
not required as explored in other 
estimands. 
Based on the US FDA 
recommendation. 
Section 7.6.4.1 Secondary 
BMD Endpoints 
Clarified that Estimand 1a-US 
FDA (Efficacy) will be performed 
but without the penalty being 
applied. 
Based on the US FDA 
recommendation. 
Page 7 of 140

Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
Section # and Name 
Description of Change 
Brief Rationale 
Section 7.6.9 Other 
Analyses 
The occurrence and time to 
intercurrent events will be 
considered and compared for the 
treatment groups. 
Based on the US FDA 
recommendation. 
Table 13-1 (Schedule of 
Events) 
Added a footnote to clarify that 
FSH is not required for women 
with surgical menopause as their 
postmenopausal status will be 
confirmed via their medical 
history. 
Clarification
Page 8 of 140

Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
Table of Contents 
Title Page ........................................................................................................................... 2
Protocol Amendment Summary of Changes ...................................................................... 6
Table of Contents ............................................................................................................... 9
List of Tables .................................................................................................................... 14
List of Figures .................................................................................................................. 15
Protocol Synopsis............................................................................................................. 16
List of Abbreviations........................................................................................................ 35
1
Introduction .............................................................................................................. 38
1.1
Background ..................................................................................................... 38
1.2
Denosumab ..................................................................................................... 38
1.3
Bmab 1000 ...................................................................................................... 39
1.4
Clinical Studies ............................................................................................... 39
1.4.1
Bmab 1000 ....................................................................................... 39
1.4.2
Prolia ................................................................................................ 40
1.5
Study Rationale ............................................................................................... 41
1.5.1
Rationale for Study Population ........................................................ 42
1.5.2
Rationale for Dose Selection ........................................................... 42
1.6
Benefit-Risk Assessment ................................................................................ 42
2
Study Objectives, Endpoints, and Estimands ........................................................... 44
2.1
Primary Objectives, Endpoints, and Estimands .............................................. 44
2.2
Secondary Objectives and Endpoints of Double-Blind Active-Controlled 
Period (Part 1) ......................................................................................... 45
2.3
Key Secondary Objectives and Endpoints for the Transition Period (Part 2) . 46
2.4
Other Secondary Objectives and Endpoints of Transition Period (Part 2) ..... 47
3
Investigational Plan .................................................................................................. 48
3.1
Study Design ................................................................................................... 48
3.1.1
Independent Safety Review Committee .......................................... 50
4
Patient Selection and Withdrawal Criteria ............................................................... 51
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Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
4.1
Selection of Study Patients ............................................................................. 51
4.1.1
Inclusion Criteria ............................................................................. 51
4.1.2
Exclusion Criteria ............................................................................ 51
4.2
Discontinuation From Study Treatment and/or Withdrawal From the Study . 56
4.2.1
Discontinuation From the Study Treatment ..................................... 56
4.2.2
Pausing of Study Treatment or Enrollment or Study Termination and 
ISRC Review ................................................................................... 59
4.2.3
Withdrawal From the Study ............................................................. 59
4.2.4
Lost to Follow-Up ............................................................................ 60
4.2.5
Replacements and Screen Failures .................................................. 60
5
Study Treatments ...................................................................................................... 62
5.1
Method of Assigning Patients to Treatment Groups ....................................... 62
5.2
Treatments Administered ................................................................................ 62
5.2.1
Bmab 1000 and Prolia...................................................................... 62
5.2.2
Calcium and Vitamin D Supplements .............................................. 63
5.2.2.1
Managing Hypercalcemia and Hypocalcemia ................................. 63
5.3
Identity of Investigational Product.................................................................. 64
5.4
Management of Clinical Supplies ................................................................... 65
5.4.1
Investigational Product Packaging and Storage............................... 65
5.4.2
Investigational Product Accountability ............................................ 65
5.4.3
Calcium and Vitamin D Supplies ..................................................... 66
5.5
Overdose, Underdose, and Medication Errors ................................................ 66
5.6
Blinding........................................................................................................... 67
5.6.1
Breaking the Blind ........................................................................... 67
5.7
Compliance With Study Treatment ................................................................. 68
5.8
Prior and Concomitant Therapies ................................................................... 68
5.8.1
Prohibited Concomitant Medications .............................................. 69
5.9
Intervention After the End of the Study or Treatment Discontinuation .......... 70
6
Study Assessments and Procedures .......................................................................... 71
6.1
Efficacy Assessments ...................................................................................... 71
6.1.1
Bone Mineral Density ...................................................................... 71
6.1.1.1
Screening Bone Mineral Density Assessment ................................. 72
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Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
P
6.1.1.2
On-Study Bone Mineral Density Assessment .................................. 72
6.1.2
Incidence of Fracture ....................................................................... 72
6.2
Safety Assessments ......................................................................................... 73
6.2.1
Adverse Events ................................................................................ 73
6.2.1.1
Definitions ....................................................................................... 73
6.2.1.1.1
Adverse Events ..................................................................... 73
6.2.1.1.2 
Adverse Drug Reaction ........................................................ 74
6.2.1.1.3 
Unexpected Adverse Drug Reaction .................................... 74
6.2.1.1.4 
Serious Adverse Events ........................................................ 74
6.2.1.1.5
Suspected Unexpected Serious Adverse Reaction ............... 76
6.2.1.1.6
Adverse Events of Special Interest ....................................... 76
6.2.1.2
Eliciting and Documenting Adverse Events .................................... 78
6.2.1.2.1 
Assessment of Severity ........................................................ 79
6.2.1.2.2 
Assessment of Causality ....................................................... 80
6.2.1.3
Reporting Adverse Events ............................................................... 81
6.2.1.3.1 
Reporting Serious Adverse Events ....................................... 82
6.2.1.3.2 
Reporting Suspected Unexpected Serious Adverse Reactions
 .............................................................................................. 83
6.2.1.4
Follow-Up of Patients Reporting Adverse Events ........................... 83
6.2.1.5
PFS Related Issues/ Adverse Events ................................................ 84
6.2.2
Clinical Safety Laboratory Assessments.......................................... 85
6.2.2.1
Hepatitis B Virus, Hepatitis C Virus, Human Immunodeficiency 
Virus, and SARS-CoV-2 .................................................................. 87
6.2.2.2
Follicle-Stimulating Hormone ......................................................... 88
6.2.3
Physical Examinations ..................................................................... 88
6.2.4
Vital Signs ........................................................................................ 89
6.2.5
Electrocardiograms .......................................................................... 89
6.2.6
Other Safety Assessments ................................................................ 89
6.2.6.1
Medical History, Disease History, and Demographic Information .. 89
6.2.6.2
Injection Site Reaction Monitoring.................................................. 89
6.2.6.3
Hypersensitivity/Allergic Reaction Monitoring .............................. 90
6.2.6.4
New York Heart Association Functional Classification .................. 90
6.3
Pharmacokinetics ............................................................................................ 90
6.4
Pharmacodynamics and Biomarkers ............................................................... 91
6.4.1
Pharmacodynamic Endpoints .......................................................... 91
6.5
Immunogenicity Assessments ......................................................................... 92
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Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
7
Statistical Considerations ......................................................................................... 93
7.1
Estimands and Intercurrent Events ................................................................. 93
7.1.1
Intercurrent Events ........................................................................... 93
7.1.2
Estimands ......................................................................................... 94
7.1.2.1
Choice of Primary and Key Secondary Estimands .......................... 97
7.2
Statistical Hypothesis ...................................................................................... 97
7.3
Sample Size Determination............................................................................. 98
7.4
Analysis Sets ................................................................................................... 99
7.4.1
Full Analysis Set .............................................................................. 99
7.4.1.1
Modified Full Analysis Set .............................................................. 99
7.4.2
Safety Analysis Set .......................................................................... 99
7.5
Description of Subgroups to Be Analyzed ...................................................... 99
7.6
Statistical Analysis Methodology ................................................................. 100
7.6.1
General Considerations .................................................................. 100
7.6.2
Overview of Statistical Methods: Estimation of Estimands and 
Sensitivity Analyses ....................................................................... 101
7.6.3
Analysis of Primary Efficacy Endpoints ....................................... 105
7.6.3.1
Main Estimation of Estimand 1a-US FDA (Efficacy) ................... 105
7.6.3.2
Main Estimation of Estimand 1a-EMA (Co-primary Efficacy) ..... 106
7.6.3.3
Main Estimation of Estimand 1b-EMA (Co-primary PD) ............. 106
7.6.3.4
Sensitivity Analysis for Estimand 1a-EMA (Co-primary Efficacy)
 ....................................................................................................... 106
7.6.3.5
Multiple Imputation Model Under Missing at Random ................ 107
7.6.3.5.1
Penalties for Non-Inferiority and Non-Superiority ............ 107
7.6.3.6
Sensitivity and Supplementary Analyses of Estimand 1b-EMA 
(Co-primary PD) ............................................................................ 108
7.6.3.7
Supplementary Analysis for Estimand 1a-EMA (Co-primary 
Efficacy) ......................................................................................... 109
7.6.4
Analysis of Secondary Efficacy Endpoints ................................... 109
7.6.4.1
Secondary BMD Endpoints ........................................................... 109
7.6.4.2
Analyses of BMD After Transition ................................................ 109
7.6.4.3
Summary of Fractures .................................................................... 110
7.6.5
Analyses of Secondary Pharmacodynamic Endpoints .................. 110
7.6.6
Analyses of Secondary Pharmacokinetic Endpoints ..................... 110
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Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
7.6.7
Analyses of Secondary Immunogenicity Endpoints ...................... 110
7.6.8
Safety Analyses .............................................................................. 111
7.6.8.1
Adverse Events .............................................................................. 111
7.6.8.2
Clinical Laboratory Assessments ................................................... 111
7.6.8.3
Vital Signs ...................................................................................... 112
7.6.8.4
Physical Examination .................................................................... 112
7.6.8.5
Electrocardiograms ........................................................................ 112
7.6.8.6
Transition Safety ............................................................................ 112
7.6.9
Other Analyses ............................................................................... 113
7.6.9.1
Demographic and Baseline Disease Characteristics ...................... 113
7.6.9.2
Medical History ............................................................................. 113
7.6.9.3
Study Treatment Exposure ............................................................. 113
7.6.9.4
Prior and Concomitant Medications .............................................. 113
7.6.9.5
Vitamin D and Calcium Accountability ......................................... 113
7.6.10
Protocol Deviations........................................................................ 114
7.7
Handling of Missing Data ............................................................................. 114
7.8
Interim Analyses ........................................................................................... 114
7.9
Independent Safety Review Committee........................................................ 115
8
Data Quality Assurance .......................................................................................... 116
8.1
Data Management ......................................................................................... 116
9
Ethics ...................................................................................................................... 117
9.1
Independent Ethics Committee or Institutional Review Board .................... 117
9.2
Ethical Conduct of the Study ........................................................................ 117
9.3
Patient Information and Consent .................................................................. 117
10 Investigator’s Obligations ...................................................................................... 119
10.1 Confidentiality .............................................................................................. 119
10.2 Data Protection.............................................................................................. 119
10.3 Financial Disclosure and Obligations ........................................................... 119
10.4 Investigator Documentation .......................................................................... 120
10.5 Study Conduct ............................................................................................... 120
10.6 Adverse Events and Study Report Requirements ......................................... 120
10.7 Investigator’s Final Report ........................................................................... 120
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Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
10.8 Records Retention ......................................................................................... 121
10.9 Publications and Results Disclosures............................................................ 121
11 Study Management ................................................................................................. 122
11.1 Monitoring .................................................................................................... 122
11.1.1
Monitoring of the Study ................................................................. 122
11.1.2
Inspection of Records .................................................................... 122
11.2 Management of Protocol Amendments and Deviations................................ 122
11.2.1
Modification of the Protocol .......................................................... 122
11.2.2
Protocol Deviations........................................................................ 123
11.3 Study or Study Site Termination ................................................................... 123
11.4 Clinical Study Report .................................................................................... 124
12 References .............................................................................................................. 125
13 Appendices ............................................................................................................. 128
13.1 Appendix: Schedule of Events ...................................................................... 128
13.2 Risk Assessment and Mitigation Plan due to COVID-19 ............................. 133
13.3 Appendix: Protocol Amendment History...................................................... 138
List of Tables 
Table 2-1 
Primary Objectives, Endpoints, and Estimands .............................................. 44
Table 2-2 
Secondary Objectives and Endpoints of Double-Blind Active-Controlled 
Period (Part 1) ................................................................................................. 45
Table 2-3
Key Secondary Objectives and Endpoints for the Transition Period 
(Part 2) ............................................................................................................ 46
Table 2-4 
Other Secondary Objectives and Endpoints for the Transition Period 
(Part 2) ............................................................................................................ 47
Table 6-1 
Classification of Assessment of PFS Related Adverse Events ....................... 84
Table 6-2 
Eligibility Based on Serologic Markers for Hepatitis B Infection .................. 87
Table 7-1 
Intercurrent Event Types ................................................................................. 93
Table 7-2 
Key Estimands with Rationale for Strategies to Address Intercurrent 
Events .............................................................................................................. 94
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Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
Table 7-3
Summary of Statistical Methods, Including Sensitivity Analyses ................ 102
Table 13-1 
Schedule of Events ........................................................................................ 128
List of Figures 
Figure 3-1
Study Design ................................................................................................... 50
Figure 4-1
Follow-up of Patients After Study Treatment Discontinuation ...................... 58
Page 15 of 140

Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
Protocol Synopsis 
Protocol Number: B1000-PMO-03-G-02 
Title: A Randomized, Double-Blind, Multicenter, Parallel-Arm Phase 3 Study to Compare 
the Efficacy, Pharmacodynamics, Safety, and Immunogenicity Between Bmab 1000 and 
Prolia in Postmenopausal Women with Osteoporosis
Sponsor: Biocon Biologics UK Limited
16, Great Queen Street 
Covent Garden 
London, WC2B 5AH 
United Kingdom 
Study Phase: Phase 3 
Study Sites: Approximately 480 patients will be enrolled at approximately 47 sites in Europe 
and the United States. 
Indication: Postmenopausal women with osteoporosis 
Rationale: 
Bmab 1000 is currently being developed as a proposed biosimilar to Prolia. This is a 
randomized, double-blind, multicenter, parallel-arm, Phase 3 study that will be conducted as 
a part of the clinical development program of Bmab 1000 and will assess the therapeutic 
equivalence in efficacy, safety, and PD of Bmab 1000 compared with US-licensed Prolia. 
The design of this study considers the EU Guideline on Similar Biological Medicinal 
Products Containing Monoclonal Antibodies: Nonclinical and Clinical Issues, the US FDA 
Guidance on Scientific Considerations in Demonstrating Biosimilarity to a reference product, 
and PMDA Guideline on the Quality, Safety and Efficacy Assurance of Follow-on Biologics. 
This study protocol is designed to allow a global study that would address the needs of 
various regulatory bodies. For EMA, the PD endpoint AUEC of sCTX from baseline to 
26 weeks is considered as Co-primary endpoint, while, for US FDA, this endpoint is 
considered as a key secondary endpoint. For US FDA, after completion of double-blind 
active-controlled period (Day 1 to Week 52 [pre-dose]), the study is designed to include the 
Page 16 of 140

Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
transition period (Week 52 to Week 78), where patients who have received Prolia will be re-
randomized to receive either Bmab 1000 or Prolia. 
The study population in this study was selected to be representative of the clinical studies 
supporting the development and marketing of the reference product (Prolia), and to align 
with the indications approved for the reference product. 
Detailed information about the known and expected benefits and risks and reasonably 
expected AEs of Bmab 1000 is provided in the IB. Bmab 1000 will have the same 
pharmaceutical formulation and strength as Prolia (60 mg). The proposed dosing regimen is 
in line with the approved labeling for Prolia. The proposed safety monitoring is deemed to be 
sufficient to monitor potential risks of Bmab 1000 administration. In view of the structural 
and biological similarity, Bmab 1000 is expected to display a safety profile similar to Prolia. 
Based upon the proven safety profile of Prolia, the benefits of the conduct of the proposed 
clinical study outweigh the associated risks. 
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Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
Objectives and Estimands:
The primary objectives, endpoints, and estimands are presented in the table below: 
Primary Objectives 
Endpoints (Including Estimand Description) 
To demonstrate equivalent efficacy between 
Bmab 1000 and Prolia based on percentage 
change from baseline at Week 52 in lumbar 
spine BMD (Co-primary for EMA and 
Primary for US FDA) 
Endpoint: Percentage change from baseline at Week 52 in the 
lumbar spine BMD by DXA (Time Frame: Baseline and 
Week 52) 
Estimand 1a-EMA (Co-primary Efficacy): Difference in means 
(Bmab 1000 – Prolia) in % change from baseline in lumbar 
spine BMD by DXA after 52 weeks in postmenopausal 
womena with osteoporosis treated with SC injections every 
6 months assuming that all women receive 2 doses without any 
errors or deviations in dosing and without receipt of any other 
medications affecting bones except for vitamin D and calcium 
supplements 
 
Estimand 1a-US FDA (Efficacy): Difference in means 
(Bmab 1000 – Prolia) in composite endpoint of % change from 
baseline in lumbar spine BMD by DXA after 52 weeks 
(where % change from baseline of zero is taken for anyone 
who dies) in postmenopausal womena with osteoporosis treated 
with SC injections every 6 months irrespective of 
discontinuation of treatment for any reason, errors or 
deviations in dosing and whether any other osteoporosis 
medications are taken 
To demonstrate pharmacodynamic 
equivalence between Bmab 1000 and Prolia 
based on AUEC of the bone resorption 
marker sCTX from baseline to week 26 (Co-
primary for EMA and secondary for US 
FDA) 
Endpoint: AUEC of sCTX from baseline to 26 weeks (Time 
Frame: Baseline to Week 26) 
Estimand 1b-EMA (Co-primary PD): Ratio of geometric 
means (Bmab 1000/Prolia) in AUEC in (fasted) sCTX up to 
26 weeks in postmenopausal womena with osteoporosis treated 
with a SC injection without any dosing error and no receipt of 
any other medications affecting bones except for vitamin D 
and calcium supplements 
Abbreviations: AUEC, area under the effect curve; BMD, bone mineral density; DXA, dual-energy X-ray 
absorptiometry; SC, subcutaneous; sCTX, serum C-terminal telopeptide of Type 1 collagen 
Note: The screening BMD assessment will be taken as the baseline BMD assessment. 
a. 
Women should not have been previously treated with denosumab but may have had prior treatment with 
bisphosphonates and will be co-administered vitamin D and calcium supplements. 
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Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
31-Aug-2022 
The secondary objectives and endpoints of double-blind active-controlled period (Part 1) are 
presented in the table below: 
Secondary Objective(s) 
Endpoints 
To compare other efficacy parameters (BMD of 
lumbar spine, total hip and femoral neck; fracture 
incidence) between Bmab 1000 and Prolia 
 
Percentage change from baseline at Week 26 in 
lumbar spine BMD by DXA (Time Frame: Baseline 
and Week 26) 
 
Percentage change from baseline at Weeks 26 and 52 
in total hip BMD by DXA (Time Frame: Baseline, 
Week 26, and Week 52) 
 
Percentage change from baseline at Weeks 26 and 52 
in femoral neck BMD by DXA (Time Frame: 
Baseline, Week 26, and Week 52) 
 
Incidence of fracture up to Week 52 (Time Frame: 
Baseline up to Week 52) 
To compare bone turnover between Bmab 1000 
and Prolia based on sCTX and P1NP 
 
Cmin of sCTX (Time Frame: Baseline up to Week 26) 
 
Serum concentrations of P1NP (Time Frame: 
Baseline up to Week 52) 
 
PD parameters of sCTX: Imax, TImax, AUIC (Time 
Frame: Baseline up to Week 26) 
To compare safety and tolerability of 
2 administrations of Bmab 1000 and Prolia 
6 months apart 
 
Incidence of TEAEs up to 6 months after the second 
dose (Time Frame: Baseline up to Week 52) 
 
Incidence of clinically significant changes in vital 
sign, physical examinations, laboratory safety tests, 
and ECGs up to 6 months after the second dose 
(Time Frame: Baseline up to Week 52) 
To compare immunogenicity between Bmab 1000 
and Prolia 
 
Incidence and titer of ADA, incidence of NAb up to 
Week 52 (Time Frame: Baseline up to Week 52) 
To assess denosumab serum concentrations 
following Bmab 1000 and Prolia administration 
 
Denosumab concentrations at Weeks 2, 4, 12, 26, 38, 
and 52 (Time Frame: Baseline up to Week 52) 
Abbreviations: ADA, anti-drug antibodies; AUEC, area under the effect curve; AUIC, the area under the % 
inhibition curve; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; ECG, 
electrocardiogram; Cmin, minimum concentration; Imax, maximum % inhibition; NAb, neutralizing antibodies; 
P1NP, procollagen Type 1 N-terminal propeptide; sCTX, serum C-terminal telopeptide of Type 1 collagen; 
TEAE, treatment-emergent adverse event; TImax, the time of occurrence of maximum % inhibition 
Note: The screening BMD assessment will be taken as the baseline BMD assessment. 
Page 19 of 140

Biocon Biologics UK Limited 
Bmab 1000 
Protocol B1000-PMO-03-G-02 Version 3.0 
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The key secondary objectives and endpoints of transition period (Part 2, for US FDA) are 
presented in the table below: 
Secondary Objective(s) 
Endpoints 
To assess the risk of hypersensitivity and adverse 
events up to 6 months after the single transition from 
Prolia to Bmab 1000 compared with those continuing 
on Prolia 
 
Incidence of TEAEs from the third dose at 
Week 52 and up to and including Week 78 (Time 
Frame: from Week 52 up to Week 78) 
 
Incidence of clinically significant changes in 
physical examinations, laboratory safety tests, 
ECG and vital signs from the third dose at 
Week 52 and up to and including Week 78 (Time 
Frame: from Week 52 up to Week 78) 
 
Incidence of deaths and SAEs from the third dose 
at Week 52 and up to and including Week 78 
(Time Frame: from Week 52 up to Week 78) 
To assess the risk of immunogenicity through 
formation of anti-drug antibodies after the single 
transition from Prolia to Bmab 1000 compared with 
those continuing on Prolia 
 
Incidence and titer of ADA, incidence of NAb at 
Week 78 split by serostatus at Week 52 (Time 
Frame: from Week 52 up to Week 78) 
Abbreviations: ADA, anti-drug antibodies; ECG, electrocardiogram; Nab, neutralizing antibodies; PD, 
pharmacodynamic; PK, pharmacokinetic; SAE, serious adverse event; TEAE, treatment-emergent adverse event 
The other secondary objectives and endpoints of transition period (Part 2, for US FDA) are 
presented in the table below: 
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Other Secondary Objective(s) 
Endpoints 
To assess efficacy after the single transition from 
Prolia to Bmab 1000 compared with those to 
continuing on Prolia 
 
Percentage change from Week 52 at Week 78 in 
lumbar spine BMD by DXA (Time Frame: from 
Week 52 up to Week 78) 
To assess efficacy of 3 doses of Bmab 1000 compared 
to Prolia 
 
Percentage change from (original) baseline at 
Week 78 in lumbar spine, hip and femoral neck 
BMD by DXA (Time Frame: Day 1 up to 
Week 78) 
To assess PK and PD:
i. 
after the single transition from Prolia to 
Bmab 1000 
ii. 
on Bmab 1000 throughout 
each compared with those on Prolia throughout 
 
Serum concentrations of denosumab at Week 56, 
64, and 78 (PK) (Time Frame: from Week 56 up 
to Week 78) 
 
Serum concentrations of CTX at Week 78 (PD) 
(Time Frame: Week 78) 
To assess the adverse events on Bmab 1000 
throughout compared to Prolia throughout 
 
Incidence of TEAEs from the first dose up to and 
including Week 78 (Time Frame: Day 1 up to 
Week 78) 
 
Incidence of clinically significant changes in 
physical examinations, laboratory safety tests, 
ECG and vital signs from the first dose up to and 
including Week 78 (Time Frame: Day 1 up to 
Week 78) 
 
Incidence of deaths and SAEs from the first dose 
up to and including Week 78 (Time Frame: 
Day 1 up to Week 78) 
To assess the risk of immunogenicity through 
formation of anti-drug antibodies on Bmab 1000 
throughout compared to Prolia throughout 
 
Incidence and titer of ADA, incidence of NAb at 
any point from the first dose up to Week 78 (Time 
Frame: Day 1 up to Week 78) 
Abbreviations: ADA, anti-drug antibodies; ECG, electrocardiogram; Nab, neutralizing antibodies; PD, 
pharmacodynamic; PK, pharmacokinetic; CTX, carboxy-terminal cross-linking telopeptide of Type 1 collagen; 
serious adverse event; TEAE, treatment-emergent adverse event 
Diagnosis and Main Criteria for Inclusion and Exclusion: 
Inclusion Criteria: Each patient must meet all of the following criteria to be enrolled in this 
study: 
1. Willingness to sign the written ICF, ambulatory, able to follow study instructions and 
comply with the protocol requirements, and not visually impaired as per the 
investigator’s opinion to participate in the trial. 
2. 
mIU/mL 
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at screening or 6 weeks postsurgical bilateral oophorectomy with or without 
hysterectomy.
3. Evidence of osteoporosis as assessed by lumbar spine (L1-L4) absolute BMD 
corresponding to a T-
–
–4.0. Bone mineral density 
measurements should be performed by DXA using Hologic or Lunar densitometers at 
screening visit. All DXA scans will be assessed by a central imaging center for this 
purpose. 
4. At least 3 vertebrae in the L1-L4 region and at least one hip joint are evaluable by 
DXA at screening.
5.
Exclusion Criteria: Patients meeting any of the following criteria will be excluded from the 
study: 
1. Patients with T-
 
2. Known history of previous exposure to denosumab (Prolia®, Xgeva®, or any 
biosimilar denosumab). 
3. Use of any biologic drugs (with the exception of insulin and insulin analogue and 
GLP-1 receptor agonists) within 90 days or within five half-lives of the drug, 
whichever is longer prior to the screening. 
4. Known hypersensitivity to denosumab or its constituents or latex allergy or hereditary 
problems of fructose intolerance. 
5. For prior or ongoing use of any osteoporosis treatment (other than calcium and 
vitamin D supplements), following points to be considered for the washout periods 
prior to the screening visit: 
a. Oral bisphosphonate 
i. Ineligible if used for 3 or more years cumulatively 
ii. 
required at the screening visit 
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b. Dose received any time for the following: intravenous bisphosphonate, 
strontium, fluoride (for osteoporosis), drugs being investigated for 
osteoporosis, teriparatide or any parathyroid hormone analogs, tibolone, oral 
or transdermal estrogen, selective estrogen receptor modulators, calcitonin, 
and cinacalcet 
6. Systemic glucoco
within past 3 months before screening. Topical and nasal corticosteroids are allowed. 
7. Other bone active drugs including but not limited to anticoagulants, antiplatelet (with 
the exception of acetylsalicylic acid), anticonvulsants (with the exception of 
benzodiazepines), systemic ketoconazole, adrenocorticotropic hormone, lithium, 
gonadotropin releasing hormone agonists, and anabolic steroids within the last 
3 months before screening. Direct oral anticoagulants will be allowed. Receipt of PPI 
for >1 year continuously will be allowed only after 3 months of washout prior to the 
continuously are not allowed if they plan 
to continue the use of PPI during the study such that the continuous use of PPI will be 
>1 year.
8. Patients with ongoing serious infections including cellulitis, or infection requiring 
parenteral antibiotics within 4 weeks prior to the first administration of the study 
treatment, or oral antibiotics within 2 weeks prior to the first administration of the 
study treatment. 
9. Evidence of any of the following per the patient’s history, DXA, or X-ray review 
and/or current disease: 
a.
Patient in bed rest for 2 or more weeks during the last 3 months prior to 
screening 
b. Current hyperthyroidism or hypothyroidism (patients on stable thyroid 
treatment will be allowed). Patients with subclinical hyperthyroidism (TSH 
 
 mIU/L) will be excluded 
c.
History and/or current hyperparathyroidism or hypoparathyroidism 
d. Patients who have had recurrent episode of hypocalcemia in the past which, as 
per the investigator, is a risk to her participation in the trial 
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e.
Current hypocalcemia or hypercalcemia based on albumin-adjusted serum 
calcium
f.
Any bone disease including bone metastasis or metabolic disease (except for 
osteoporosis), eg, osteomalacia or osteogenesis imperfecta, rheumatoid 
arthritis, Paget’s disease, ALP elevation (at investigator’s discretion), 
Cushing’s disease, clinically significant hyperprolactinemia (at investigator’s 
discretion), fibrous dysplasia, malabsorption syndrome which may interfere 
with the interpretation of the results
g. Malignancy (except squamous cell carcinoma, basal cell carcinoma, cervical 
or breast ductal carcinoma in situ) within the last 5 years from screening visit
h. Height, weight, and girth which may preclude accurate DXA measurements 
i.
Advanced scoliosis or extensive lumbar fusion which would preclude 
vertebral fracture assessment
j. History and/or presence of one severe or 3 or more moderate vertebral 
s 
(as determined by central reading of lateral spine X-ray during the screening 
period). Severe vertebral fracture (Grade 3) is defined as >40% vertebral 
height loss, and moderate vertebral fracture (Grade 2) is defined as 25% to 
40% vertebral height loss 
k. History and/or presence of hip fracture or bilateral hip replacement or history 
of atypical femoral fracture 
l. Presence of an active healing fracture according to assessment of investigator
m. History of severe skeletal pain with bisphosphonates which, as per the 
investigator, is a risk to her participation in the trial 
n. Oral/dental or periodontal conditions: Prior history or current evidence of 
osteomyelitis, osteonecrosis of the jaw (or risk of developing osteonecrosis of 
the jaw as per the investigator’s opinion), osteonecrosis of the external 
auditory canal; active dental or jaw condition which requires oral surgery; 
planned invasive dental procedure (dental implants); or non-healed dental or 
oral surgery 
o. Any organic or psychiatric disorder or laboratory abnormality or underlying 
condition (including, but not limited to metabolic, hematologic, renal, hepatic, 
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pulmonary, neurologic, endocrine, cardiac, infectious, or gastrointestinal, 
which, in the opinion of the investigator, will prevent the patient from 
completing the study or interfere with the interpretation of the study results, or 
will put the patient into unacceptable risk for participating in the trial
p. History of presence of a severe allergic reaction (eg, anaphylaxis). 
q. Personal/family history of prolonged QT interval syndrome or family history 
of sudden death. 
10. New York Heart Association Class III or IV chronic heart failure, any unstable 
cardiovascular disease, pulmonary disease, autoimmune disease or ECG 
abnormalities, which can be judged as clinically significant at the investigator’s 
discretion. 
11. Patient has a planned surgical intervention during the study period except those related 
to the underlying disease and which, in the opinion of the investigator, will put the 
patient at further risk or hinder the patient’s ability to maintain compliance with study 
treatment and the visit schedule.
12. One of the following laboratory test results at screening: 
a. Vitamin D deficiency (serum 25-hydroxy vitamin D 
 ng/mL). For 
eligibility purpose, oral vitamin D repletion is permitted at the investigator’s 
discretion if serum 25-
 ng/mL and 
vitamin D level is allowed to be retested post repletion within the screening 
period 
b.
-Gault 
 
c. 
able if bilirubin 
to contact medical monitor and/or sponsor.) 
d. 
 
13. Allergy to vitamin D or calcium supplements, or intolerant to long-term calcium or 
vitamin D supplementation, or history malabsorption of calcium or vitamin D 
supplements. 
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14. Participation in a drug study within 90 days or 5 half-lives of the previous drug (if 
known), whichever is longer, prior to drug administration. 
15. Known case of active hepatitis B, hepatitis C or HIV infection. Has a hepatitis B, 
hepatitis C or HIV positive test result at screening. A patient with past hepatitis B or C 
virus infection is allowed if recovered by the time of the screening visit. At screening, 
hepatitis B will be assessed in all patients. If a patient has HBsAg positive, the patient 
will be excluded from the study. If a patient has HBsAg negative and HBcAb positive, 
an HBV DNA test will be performed at screening. If the HBV DNA test result is 
positive, the patient will be excluded from the study. At screening, hepatitis C 
antibody will be assessed in all patients. If hepatitis C antibody test result is positive, 
an HCV RNA test will be performed at screening. If the HCV RNA test result is 
positive, the patient will be excluded from the study; If the HCV RNA test result is 
negative, the patient can be included at the investigator’s discretion. 
16. Evidence of alcohol or substance-abuse within the last 12 months prior to screening 
that the investigator believes would interfere with understanding or completing the 
study. 
17. Confirmed or suspected with infection with SARS-CoV-2 from screening to 
randomization, or who has been diagnosed with COVID-19 (as per site and/or local 
regulatory guidelines) or history of COVID-19 infection requiring oxygen 
supplementation in the last 8 weeks prior to screening or had contact with a 
COVID-19 patient 14 days prior to screening and within the screening period up to 
randomization. 
18. Patient has received live virus vaccine within 4 weeks prior to screening or within the 
screening period up to randomization. 
Study Design: 
This is a randomized, double-blind, multicenter, parallel-arm, Phase 3 study to compare the 
efficacy, PK, PD, safety, and immunogenicity of Bmab 1000 and Prolia in postmenopausal 
women with osteoporosis. 
The study will consist of 3 study periods: Screening period; Part 1, double-blind 
active-controlled period; and Part 2, transition period. 
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Screening Period (from Day –28 to Day –1) 
Screening evaluations will be completed within 28 days prior to the randomization. 
Part 1, Double-Blind Active-Controlled Period (from Week 0 [Day 1] to Week 52 Pre-dose) 
In the double-blind active-controlled period, eligible patients will be randomly assigned (1:1) 
to receive either Bmab 1000 (60 mg) or Prolia (60 mg) via SC injection on Day 1 (Week 0, 
the same date as randomization) and at Week 26. Patients will be followed-up for 26 weeks 
after the second dose. The randomization will be stratified by 
Part 2, Transition Period (from Week 52 to Week 78 [EoS Visit]):
All patients who complete Part 1 will undergo the re-randomization process prior to the study 
treatment administration at Week 52. Prior to dosing at Week 52, patients in the Prolia arm 
will be randomly assigned in a 1:1 ratio to receive either Bmab 1000 or Prolia at Week 52. 
This is done to obtain data after single switch in patients who have been treated with Prolia. 
To maintain the study blinding, the patients in the original Bmab 1000 arm will also go 
through the re-randomization procedure; however, they will continue to receive Bmab 1000.  
The re-randomization will take place within the original strata used for the randomization at 
baseline. All applicable assessments including efficacy, PK, PD, safety including 
immunogenicity will be performed as per Schedule of Events. 
End-of-study visit will be at Week 78 post randomization (Month 18). 
An Independent Safety Review Committee (ISRC) will periodically review the safety data to 
ensure safety of patients is protected. The ISRC will consist of therapeutic area experts (at 
least 3 members) who are independent of this study conduct. The initial meeting of the ISRC 
will be conducted after the first 10% of patients have completed Day 15 visit. The ISRC will 
continue to review the emerging safety data.
The ISRC will review the unblinded safety data to determine if the incidence of a serious 
adverse drug reaction was unacceptably high in the Bmab 1000 arm (or notably higher than 
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the Prolia arm) such that continued administration of the product would present an 
unacceptable risk to patients. 
The roles, responsibilities, and review process will be defined in the ISRC Charter. 
Duration of Treatment:
The patients will receive the study treatment on Day 1 and at Week 26 and Week 52. The 
maximum study duration for a patient will be approximately 18 months (excluding 
screening).
Efficacy Assessments:
Bone Mineral Density: Bone mineral density will be assessed by DXA scan at screening, 
Week 26, Week 52, and Week 78. All DXA scans will be analyzed by the central imaging 
vendor. 
Fracture: Lateral spine X-ray will be assessed at a central imaging center at screening, 
Week 26, and Week 52. Additional radiographs will be performed as required during the 
study for confirmation of suspected new clinical fractures. Any new fractures confirmed by 
the central imaging vendor will be recorded as an adverse event.
Pharmacokinetic Assessments: 
Blood samples for measuring serum concentrations of denosumab will be collected at Day 1 
(pre-dose), Day 15, Day 29, Day 85, Day 162, Day 183 (pre-dose), Day 267, Day 365 (pre-
dose), Day 393, Day 449, and Day 547. 
Pharmacodynamic Assessments
Blood samples for PD parameters (sCTX, P1NP) will be collected at Day 1 (pre-dose), 
Day 3, Day 15, Day 29, Day 85, Day 141, Day 162, Day 183 (pre-dose), Day 267, Day 365 
(pre-dose), and Day 547. 
Immunogenicity Assessments: 
The immunogenicity of Bmab 1000 and Prolia will be assessed by ADA and NAb test in a 
validated immunoassay. Blood samples for immunogenicity assessments will be collected at 
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Day 1 (pre-dose), Day 15, Day 29, Day 85, Day 183 (pre-dose), Day 267, Day 365 
(pre-dose), Day 393, Day 449, and Day 547. 
Safety Assessments:
Safety will be assessed through the collection and evaluation of AEs, including TEAEs, 
SAEs, AESIs (treatment-related hypersensitivity/allergic reaction monitoring, serious 
infections, hypocalcemia, osteonecrosis of the jaw, atypical femoral fracture, and 
dermatologic reactions), clinical laboratory assessments, physical examinations, vital sign 
measurements, and ECGs. 
Any fracture will be recorded as an AE/SAE/AESI (as applicable). 
Study Treatment, Dosage, and Route of Administration: 
Bmab 1000 (60 mg) or Prolia (60 mg) will be administered subcutaneously using a PFS of 
60 mg/mL solution for injection on Day 1 and at Week 26 and Week 52. 
Sample Size:
The initial sample size calculation is based on the primary endpoint, percent change from 
baseline in lumbar spine BMD by DXA at Week 52. 
Equivalence will be established if the 95% CI of the difference (T-R) in mean percent change 
in lumbar spine BMD from baseline at Week 52 is within equivalence margin of (±1.45%). 
Equivalence margin is derived from meta-analysis of previous similar studies, which gave the 
pooled denosumab treatment effect 
 Based on the lower 
bound of the 95% CI, a 1.45% margin will preserve
Assuming that the treatments are equally effective and that the common SD for percent 
change from baseline in lumbar spine BMD at Week 52 is 
 a sample size of 204 patients 
per treatment group (total 408 patients) ensures a power of minimum 80% with 2.5% level of 
significance. Considering a dropout of 15%, the total sample size required is 480 patients 
(240 per treatment group). Note that the US FDA require a 90% CI to establish equivalence 
which provides more power for this sample size (this will be reflected in the efficacy 
analyses). 
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The current sample size has high power for the (Co-primary) sCTX AUEC endpoint; 204 
evaluable patients/group with a margin of 80%-125% and between-patient CV of 45% would 
give >95% power to demonstrate similarity. 
Statistical Methods:
Analysis Sets:
The following analysis sets will be used in the statistical analyses.
Full analysis set: The FAS will consist of all randomized patients who meet the eligibility 
criteria and receive at least one dose of study treatment. Patients from the FAS will be 
analyzed under the treatment as randomized. This will be used as the analysis dataset for 
estimation of Estimand 1a-US FDA (Efficacy). 
Modified full analysis set: The term mFAS will be used to define the analysis data set which 
includes a data record at each time point for all patients in the FAS but excludes data 
observed after the first occurrence of those intercurrent events where a hypothetical strategy 
is taken for (eg, missing a dose, errors or deviations in dosing, or receipt of any other 
osteoporosis medication or medication affecting bone health). Data in the mFAS will be 
analyzed under the treatment as randomized and used as the primary analysis data set for this 
estimation of Estimand 1a-EMA (Co-primary Efficacy) and Estimand 1b-EMA (Co-primary 
PD) and other key efficacy, PD and PK analyses. For PD, data points within 8 hours of food-
intake or 48-hours of intense physical activity will not be used. 
Safety analysis set: The SAF will consist of all randomized patients who received at least one 
administration of study treatment. The SAF will be used for all safety and immunogenicity 
analyses. In the SAF, patients will be analyzed per the actual treatment received. 
Efficacy Endpoint
Main Estimation of Estimand 1a-US FDA (Efficacy) 
In order to estimate Estimand 1a-US FDA, an ANCOVA model will be fitted to the 
composite percent change from baseline in lumbar spine BMD (where % change from 
baseline of zero is taken for anyone who dies) at Week 52 on the FAS multiply imputed data 
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sets including terms for randomization strata, treatment, and baseline BMD included as a 
continuous covariate. Rubin’s method will be used to pool results. 
Multiple imputation will be used to produce 30 multiply imputed data sets so that any 
missing BMD data at Week 52 are imputed under MAR, by treatment. A penalty (delta of -
1.45 and 1.45) will be applied to imputed values for the BMab 1000 group reflecting the 
noninferiority and non-superiority null hypotheses (H0) respectively and two separate one-
sided tests at alpha=0.05 conducted (Tests 1 and 2 below, respectively): 
Test 1: for non-inferiority (delta =–1.45): 
H0: µBMab 1000 - µProlia 
–1.45% 
H1: –
BMab 1000 - µProlia  
Test 2: for non-superiority (delta =1.45): 
H0: µBMab 1000 - µProlia  +1.45% 
H1: µBMab 1000 - µProlia 
 
where µBmab 1000 and µProlia denotes the true mean % change from baseline in lumbar spine 
BMD by DXA at Week 52 for Bmab 1000 and Prolia, respectively. The estimated mean 
difference in % change from baseline in lumbar spine BMD at Week 52 will be presented 
with 90% CI for each delta. The two one-sided tests of alpha=0.05 are equivalent to showing 
that each 90% CI falls within predefined equivalence margins of [–1.45%, 1.45%]. If these 
criteria are met, equivalence will be concluded for the US FDA submission. 
Main Estimation of Estimand 1a-EMA (Co-primary Efficacy) 
For the primary efficacy analysis, an MMRM will be fitted to the % change from baseline in 
lumbar spine BMD at Week 26 and Week 52 on the mFAS. The MMRM will include terms 
for randomization strata, visit by treatment, and baseline BMD included as a continuous 
covariate. The repeated measures on patients will be modeled with an unstructured 
covariance structure.  
The estimated mean difference in % change from baseline in lumbar spine BMD will be 
presented with 95% CI at each time point. 
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The estimated mean difference in % change from baseline in lumbar spine BMD at Week 52 
will be presented with 95% CI and equivalence concluded if this falls within predefined 
equivalence margins of [–1.45%, 1.45%]. 
Note: The main analysis method is on the mFAS and therefore does not use data after any 
dosing errors, treatment discontinuation or receipt of any other medications affecting bone 
health (except for supplements). 
Main Estimation of Estimand 1b-EMA (Co-primary PD)
Comparability of sCTX levels between Bmab 1000 and Prolia will be assessed by fitting an 
ANCOVA to AUEC data on a log scale to give the ratio of geometric means with 95% CI. 
Logged pre-dose sCTX concentrations will be fitted as a covariate since baseline-adjustment 
is not included in the AUEC calculation, baseline eGFR will be included as a covariate since 
renal function is known to affect sCTX levels, and treatment group and all stratification 
factors will be fitted as fixed effects. Comparability between Bmab 1000 and Prolia will be 
concluded if the 95% CI around the geometric mean ratios for AUEC lie entirely within 
80.00% - 125.00%.
Secondary Efficacy Endpoints
Secondary BMD Endpoints 
An MMRM, as per the main estimation of Estimand 1a-EMA (Co-primary Efficacy), will be 
used to estimate the mean percent change from baseline and difference between treatments 
for the mFAS in lumbar spine BMD after 26 weeks, hip BMD after 26 and 52 weeks, and 
femoral neck BMD after 26 and 52 weeks. Similarly, ANCOVA on composite endpoint of 
percent change from baseline for FAS as per main estimation of Estimand 1a-US FDA
(Efficacy) will be performed (see Section 7.6.3.1) but without the penalty being applied. 
Analyses of BMD After Transition 
BMD percentage change from baseline and percentage change at Week 78 from Week 52 will 
be summarized by treatment for lumbar spine, hip, and femoral neck BMD by DXA. 
Statistical analyses to present 95% CIs will be performed on Week 78 lumbar spine BMD in 
2 separate analyses which will considering either original baseline or Week 52 baseline as a 
covariate.
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Summary of Fractures
Any incidence of fractures up to and including Week 52 and from Week 52 to Week 78 will 
be summarized with descriptive statistics.
Secondary Pharmacodynamic Endpoints 
Serum C-terminal telopeptide of Type 1 collagen and P1NP concentrations will be listed, 
summarized with descriptive statistics by treatment and visit, and presented graphically, as 
appropriate. 
Cmin for sCTX will be analyzed in a similar manner to sCTX AUEC as a secondary PD 
endpoint on mFAS. In addition, PD parameters estimated for sCTX using change from 
baseline observations (ie, Imax and AUIC) will be analyzed in a similar manner to sCTX 
AUEC as additional secondary PD endpoints on mFAS. 
Following the transition period, serum concentrations of CTX and P1NP at Week 78 will be 
summarized for those transitioning to Bmab 1000 and those continuing on Bmab 1000, 
compared to those continuing on Prolia. 
Secondary Pharmacokinetic Endpoints 
Serum denosumab concentrations will be listed and summarized with descriptive statistics at 
each visit. Pharmacokinetic parameter estimation and formal statistical analyses of PK data 
are not planned in this study; however, population PK and/or PK/PD modeling may be 
performed and reported separately from the main clinical study report, if deemed necessary. 
Following the transition period, serum concentrations at Week 78 will be summarized. 
Secondary Immunogenicity Endpoints 
Incidence and titer of anti-drug antibody, incidence of neutralizing antibody up to Week 52 
will be summarized by treatment and timepoints per the Schedule of Events. Similar 
summaries will be presented for the transition period, split by Week 52 serostatus, to 
compare the transition to Bmab 1000 against continuing on Prolia. 
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Safety Analysis
Treatment-emergent adverse events and serious adverse events recorded during the study will 
be summarized by system organ class, preferred term, and treatment, and will include the 
total number of events with number and percentage of patients with adverse events. Adverse 
events and medical history will be coded using the most current version of MedDRA. 
Summaries of the number and percentage of patients (and number and percentage of events) 
for study treatment-related adverse events, severe adverse events, serious adverse events, 
adverse events with an outcome of death, and adverse events leading to discontinuation of 
the study treatment will be provided by treatment. 
Incidence and grade of AESI including treatment-related hypersensitivity/allergic reaction, 
serious infections, hypocalcemia, osteonecrosis of the jaw, atypical femoral fracture, and 
dermatologic reactions from baseline (Day 1) through the EoS will be summarized by 
treatment group. 
Descriptive statistics and listings will be presented for other safety assessments, ie, vital 
signs, clinical laboratory assessments, abnormal physical examination findings, ECGs, and 
concomitant medications. 
Following completion of the Transition Period, summaries will be produced for incidence of 
TEAEs, deaths, and SAEs from the third dose to Week 78, and incidence of clinically 
significant changes in physical examinations, laboratory safety tests, ECG, and vital signs 
will also be summarized for the same period.
Version and Date of Protocol: Version 3.0, 31-Aug-2022 
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List of Abbreviations  
Abbreviation
Definition
ADA
anti-drug antibody 
ADR
adverse drug reaction
AE
adverse event
AESI 
adverse event of special interest
ALP 
alkaline phosphatase 
ALT 
alanine transaminase
ANCOVA 
analysis of covariance
AST
aspartate transaminase
ATC
Anatomical Therapeutic Chemical Classification System 
AUEC 
area under the effect curve 
AUIC 
the area under the % inhibition curve 
BMD
bone mineral density
CFR
Code of Federal Regulations
CHO 
Chinese hamster ovary 
CI 
confidence interval 
Cmin
minimum concentration
COVID-19 
coronavirus disease 2019
CRO
contract research organization
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX
C-terminal telopeptide of Type 1 collagen 
DXA
dual-energy X-ray absorptiometry 
ECG
electrocardiogram
eCRF
electronic case report form 
eGFR
estimated glomerular filtration rate
EMA 
European Medicines Agency 
EoS 
end-of-study 
FAS 
full analysis set
FDA
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FT3 
free tri-iodothyroinine 
FT4 
free throxine 
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Abbreviation 
Definition
GCP
Good Clinical Practice
GLP-1 
glucagon-like peptide-1 
GMP
Good Manufacturing Practice 
HBV
hepatitis B virus
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB
investigator’s brochure
ICE
intercurrent event
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC
independent ethics committee 
IgG2
immunoglobulin G2
Imax
maximum % inhibition
IRB 
institutional review board 
ISRC 
independent safety review committee 
IWRS
interactive web response system 
LOCF
last observation carried forward 
MAR
missing at random 
MedDRA
Medical Dictionary for Regulatory Activities
mFAS
modified full analysis set
MI
multiple imputation
MMRM
mixed model for repeated measures 
NAb 
neutralizing antibody 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
P1NP
procollagen Type 1 N-terminal propeptide
PD
pharmacodynamic 
PFS 
prefilled syringe 
PK 
pharmacokinetic 
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Abbreviation 
Definition
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPI
proton-pump inhibitor 
PVG
pharmacovigilance 
RANKL
receptor activator of nuclear factor kappa-B ligand
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAF 
safety analysis set
SAS
statistical analysis system
SC
subcutaneous 
sCTX 
serum C-terminal telopeptide of Type 1 collagen
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone 
TImax
the time of occurrence of maximum % inhibition
Tmin 
time of occurrence of the minimum concentration 
UK 
United Kingdom 
ULN
upper limit of normal 
UN
United Nations 
US
United States
WHO
World Health Organization 
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1 Introduction 
1.1 Background 
Osteoporosis, a systemic skeletal disease characterized by low BMD and micro-architectural 
deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to 
fractures, is a global public health concern (Klibanski et al., 2001). With 200 million 
individuals estimated to have osteoporosis worldwide, around 9 million fragility fractures 
each year are noted, with a fracture occurring every 3 seconds causing pain, disability, loss of 
independence and death (IOF 2019). This includes 1.6 million hip fractures, which result in 
the most morbidity, mortality, and healthcare costs. The 1.4 million individuals who sustain 
compression fractures of the vertebrae endure back pain, loss of height and adversely affect 
the quality of life. Traumatic fractures of the wrist and femoral neck are also common 
osteoporotic fractures, which cause a substantial clinical and economic burden for society. As 
the world population is ageing fast, UN projects that by 2050, 2.1 billion people will be over 
60 years of age and at risk of osteoporosis. In case of the hip fracture alone, it is expected 
that the cases will range from 7 million to 21 million by 2050 (IOF 2019). 
Many pharmacological agents for treating osteoporosis have been evaluated in large clinical 
trials and proven to reduce fracture risk. The aim of the pharmacological intervention is to 
decrease the incidence of fractures. Earlier approved classes of drugs for this indication are 
antiresorptive agents (bisphosphonates, HRT, and selective estrogen receptor modulators); 
the parathyroid hormone analog teriparatide that has an anabolic effect on bone tissue, and 
strontium ranelate that increases bone formation and decreases bone resorption (Tella and 
Gallagher 2014; Chang et al., 2018).
1.2 Denosumab
Denosumab is marketed in the US and Europe by Amgen under the brand name Prolia as a 
single-use prefilled syringe (PFS) containing 60 mg of denosumab in 1 mL of solution (60 
mg/mL) and will be used as a reference treatment in this study. 
Denosumab is a fully human IgG2 monoclonal antibody to RANKL, a cytokine expressed by 
cells of the osteoblast lineage that is a key regulator of osteoclastic bone resorption. By 
binding and neutralizing RANKL, denosumab inhibits osteoclast differentiation, activity, and 
survival, thereby decreasing bone resorption in cortical and trabecular bone. Prolia® is
indicated for the treatment of following conditions in patients with high risk of fracture: 
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postmenopausal women with osteoporosis at high risk for fracture, men with osteoporosis at 
high risk for fracture, glucocorticoid-induced osteoporosis in men and women at high risk for 
fracture, men at high risk for fracture receiving androgen deprivation therapy for 
nonmetastatic prostate cancer, and women at high risk of fracture receiving adjuvant 
aromatase inhibitor therapy for breast cancer (Prolia USPI 2021; Prolia SmPC 2021). 
1.3 Bmab 1000
Bmab 1000 is a proposed biosimilar to Prolia and is a monoclonal antibody of IgG2
consisting of 2 identical heavy chains, each comprising of 448 amino acids (including 
C-terminal lysine) and 2 identical light chains, each comprising of 215 amino acids. The 
average mass of intact Bmab 1000 is 147.4 kDa, which is similar to denosumab in Prolia. 
Bmab 1000 is produced in suspension culture in the CHO cell line. Qualitatively and 
quantitatively, the formulation composition for Bmab 1000 is identical to the reference 
product Prolia. The final formulation is filled into a PFS containing 60 mg of Bmab 1000 in 
1 mL of solution (60 mg/mL).
1.4 Clinical Studies 
1.4.1 Bmab 1000 
Physicochemical, analytical, and preclinical (functional assays) characterizations and 
comparability evaluations have shown Bmab 1000 to be of similar structure, biological 
activity and quality profile as that of Prolia.
To date, no clinical studies have been initiated with Bmab 1000. As part of the biosimilar 
development program and in accordance with the applicable biosimilar guidelines, the 
following clinical studies are planned to be conducted with Bmab 1000: 
 Study B1000-NHV-01-G-01: A Randomized, Double-blind, Two-arm, Single-dose, 
Parallel-Group Study to Compare the Pharmacokinetics, Pharmacodynamics, Safety, and 
Tolerability of Bmab 1000 and Prolia® in Normal Healthy Male Volunteers. 
 Study B1000-PMO-03-G-02 (present study): A Randomized, Double-blind, Multicenter, 
Parallel-arm Phase 3 Study to Compare the Efficacy, Pharmacodynamics, Safety, and 
Immunogenicity between Bmab 1000 and Prolia in Postmenopausal Women with 
Osteoporosis. 
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In the absence of any clinical data pertaining to Bmab 1000 and considering the biosimilar 
development pathway, relevant efficacy and safety data from clinical studies conducted with 
Prolia (denosumab) are summarized in the section below. 
Further detailed information can be found in the Investigator’s Brochure (IB). 
1.4.2 Prolia 
The efficacy and safety of Prolia in the treatment of postmenopausal osteoporosis was 
demonstrated in a 3-year, randomized, double-blind, placebo-controlled, multinational study 
of 7808 postmenopausal women aged 60 to 91 years. Women with a baseline BMD T-score 
between –2.5 and –4.0 at either the lumbar spine or total hip were enrolled. A total of 3902 
women were enrolled in placebo group and 3886 women were enrolled in Prolia (60 mg) 
group (Prolia USPI 2021).
Prolia significantly reduced the incidence of new morphometric vertebral fractures at 3 years 
(primary efficacy variable) compared with the placebo (2.3% versus 7.2%, respectively; 
P
4.8%, and relative risk reduction was 68%. 
Prolia significantly reduced the incidence of hip fracture at 3 years compared with the 
placebo (0.7% versus 1.4%, respectively; P = 0.04). The age-adjusted absolute risk reduction 
was 0.3% and a relative risk reduction was 40%. Prolia significantly reduced the incidence of 
nonvertebral fracture at 3 years compared with the placebo (6.5% versus 8.0%, respectively; 
P = 0.01). The absolute risk reduction was 1.5%, and relative risk reduction was 20%. 
Treatment with Prolia significantly increased BMD at all anatomic sites measured at 3 years. 
The treatment differences in BMD at 3 years were 8.8% at the lumbar spine, 6.4% at the total 
hip, and 5.2% at the femoral neck (Prolia USPI 2021).
In clinical trials, treatment with Prolia reduced the level of sCTX by approximately 85% by 
3 days, with maximal reductions occurring by 1 month. Within 1 to 3 months after dosing, 
the sCTX levels were below the limit of quantitation in 39% to 68% of patients. At the end of 
dosing interval, the suppression of sCTX partially reduced from a maximal reduction of 
g. 
After further dosing, these effects were sustained. Similar effect was also observed for the 
level of P1NP (Prolia USPI 2021).
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The most common adverse reactions reported with Prolia in patients with postmenopausal 
osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, 
and cystitis (Prolia USPI 2021).
1.5 Study Rationale
Bmab 1000 is currently being developed as a proposed biosimilar to Prolia. For a proposed 
biosimilar to be approved, it must be proven that there are no clinically meaningful 
differences between the biosimilar and the reference innovator product. The PK, PD, and 
safety profile of Bmab 1000 and the US-licensed Prolia will be compared to demonstrate PK 
equivalence in a Phase 1 study in healthy volunteers (Study B1000-NHV-01-G-01). 
The current randomized, double-blind, multicenter, parallel-arm study will be conducted as a 
part of the clinical development program of Bmab 1000 and will assess the therapeutic 
equivalence in efficacy, safety, and PD of Bmab 1000 compared with US-licensed Prolia. 
The sponsor considers that the proposed clinical development program will be sufficient to 
demonstrate PK equivalence (Study B1000-NHV-01-G-01) and therapeutic equivalence and 
safety (Study B1000-PMO-03-G-02) of Bmab 1000 to the reference product. After collecting 
the totality of evidence proving its biosimilarity to Prolia, Bmab 1000 will provide an 
opportunity to improve access to treatment with potentially lowering health care costs. 
The design of this study considers the EU Guideline on Similar Biological Medicinal 
Products Containing Monoclonal Antibodies: Nonclinical and Clinical Issues (EMA 2012), 
the US FDA Guidance on Scientific Considerations in Demonstrating Biosimilarity to a 
reference product (FDA 2015), and PMDA Guideline on the Quality, Safety and Efficacy 
Assurance of Follow-on Biologics (PMDA 2009). 
This study protocol is designed to allow a global study that would address the needs of 
various regulatory bodies. For EMA, the PD endpoint AUEC of sCTX from baseline to 
26 weeks is considered as Co-primary endpoint, while, for US FDA, this endpoint is 
considered as a key secondary endpoint. For US FDA, after completion of double-blind 
active-controlled period (Day 1 to Week 52 [pre-dose]), the study is designed to include the 
transition period (Week 52 to Week 78), where patients who have received Prolia will be 
re-randomized to receive either Bmab 1000 or Prolia (Section 3).
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1.5.1 Rationale for Study Population 
International regulations (World Health Organization 2009; EMA 2012; FDA 2015; 
FDA 2019) suggest that proposed biosimilars shall be tested in a population representative of 
the approved therapeutic indications of the reference product and sufficiently sensitive for 
detecting potential differences between the proposed biosimilar and the reference product. 
The study population in this study was selected to be representative of the clinical studies 
supporting the development and marketing of the reference product (Prolia), and to align 
with the indications approved for the reference product. 
Postmenopausal female patients aged 
with the BMD T-score at the lumbar 
selected based on the statistics that the mean age of natural menopause is 51 years in 
industrialized nations, compared with 48 years in poor and nonindustrialized nations. With 
the average life span extended to 70 years, the upper age limit is selected as 80 years (Ji and 
Yu 2015). The BMD T-score inclusion criteria is based on a 3-year, randomized, 
double-blind, placebo-controlled trial conducted in 7808 women to evaluate efficacy and 
safety of Prolia in the treatment of postmenopausal osteoporosis, which had enrolled women 
with a baseline BMD T-score between –2.5 and –4.0 at either the lumbar spine or total hip 
(Prolia USPI 2021; Prolia SmPC 2021).
1.5.2 Rationale for Dose Selection 
The recommended dose of Prolia is 60 mg administered as a single SC injection once every 
6 months. The same dose has been selected for Bmab 1000 to allow comparisons between the 
reference product and the proposed biosimilar. 
1.6 Benefit-Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably 
expected AEs of Bmab 1000 is provided in the IB. Bmab 1000 is being developed as a 
proposed biosimilar to Prolia; analytical and biological similarity has been demonstrated 
between Bmab 1000 and Prolia based on physicochemical and functional characterization 
using sensitive, orthogonal, and state of the art analytical methods and functional assays. 
Therefore, it is expected that efficacy, safety, and immunogenicity of Bmab 1000 will be 
comparable to Prolia. Bmab 1000 will have the same pharmaceutical formulation and 
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strength as Prolia (60 mg). The proposed dosing regimen is in line with the approved labeling 
for Prolia (Prolia USPI 2021). The proposed safety monitoring is deemed to be sufficient to 
monitor potential risks of Bmab 1000 administration. In view of the structural and biological 
similarity, Bmab 1000 is expected to display a safety profile similar to Prolia. Based upon the 
proven safety profile of Prolia, the benefits of the conduct of the proposed clinical study 
outweigh the associated risks. 
The benefit and risk assessments and the risk mitigation plans for COVID-19 are specified in 
Section 13.2.
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2 Study Objectives, Endpoints, and Estimands 
2.1 Primary Objectives, Endpoints, and Estimands 
The primary objectives, endpoints, and estimands are presented in Table 2-1.
Table 2-1 
Primary Objectives, Endpoints, and Estimands
Primary Objectives
Endpoints (Including Estimand Description)
To demonstrate equivalent efficacy between 
Bmab 1000 and Prolia based on percentage 
change from baseline at Week 52 in lumbar 
spine BMD (Co-primary for EMA, and 
Primary for US FDA) 
Endpoint: Percentage change from baseline at Week 52 in the 
lumbar spine BMD by DXA (Time Frame: Baseline and Week 
52) 
Estimand 1a-EMA (Co-primary Efficacy): Difference in means 
(Bmab 1000 – Prolia) in % change from baseline in lumbar 
spine BMD by DXA after 52 weeks in postmenopausal 
womena with osteoporosis treated with SC injections every 
6 months assuming that all women receive 2 doses without any 
errors or deviations in dosing and without receipt of any other 
medications affecting bones except for vitamin D and calcium 
supplements 
 
Estimand 1a-US FDA (Efficacy): Difference in means 
(Bmab 1000 – Prolia) in composite endpoint of % change from 
baseline in lumbar spine BMD by DXA after 52 weeks 
(where % change from baseline of zero is taken for anyone 
who dies) in postmenopausal womena with osteoporosis treated 
with SC injections every 6 months irrespective of 
discontinuation of treatment for any reason, errors or 
deviations in dosing and whether any other osteoporosis 
medications are taken 
To demonstrate pharmacodynamic 
equivalence between Bmab 1000 and Prolia 
based on AUEC of the bone resorption 
marker sCTX from baseline to week 26 (Co-
primary for EMA and secondary for US 
FDA) 
Endpoint: AUEC of sCTX from baseline to 26 weeks (Time 
Frame: Baseline to Week 26) 
Estimand 1b-EMA (Co-primary PD): Ratio of geometric 
means (Bmab 1000/Prolia) in AUEC in (fasted) sCTX up to 
26 weeks in postmenopausal womena with osteoporosis treated 
with a SC injection without any dosing error and no receipt of 
any other medications affecting bones except for vitamin D 
and calcium supplements 
Abbreviations: AUEC, area under the effect curve; BMD, bone mineral density; DXA, dual-energy X-ray 
absorptiometry; SC, subcutaneous; sCTX, serum C-terminal telopeptide of Type 1 collagen 
Note: The screening BMD assessment will be taken as the baseline BMD assessment. 
a. 
Women should not have been previously treated with denosumab but may have had prior treatment with 
bisphosphonates and will be co-administered vitamin D and calcium supplements. 
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2.2 Secondary Objectives and Endpoints of Double-Blind 
Active-Controlled Period (Part 1) 
The secondary objectives and endpoints of double-blind active-controlled period (Part 1) are 
presented in Table 2-2.
Table 2-2 
Secondary Objectives and Endpoints of Double-Blind 
Active-Controlled Period (Part 1) 
Secondary Objective(s)
Endpoints
To compare other efficacy parameters (BMD of 
lumbar spine, total hip and femoral neck; fracture 
incidence) between Bmab 1000 and Prolia 
 
Percentage change from baseline at Week 26 in 
lumbar spine BMD by DXA (Time Frame: Baseline 
and Week 26) 
 
Percentage change from baseline at Weeks 26 and 52 
in total hip BMD by DXA (Time Frame: Baseline, 
Week 26, and Week 52) 
 
Percentage change from baseline at Weeks 26 and 52 
in femoral neck BMD by DXA (Time Frame: 
Baseline, Week 26, and Week 52) 
 
Incidence of fracture up to Week 52 (Time Frame: 
Baseline up to Week 52) 
To compare bone turnover between Bmab 1000 
and Prolia based on sCTX and P1NP 
 
Cmin of sCTX (Time Frame: Baseline up to Week 26) 
 
Serum concentrations of P1NP (Time Frame: 
Baseline up to Week 52) 
 
PD parameters of sCTX: Imax, TImax, AUIC (Time 
Frame: Baseline up to Week 26) 
To compare safety and tolerability of 
2 administrations of Bmab 1000 and Prolia 
6 months apart 
 
Incidence of TEAEs up to 6 months after the second 
dose (Time Frame: Baseline up to Week 52) 
 
Incidence of clinically significant changes in vital 
sign, physical examinations, laboratory safety tests, 
and ECGs up to 6 months after the second dose 
(Time Frame: Baseline up to Week 52) 
To compare immunogenicity between Bmab 1000 
and Prolia 
 
Incidence and titer of ADA, incidence of NAb up to 
Week 52 (Time Frame: Baseline up to Week 52) 
To assess denosumab serum concentrations 
following Bmab 1000 and Prolia administration 
 
Denosumab concentrations at Weeks 2, 4, 12, 26, 38, 
and 52 (Time Frame: Baseline up to Week 52) 
Abbreviations: ADA, anti-drug antibodies; AUEC, area under the effect curve; AUIC, the area under the 
% inhibition curve; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; ECG, 
electrocardiogram; Cmin, minimum concentration; Imax, maximum % inhibition; NAb, neutralizing antibodies; 
P1NP, procollagen Type 1 N-terminal propeptide; sCTX, serum C-terminal telopeptide of Type 1 collagen; 
TEAE, treatment-emergent adverse event; TImax, the time of occurrence of maximum % inhibition 
Note: The screening BMD assessment will be taken as the baseline BMD assessment. 
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2.3 Key Secondary Objectives and Endpoints for the Transition Period 
(Part 2) 
The key secondary objectives and endpoints of transition period (Part 2, for US FDA) are 
presented in Table 2-3.
Table 2-3 
Key Secondary Objectives and Endpoints for the Transition 
Period (Part 2)
Secondary Objective(s)
Endpoints
To assess the risk of hypersensitivity and adverse 
events up to 6 months after the single transition from 
Prolia to Bmab 1000 compared with those continuing 
on Prolia 
 
Incidence of TEAEs from the third dose at 
Week 52 and up to and including Week 78 (Time 
Frame: from Week 52 up to Week 78) 
 
Incidence of clinically significant changes in 
physical examinations, laboratory safety tests, 
ECG and vital signs from the third dose at 
Week 52 and up to and including Week 78 (Time 
Frame: from Week 52 up to Week 78) 
 
Incidence of deaths and SAEs from the third dose 
at Week 52 and up to and including Week 78 
(Time Frame: from Week 52 up to Week 78) 
To assess the risk of immunogenicity through 
formation of anti-drug antibodies after the single 
transition from Prolia to Bmab 1000 compared with 
those continuing on Prolia 
 
Incidence and titer of ADA, incidence of NAb at 
Week 78 split by serostatus at Week 52 (Time 
Frame: from Week 52 up to Week 78) 
Abbreviations: ADA, anti-drug antibodies; ECG, electrocardiogram; Nab, neutralizing antibodies; PD, 
pharmacodynamic; PK, pharmacokinetic; SAE, serious adverse event; TEAE, treatment-emergent adverse event 
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2.4 Other Secondary Objectives and Endpoints of Transition Period 
(Part 2) 
The other secondary objectives and endpoints of transition period (Part 2, for US FDA) are 
presented in Table 2-4.
Table 2-4 
Other Secondary Objectives and Endpoints for the Transition 
Period (Part 2)
Other Secondary Objective(s)
Endpoints
To assess efficacy after the single transition from 
Prolia to Bmab 1000 compared with those to 
continuing on Prolia 
 
Percentage change from Week 52 at Week 78 in 
lumbar spine BMD by DXA (Time Frame: from 
Week 52 up to Week 78) 
To assess efficacy of 3 doses of Bmab 1000 compared 
to Prolia 
 
Percentage change from (original) baseline at 
Week 78 in lumbar spine, hip and femoral neck 
BMD by DXA (Time Frame: Day 1 up to 
Week 78) 
To assess PK and PD: 
i. 
after the single transition from Prolia to 
Bmab 1000 
ii. 
on Bmab 1000 throughout 
each compared with those on Prolia throughout 
 
Serum concentrations of denosumab at Week 56, 
64, and 78 (PK) (Time Frame: from Week 56 up 
to Week 78) 
 
Serum concentrations of CTX at Week 78 (PD) 
(Time Frame: Week 78) 
To assess the adverse events on Bmab 1000 
throughout compared to Prolia throughout 
 
Incidence of TEAEs from the first dose up to and 
including Week 78 (Time Frame: Day 1 up to 
Week 78) 
 
Incidence of clinically significant changes in 
physical examinations, laboratory safety tests, 
ECG and vital signs from the first dose up to and 
including Week 78 (Time Frame: Day 1 up to 
Week 78) 
 
Incidence of deaths and SAEs from the first dose 
up to and including Week 78 (Time Frame: 
Day 1 up to Week 78) 
To assess the risk of immunogenicity through 
formation of anti-drug antibodies on Bmab 1000 
throughout compared to Prolia throughout 
 
Incidence and titer of ADA, incidence of NAb at 
any point from the first dose up to Week 78 (Time 
Frame: Day 1 up to Week 78) 
Abbreviations: ADA, anti-drug antibodies; ECG, electrocardiogram; Nab, neutralizing antibodies; PD, 
pharmacodynamic; PK, pharmacokinetic; CTX, serum carboxy-terminal cross-linking telopeptide of Type 1 
collagen; serious adverse event; TEAE, treatment-emergent adverse event 
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3 Investigational Plan 
3.1 Study Design 
This is a randomized, double-blind, multicenter, parallel-arm, Phase 3 study to compare the 
efficacy, PK, PD, safety, and immunogenicity of Bmab 1000 and Prolia in postmenopausal 
women with osteoporosis. 
value consistent with a T-
 at the lumbar spine will be enrolled. 
Figure 3-1 shows the study design for the study. The study will consist of 3 study periods: 
Screening period; Part 1, double-blind active-controlled period; and Part 2, transition period. 
Screening Period (from Day –28 to Day –1) 
Screening evaluations will be completed within 28 days prior to the randomization. 
Part 1, Double-Blind Active-Controlled Period (from Week 0 [Day 1] to Week 52 
Pre-dose) 
In the double-blind active-controlled period, eligible patients will be randomly assigned (1:1) 
to receive either Bmab 1000 (60 mg) or Prolia (60 mg) via SC injection on Day 1 (Week 0, 
the same date as randomization) and at Week 26. Patients will be followed-up for 26 weeks 
after the second dose. The randomization will be stratified by 
Efficacy, PK, PD, and safety including immunogenicity data will be collected as per 
Schedule of Events (Table 13-1).
Part 2, Transition Period (from Week 52 to Week 78 [EoS Visit]) 
All patients who complete Part 1 will undergo the re-randomization process prior to the study 
treatment administration at Week 52. Prior to dosing at Week 52, patients in the Prolia arm 
will be randomly assigned in a 1:1 ratio to receive either Bmab 1000 or Prolia at Week 52. 
This is done to obtain data after single switch in patients who have been treated with Prolia. 
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To maintain the study blinding, the patients in the original Bmab 1000 arm will also go 
through the re-randomization procedure; however, they will continue to receive Bmab 1000.  
The re-randomization will take place within the original strata used for the randomization at 
baseline. All applicable assessments including efficacy, PK, PD, safety including 
immunogenicity will be performed as per Schedule of Events (Table 13-1). 
End-of-study visit will be at Week 78 post randomization (Month 18). 
Patients who discontinue the study treatment early will be followed as described in 
Section 4.2.1. For patients who discontinue the study early and do not wish to attend 
Week 26 and/or Week 52 visit(s) as described in Section 4.2.1, all procedures specified for 
EoS visit (Table 13-1) will be performed at early withdrawal visit; however, DXA scan 
should be performed only if the last scan was not performed within 90 days prior to the early 
withdrawal visit. Lateral spine X-ray can be performed if clinically indicated.
The maximum study duration for a patient will be approximately 18 months (excluding 
screening).
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Figure 3-1 
Study Design
Abbreviations: AUEC, area under the effect curve; BMD, bone mineral density; cfb, change from baseline; 
EoS, end-of-study; LS, lumbar spine; PD, pharmacodynamic; sCTX, serum C-terminal telopeptide of Type 1 
collagen; R-1, first randomization; R-2, re-randomization
a.
At Week 52, patients in the Prolia arm will be re-randomized in 1:1 ratio to receive Bmab 1000 or Prolia. 
To maintain the blinding, patients in Bmab 1000 arm will undergo re-randomization procedure however, 
they will continue to receive Bmab 1000.
3.1.1 Independent Safety Review Committee
An Independent Safety Review Committee (ISRC) will periodically review the safety data to 
ensure safety of patients is protected (see Section 4.2.2). The ISRC will consist of therapeutic 
area experts (at least 3 members) who are independent of this study conduct. The initial 
meeting of the ISRC will be conducted after the first 10% of patients have completed Day 15 
visit. The ISRC will continue to review the emerging safety data. 
The ISRC will review the unblinded safety data to determine if the incidence of a serious 
adverse drug reaction was unacceptably high in the Bmab 1000 arm (or notably higher than 
the Prolia arm) such that continued administration of the product would present an 
unacceptable risk to patients.
The roles, responsibilities, and review process will be defined in the ISRC Charter. 
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4 Patient Selection and Withdrawal Criteria 
4.1 Selection of Study Patients 
Approximately 480 patients will be enrolled at approximately 47 sites in Europe and the 
United States. Patients will be assigned to study treatment only if they meet all of the 
inclusion criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or patient 
safety. Therefore, adherence to the eligibility criteria as specified in the protocol is essential.
4.1.1 Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Willingness to sign the written ICF, ambulatory, able to follow study instructions and 
comply with the protocol requirements, and not visually impaired as per the 
investigator’s opinion to participate in the trial. 
2. 
mIU/mL 
at screening or 6 weeks postsurgical bilateral oophorectomy with or without 
hysterectomy. 
3. Evidence of osteoporosis as assessed by lumbar spine (L1-L4) absolute BMD 
corresponding to a T-
–
–4.0. Bone mineral density 
measurements should be performed by DXA using Hologic or Lunar densitometers at 
screening visit. All DXA scans will be assessed by a central imaging center for this 
purpose. 
4. At least 3 vertebrae in the L1-L4 region and at least one hip joint are evaluable by 
DXA at screening. 
5. Patients with body weigh
 
4.1.2 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. Patients with T-
 
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2. Known history of previous exposure to denosumab (Prolia®, Xgeva®, or any 
biosimilar denosumab). 
3. Use of any biologic drugs (with the exception of insulin and insulin analogue and 
GLP-1 receptor agonists) within 90 days or within five half-lives of the drug, 
whichever is longer prior to the screening. 
4. Known hypersensitivity to denosumab or its constituents or latex allergy or hereditary 
problems of fructose intolerance. 
5. For prior or ongoing use of any osteoporosis treatment (other than calcium and 
vitamin D supplements), following points to be considered for the washout periods 
prior to the screening visit: 
a. Oral bisphosphonate 
i. Ineligible if used for 3 or more years cumulatively 
ii. 
required at the screening visit 
b. Dose received any time for the following: intravenous bisphosphonate, 
strontium, fluoride (for osteoporosis), drugs being investigated for 
osteoporosis, teriparatide or any parathyroid hormone analogs, tibolone, oral 
or transdermal estrogen, selective estrogen receptor modulators, calcitonin, 
and cinacalcet 
6. 
within past 3 months before screening. Topical and nasal corticosteroids are allowed. 
7. Other bone active drugs including but not limited to anticoagulants, antiplatelet (with 
the exception of acetylsalicylic acid), anticonvulsants (with the exception of 
benzodiazepines), systemic ketoconazole, adrenocorticotropic hormone, lithium, 
gonadotropin releasing hormone agonists, and anabolic steroids within the last 
3 months before screening. Direct oral anticoagulants will be allowed. Receipt of PPI 
for >1 year continuously will be allowed only after 3 months of washout prior to the 
continuously are not allowed if they plan 
to continue the use of PPI during the study such that the continuous use of PPI will be 
>1 year.
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8. Patients with ongoing serious infections including cellulitis, or infection requiring 
parenteral antibiotics within 4 weeks prior to the first administration of the study 
treatment, or oral antibiotics within 2 weeks prior to the first administration of the 
study treatment.
9. Evidence of any of the following per the patient’s history, DXA, or X-ray review 
and/or current disease:
a.
Patient in bed rest for 2 or more weeks during the last 3 months prior to 
screening 
b. Current hyperthyroidism or hypothyroidism (patients on stable thyroid 
treatment will be allowed). Patients with subclinical hyperthyroidism (TSH 
 mIU/L) or subclinical hypothyroidism 
 
c.
History and/or current hyperparathyroidism or hypoparathyroidism 
d. Patients who have had recurrent episode of hypocalcemia in the past which, as 
per the investigator, is a risk to her participation in the trial 
e.
Current hypocalcemia or hypercalcemia based on albumin-adjusted serum 
calcium
f.
Any bone disease including bone metastasis or metabolic disease (except for 
osteoporosis), eg, osteomalacia or osteogenesis imperfecta, rheumatoid 
arthritis, Paget’s disease, ALP elevation (at investigator’s discretion), 
Cushing’s disease, clinically significant hyperprolactinemia (at investigator’s 
discretion), fibrous dysplasia, malabsorption syndrome which may interfere 
with the interpretation of the results
g. Malignancy (except squamous cell carcinoma, basal cell carcinoma, cervical 
or breast ductal carcinoma in situ) within the last 5 years from screening visit 
h. Height, weight, and girth which may preclude accurate DXA measurements 
i.
Advanced scoliosis or extensive lumbar fusion which would preclude 
vertebral fracture assessment
j. History and/or presence of one severe or 3 or more moderate vertebral 
fractures (as determined by central reading of lateral spine X-ray during the 
screening period). Severe vertebral fracture (Grade 3) is defined as >40% 
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vertebral height loss, and moderate vertebral fracture (Grade 2) is defined as 
25% to 40% vertebral height loss 
k. History and/or presence of hip fracture or bilateral hip replacement or history 
of atypical femoral fracture
l. Presence of an active healing fracture according to assessment of investigator 
m. History of severe skeletal pain with bisphosphonates which, as per the 
investigator, is a risk to her participation in the trial 
n. Oral/dental or periodontal conditions: Prior history or current evidence of 
osteomyelitis, osteonecrosis of the jaw (or risk of developing osteonecrosis of 
the jaw as per the investigator’s opinion), osteonecrosis of the external 
auditory canal; active dental or jaw condition which requires oral surgery; 
planned invasive dental procedure (dental implants); or non-healed dental or 
oral surgery 
o. Any organic or psychiatric disorder or laboratory abnormality or underlying 
condition (including, but not limited to metabolic, hematologic, renal, hepatic, 
pulmonary, neurologic, endocrine, cardiac, infectious, or gastrointestinal, 
which, in the opinion of the investigator, will prevent the patient from 
completing the study or interfere with the interpretation of the study results, or 
will put the patient into unacceptable risk for participating in the trial 
p. History of presence of a severe allergic reaction (eg, anaphylaxis).
q. Personal/family history of prolonged QT interval syndrome or family history 
of sudden death. 
10. New York Heart Association Class III or IV chronic heart failure, any unstable 
cardiovascular disease, pulmonary disease, autoimmune disease or ECG 
abnormalities, which can be judged as clinically significant at the investigator’s 
discretion. 
11. Patient has a planned surgical intervention during the study period except those related 
to the underlying disease and which, in the opinion of the investigator, will put the 
patient at further risk or hinder the patient’s ability to maintain compliance with study 
treatment and the visit schedule. 
12. One of the following laboratory test result at screening: 
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a.
Vitamin D deficiency (serum 25-
 ng/mL). For 
eligibility purpose, oral vitamin D repletion is permitted at the investigator’s 
discretion if serum 25-
 ng/mL and 
vitamin D level is allowed to be retested once post repletion within the 
screening period 
b.
-Gault 
 
c. 
 
 
d. 
 
13. Allergy to vitamin D or calcium supplements, or intolerant to long-term calcium or 
vitamin D supplementation, or history malabsorption of calcium or vitamin D 
supplements. 
14. Participation in a drug study within 90 days or 5 half-lives of the previous drug (if 
known), whichever is longer, prior to drug administration. 
15. Known case of active hepatitis B, hepatitis C or HIV infection. Has a hepatitis B, 
hepatitis C or HIV positive test result at screening. A patient with past hepatitis B or C 
virus infection is allowed if recovered by the time of the screening visit. At screening, 
hepatitis B will be assessed in all patients. If a patient has HBsAg positive, the patient 
will be excluded from the study. If a patient has HBsAg negative and HBcAb positive, 
an HBV DNA test will be performed at screening. If the HBV DNA test result is 
positive, the patient will be excluded from the study. At screening, hepatitis C 
antibody will be assessed in all patients. If hepatitis C antibody test result is positive, 
an HCV RNA test will be performed at screening. If the HCV RNA test result is 
positive, the patient will be excluded from the study; If the HCV RNA test result is 
negative, the patient can be included at the investigator’s discretion. 
16. Evidence of alcohol or substance-abuse within the last 12 months prior to screening 
that the investigator believes would interfere with understanding or completing the 
study. 
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17. Confirmed or suspected with infection with SARS-CoV-2 from screening to 
randomization, or who has been diagnosed with COVID-19 (as per site and/or local 
regulatory guidelines) or history of COVID-19 infection requiring oxygen 
supplementation in the last 8 weeks prior to screening or had contact with a 
COVID-19 patient 14 days prior to screening and within the screening period up to 
randomization. 
18. Patient has received live virus vaccine within 4 weeks prior to screening or within the 
screening period up to randomization. 
4.2 
Discontinuation From Study Treatment and/or Withdrawal From the 
Study 
4.2.1 Discontinuation From the Study Treatment 
Patients may discontinue from the study treatment at any time and for any reason without 
prejudice to their future medical care by the investigator or at the study site. Every effort 
should be made to keep patients in the study. If necessary, the investigator may discuss with 
the sponsor or its designee about any patient’s reason for study treatment discontinuation. 
The reasons for patients discontinuing the study treatment will be recorded on the eCRF. 
If the patient was dosed in error because she did not meet the eligibility criteria of the study, 
the patient should be discontinued from the study treatment. The patient will be followed-up 
for 6 months after the study treatment administration for safety. 
The reason for discontinuing study treatment should be collected and categorized as related 
or not related as follows: 
Related reasons: Related reasons for treatment discontinuation are related to 
intolerance to study treatment or supplements, or lack of efficacy (worsening of 
disease). The reasons will be categorized as below:
1. Any physical examination finding, change in vital signs, AE/SAE/AESI, or laboratory 
abnormality that, in the opinion of the investigator is causally related to the study 
treatment and can cause an excessive risk if the patient continued on treatment.  
2. Use of prohibited therapy for osteoporosis. 
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3. Noncompliance or inability to tolerate the calcium and vitamin D supplementation 
that, in the opinion of the investigator, compromise possible response to therapy or 
risk of hypocalcemia. 
4. Patient cannot tolerate study treatment (including PFS related issues with SC route of 
administration).
5. Lack of efficacy at investigator's discretion (BMD at the total hip or lumbar spine 
decreased by 7% or more). 
Unrelated reasons
6. AEs/SAEs not related to the study treatment and AEs not related to lack of efficacy
7. Investigator’s decision, if it is in the patient’s best interest to discontinue treatment (eg, 
new medical condition unrelated to osteoporosis, development of contraindication to 
administration of denosumab and any other reason unrelated to study treatment) 
8. Administrative or logistical reasons, such as inability of the patient, the investigator, or 
the sponsor to continue the study 
The follow-up of patients after study treatment discontinuation is described in Figure 4-1. 
A good effort will be made to follow-up on patients particularly after intercurrent events. 
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Figure 4-1 
Follow-up of Patients After Study Treatment Discontinuation
Note that Week 52 assessments are of primary importance (even if other medications administered and 
non-compliance with intermediate visits). 
All assessments will be performed after informed consent is obtained from the patient and will only be 
performed in the interest of the patient.
a.
Eligible patients wishing to discontinue from study treatment are encouraged to return for all assessments 
up to Week 52. 
b.
Treatment discontinued for “Related reason” = related to intolerance to study treatment or supplements, or 
lack of efficacy (worsening of disease).
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Any ineligible patients given the initial dose in error, should be discontinued from both the 
study treatment and discontinued from the study after a 6-month safety follow up.  Patients 
who discontinue the study treatment for any other reasons should be encouraged to return 
for the Week 52 visit (Table 13-1) and also intermediate visits, if feasible; they will not enter 
the transition period. 
BMD assessment at Week 52 is important to collect even if the patient wishes to 
discontinue treatment after the first dose for any reason and even if they transitioned to 
different osteoporosis medications or have been non-compliant with intermediate visits. 
Patients who discontinued the study treatment early for any reason will be followed for 6 months 
after the last study treatment administration for safety. If a patient cannot or is unwilling to attend 
any visit, a safety follow-up (eg, AEs, concomitant medication) will be conducted by telephone. 
4.2.2 Pausing of Study Treatment or Enrollment or Study Termination 
and ISRC Review 
The administration of the study treatment or further enrollment in the study may be 
paused/modified by Biocon based on the ISRC’s recommendation. The ISRC will review the 
safety data and provide recommendations whether to pause/continue/modify the study (see 
Section 3.1.1). In case of an unforeseen situation, where the ISRC determines upon review of 
the emerging safety data that the continued administration of the study treatment would 
present an unacceptable risk to the patients, ISRC may recommend terminating the study to 
Biocon. Further details will be provided in ISRC Charter. 
4.2.3 Withdrawal From the Study
Patients may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study site. The investigator also has 
the right to withdraw patients. The participation of patient in the study can be discontinued 
for the following reasons: 
1. Patient withdraws consent 
2. Patient's substantial noncompliance toward protocol-specified 
procedures/requirements (eg, unwilling to attend the critical visits – Week 26 and 
Week 52 visits) 
3. Patient is lost to follow-up
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4. Investigator's decision (serious or intolerable adverse event, new medical condition or 
an intercurrent illness not consistent with the protocol requirements, contraindications 
of use of study treatment) 
5. Termination of the site or study by the sponsor or regulatory authority 
For patients who discontinue the study early and do not wish to attend Week 26 and/or 
Week 52 visit(s) as described in Section 4.2.1, all procedures specified for EoS visit 
(Table 13-1) will be performed at early withdrawal visit; however, DXA scan should be 
performed only if the last DXA scan was not performed within 90 days prior to the early 
withdrawal visit. Lateral spine X-ray can be performed if clinically indicated.
4.2.4 Lost to Follow-Up 
A patient will be considered lost to follow-up if she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the site for a required study 
visit: 
 The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether the patient wishes to and/or should continue in the study. 
 Before a patient is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the patient (where possible, 2 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record.
If the patient continues to be unreachable, she will be considered to have withdrawn from the 
study. If the patient can be reached, the patient should be encouraged to return for Week 26 
and/or Week 52 Visits as described in Section 4.2.1. 
4.2.5 
Replacements and Screen Failures 
Patients who receive study treatment and discontinue before the study completion will not be 
replaced. 
At the screening visit, a COVID-19 test will be performed as per site and/or local regulatory 
guidelines. Patients who have a COVID-19 positive test result and were asymptomatic or 
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mildly symptomatic will be allowed to be rescreened after minimum of 28 days from the date 
of COVID-19 positive test result on the basis that they have a confirmatory negative 
COVID-19 test result and have completely recovered from COVID-19 before being entered 
into the study as per site and/or local regulatory guidelines. The investigator is recommended 
to discuss with the medical monitor and/or sponsor before rescreening the patients with 
positive COVID-19 test result.  
For patients who meet the exclusion criteria of laboratory assessments (exclusion 
criterion 12), one retesting of laboratory test is allowed within the screening period; however, 
except for the vitamin D deficiency (exclusion criterion 12.a), the investigator is 
recommended to discuss with the medical monitor and/or sponsor for possibility of retesting 
of laboratory test. 
Overall, only 1 retesting of laboratory parameter and 1 rescreening is allowed during the 
study. For rescreened patients, all screening procedures/tests are required to be repeated 
except DXA scan and lateral spine X-ray if performed within 90 days prior to rescreening. In 
case of history of fall or clinical signs of vertebral fracture or based on investigator’s 
decision, DXA scan and/or lateral spine X-ray can be performed even within 90 days prior to 
rescreening. The rescreened patient will be assigned with a new patient identification 
number. 
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5 Study Treatments 
5.1 Method of Assigning Patients to Treatment Groups 
An IWRS will be used for the randomization. The responsible Biostatistician will generate 
the randomization schedule using SAS software Version 9.4 or later (SAS Institute Inc, Cary, 
North Carolina) for IWRS, which will link sequential patient randomization numbers to 
treatment codes.
First Randomization for Part 1 
Patients will be randomly assigned at the baseline/randomization visit (Week 0/Day 1) to 
receive Bmab 1000 (test product) or Prolia (reference product) using a 1:1 allocation ratio. 
The first randomization to treatment assignment will be stratified by the following: 
 
 
 
 
Re-Randomization for Part 2 (Transition Period) 
Prior to dosing at Week 52, patients in the Prolia arm will be randomly assigned again in a 
ratio of 1:1 to receive either Bmab 1000 or Prolia at Week 52. All patients who were initially 
randomly assigned to the Bmab 1000 on Week 0 (Day 1) will continue their treatment.  
The second randomization process will be conducted in all arms to maintain the study blind.  
During Part 2, the randomization will be stratified by the original strata used for the 
randomization at baseline.
5.2 Treatments Administered 
5.2.1 Bmab 1000 and Prolia 
Bmab 1000 (60 mg) or Prolia (60 mg) will be administered subcutaneously using a PFS of 
60 mg/mL solution for injection on Day 1, and at Week 26 and Week 52. The study treatment 
will be administered as an SC injection, preferably in the abdomen. Whenever possible, the 
same injection site should be used for all study treatment administration. 
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The study treatment is required to be administered by the site-qualified and trained clinical 
staff member(s) (eg, nurse/physician, etc.), who is designated as an unblinded study site 
personnel who will not be involved in any other study-related procedure(s). Patients will be 
blinded through the use of a blindfold, screen, or similar method during the dosing procedure 
so that the injection syringe will not be visible to the patient. The details regarding blinding 
are described in Section 5.6.
Bmab 1000 and Prolia should be visually inspected prior to its use. The study treatment 
solution should not be injected if it is cloudy or discolored or if it contains many particles or 
foreign particulate matter. To avoid discomfort at the site of injection, the PFS should be 
allowed to reach room temperature (up to 25ºC) before injecting and inject slowly. The entire 
contents of the PFS should be injected. 
Further guidance and information for handling the study treatment is provided in the 
Pharmacy Manual. 
5.2.2 Calcium and Vitamin D Supplements 
During the screening period, oral vitamin D repletion is permitted at the investigator’s 
discretion if serum 25-
 ng/mL for eligibility purpose. 
All patients will receive daily supplementation containing at least 1000 mg of elemental 
calcium and at least 400 IU vitamin D (via any route of administration) from randomization 
until the EoS visit (Week 78). Calcium and vitamin D are co-administered to prevent low 
serum calcium level while taking study treatments. The dose can be increased at 
investigator’s discretion. Patients who are already taking calcium and vitamin D prior to the 
screening visit, will continue the supplements during the screening period. Information about 
calcium and vitamin D administration will be collected via a patient diary and will also be 
recorded in the source documents and eCRF. 
Note: On the day of PD sample collection, patients should not take calcium supplement prior 
to sample collection (to be taken after sample collection). 
5.2.2.1 Managing Hypercalcemia and Hypocalcemia 
If a patient develops hypercalcemia during the study, the calcium and/or vitamin D 
supplementation may be interrupted or reduced per the investigator’s discretion until the 
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serum calcium concentration has returned to the normal range or as per the investigator’s 
discretion. 
If a patient develops hypocalcemia, defined as albumin-adjusted total serum calcium 
be instituted as deemed acceptable by local guidelines or as per investigator’s discretion to 
return the serum calcium concentration to within the normal range. 
If a patient is intolerant of the daily calcium or vitamin D supplementation, the formulation 
may be changed (including taking a preferred product that the patient tolerated well earlier) 
or the dose can be lowered per the investigator’s discretion. The intolerance as well as the 
resolution (eg, change in formulation or dosage) shall be recorded in both the source 
documents and the eCRF. 
5.3 Identity of Investigational Product 
Bmab 1000 is a mAb that is being developed by Biocon Biologics UK Limited as a proposed 
biosimilar to Prolia. Bmab 1000, is a full-length human mAb of the IgG2 subtype produced in 
a mammalian cell line, CHO cells, by recombinant DNA technology. Like denosumab, 
Bmab 1000 consists of 2 heavy chains and 2 light chains of the kappa subclass. The average 
mass of intact Bmab 1000 is 147.4 kDa, which is similar to denosumab in Prolia. The 
International Nonproprietary Name of the commercially available reference material (Prolia) 
is denosumab and the ATC Classification System code is M05BX04. 
The reference product, US-licensed Prolia, is supplied as sterile, preservative-free, clear, 
colorless to pale yellow solution for SC administration. Each 1 mL single-dose PFS of Prolia 
contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% 
polysorbate 20, water for injection, and sodium hydroxide to a pH of 5.2 (Prolia USPI 2021). 
Bmab 1000 is supplied as a sterile, preservative-free solution of denosumab for SC 
administration in a single-use PFS with a grey needle cap (1 per carton). Bmab 1000 is a 
colorless to pale yellow solution for injection, with a pH similar to that of Prolia and is 
formulated at 60 mg of denosumab in 1 mL for SC use. Each 1 mL single-dose PFS contains 
60 mg denosumab (60 mg/mL solution), acetate, sorbitol and polysorbate-20. For further 
details, see the IB.
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The following drug supplies will be used in the study: 
Product
Supplied as
Bmab 1000 
60 mg/mL single-dose PFS 
US-licensed Prolia
60 mg/mL single-dose PFS 
Abbreviation: PFS, prefilled syringe.
Note: The Bmab 1000 PFS is supplied without needle safety guard whereas Prolia PFS is supplied with needle 
safety guard. 
5.4 Management of Clinical Supplies 
5.4.1 Investigational Product Packaging and Storage 
The sponsor will provide adequate supplies of Bmab 1000 and Prolia for distribution to the 
study sites. Bmab 1000 will be manufactured and packaged in accordance with GMP for 
medicinal products for use in human clinical trials and provided with a certificate of analysis. 
All study treatments will be labeled in accordance with GMP and local regulatory 
requirements.
Storage and handling requirements are identical to that for Prolia and will be followed when 
handling Bmab 1000. All study treatment supplies must be stored in a secured area with 
restricted access (eg, a locked cabinet) and in accordance with the manufacturer’s 
instructions. They will be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and will not be 
frozen. The immediate containers must be kept in the outer carton until use to protect the 
study treatment from light and heat and avoid vigorous shaking. Once removed from the 
refrigerator, the product must not be exposed to temperatures above 25°C (77°F) or direct 
light and must be used within 14 days. The recommended storage conditions, and expiry date 
where required, are stated on the product label approved by each regulatory authority. 
Further guidance and information for drug product stability and storage are provided in the 
Pharmacy Manual.
5.4.2 Investigational Product Accountability 
The investigator will maintain accurate records of receipt of all study treatments, including 
dates of receipt. In addition, accurate records will be kept regarding when and how much 
study treatment is dispensed and used by each patient in the study. The study treatment 
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accountability will be verified by the monitoring team during their monitoring visit and 
ensure the accountability as per the IWRS reports.
Only patients enrolled in the study may receive the study treatment and only authorized site 
personnel may supply or administer the investigational product. Reasons for departure from 
the expected dispensing regimen must also be recorded. At the completion of the study, to 
satisfy regulatory requirements regarding drug accountability, all study treatments will be 
reconciled and retained or destroyed according to applicable regulations. Further guidance 
and information for the final disposition of unused investigational products are provided in 
the Study Reference Manual. 
The used syringes can only be destroyed if it is according to local standard operating 
procedures and a specific authorization is given by the sponsor. Permission will be granted 
by the sponsor on a study-site-by-study-site basis after reviewing the study site destruction 
policy. This authorization may also be granted to destroy used syringes immediately after 
administering the study treatment to patients in a manner that preserves the blinding. The list 
of destroyed syringes must be recorded. 
5.4.3  Calcium and Vitamin D Supplies 
Calcium and vitamin D will be supplied locally to the patient as per local regulations (see 
Section 5.2.2 for further information regarding doses and adjustments). 
5.5 Overdose, Underdose, and Medication Errors 
Since study treatments are directly administered by personnel involved in the study in 
controlled manner, overdose/underdose/medication error is unlikely to occur. However, in 
case of overdose/underdose/medication error, the management will be as per the standard of 
care. In case there is overdose/underdose/medication error, it must be reported to the 
sponsor/sponsor representative immediately (ie, within 24 hours). 
In case of overdose or medication error, it is recommended that the patient be monitored for 
any signs or symptoms of adverse reactions and appropriate symptomatic treatment be 
instituted immediately. 
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5.6 Blinding 
This study will be double-blind until the EoS. The randomization codes will not be revealed 
to study patients, investigators, and study center personnel, except for delegated unblinded 
staff who will handle the study treatment, and predefined unblinded sponsor and CRO 
personnel, until all final clinical data have been entered into the database and the database is 
locked and released for analysis. 
Bmab 1000 will be supplied as PFS without needle safety guard, whereas Prolia will be 
supplied as PFS with needle safety guard. Thus, blinding from the primary packaging will 
not be feasible, but blinding will be maintained at the secondary packaging level with similar 
packaging for both the products. Therefore, 2 different teams, ie, blinded and unblinded 
teams, will be assigned to maintain the blinding and handle the study treatment 
administration. The designated, unblinded site staff will administer the study medication 
injections in such a manner that the patient remains blinded (eg, blindfold, screen, or similar 
method during the dosing procedure so that the injection syringe will not be visible to the 
patient). Blinded staff/any other person must not be involved in any activities about the 
receipt, handling, or administration of study medication. 
Analyses of double-blind active-controlled period (Part 1) will include data after all patients 
have received the Week 52 assessments (prior to the third administration of study treatment) 
or have terminated the study before Week 52. At Week 52, the investigators, patients and 
other members of staff involved with the study will remain blinded. Randomization data, 
including any documentation identifying the treatment allocation, will be kept strictly 
confidential. An unblinding plan will give full details of who will be unblinded at Week 52 
and how the flow of information is going to be handled. 
5.6.1 Breaking the Blind 
A patient’s treatment assignment will not be unblinded until the EoS (Week 78) unless 
medical treatment of the patient depends on knowing the study treatment the patient received. 
If the blind needs to be broken because of a medical emergency, the investigator may unblind 
an individual patient’s treatment allocation. The investigator should notify the sponsor or 
medical monitor in case of unblinding. 
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To the extent possible before unblinding, the investigator should contact the medical monitor 
to discuss the medical emergency and the reason for revealing the actual treatment received 
by that patient. The treatment assignment will be unblinded through IWRS. Reasons for 
treatment unblinding must be clearly explained and justified in the eCRF. The date on which 
the code was broken together with the identity of the person responsible must also be 
documented. 
The pharmacovigilance personnel from contract research organization’s PVG will have 
access to the randomization code, if SUSARs, which are subject to expedited reporting, 
should be unblinded before submission to the regulatory authorities. The unblinding process 
for SUSAR reporting will be defined in the Safety Management Plan. 
5.7 Compliance With Study Treatment  
Bmab 1000 and Prolia will be administered by the unblinded staff while the patient is at the 
study site. The date and time of each dose administered in the clinic will be recorded in the 
source documents and eCRF. The dose of study treatment and study patient identification 
will be confirmed at the time of dosing by a member of the study site personnel other than 
the person administering the study treatment. Administration of co-administered treatments 
(calcium and vitamin D) will be recorded daily by the patient in their diary. 
Every effort will be made to encourage patients’ compliance with the study visits. A dosing 
visit window of ± 7 days is allowed for Week 26 visit and Week 52 visit. If any study visit 
has to be rescheduled, subsequent visits should follow the original visit date scheduled.
5.8 Prior and Concomitant Therapies
Prior osteoporosis medications refer to medications started any time prior to screening and 
stopped prior to the first dose of study treatment. All other prior medications (ie, medication 
used for conditions other than osteoporosis) refer to medications started within 5 years prior 
to screening and stopped prior to the first dose of study treatment. 
Concomitant medications refer to medications started prior to and continued after the first 
dose of study treatment or taken any time after the first dose of study treatment up to the 
follow-up visit. 
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Use of all concomitant medications will be recorded in the patient’s eCRF. The minimum 
requirement is that drug name and the dates of administration are recorded. This will include 
all prescription drugs, herbal products, vitamins, minerals, and OTC medications. Any 
changes in concomitant medications also will be recorded in the patient’s eCRF.
Any concomitant medication deemed necessary for the welfare of the patient during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
eCRF. 
Any COVID-19 vaccination must be recorded on the concomitant page of the eCRF. 
5.8.1 Prohibited Concomitant Medications 
Patients who have received these prohibited therapies or plan to receive these prohibited 
therapies will not be enrolled in the study. Patients who receive any prohibited therapy during 
the screening period should be considered a screen failure. Patients who are permanently 
discontinued from study treatment can be treated with alternative therapies at the 
investigator’s discretion. Patients who receive any prohibited medication can be discontinued 
from the study treatment at the investigator's discretion. Intake of any of the following 
therapies by the patients while on study treatment will be considered as a protocol deviation. 
 Denosumab other than study treatment or any other monoclonal antibodies (eg, 
romosozumab), protein, or fusion protein 
 Treatments for osteoporosis (such as oral/intravenous bisphosphonates, fluoride, 
strontium, teriparatide or any parathyroid hormone analogs, tibolone, oral or 
transdermal estrogen, selective estrogen receptor modulators, calcitonin, or calcitriol)
 Other bone active drugs including but not limited to anticoagulants, antiplatelet (with 
the exception of acetylsalicylic acid), anticonvulsants (with the exception of 
benzodiazepines), systemic ketoconazole, adrenocorticotropic hormone, lithium, 
gonadotropin releasing hormone agonists, and anabolic steroids. Direct oral 
anticoagulants will be allowed. Receipt of PPIs in patients who have received for 
year continuously are not allowed if patients plan to continue the use of PPI during 
the study such that the continuous use of PPI will be >1 year. 
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 Systemic 
Topical and nasal corticosteroids will be allowed
 Use of any biologic drugs (with the exception of insulin and insulin analogue and 
GLP-1 receptor agonists) 
 Live virus vaccine 
 Any other investigational drugs 
Use of COVID-19 vaccine is encouraged, although, at the discretion of PI, an interval of 7 
days is advised between the COVID-19 vaccine and study drug administration due to 
putative adverse drug reactions. Use of COVID-19 vaccines should be captured as 
concomitant medication. 
5.9 Intervention After the End of the Study or Treatment Discontinuation 
After the EoS or study treatment discontinuation, study treatments will not be made available 
to patients. Medical care, including anti-resorptive therapy, will be provided to the patients 
following treatment discontinuation, as per institutional standard of care if in the patient’s 
best interest at the discretion of the investigator. 
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6 Study Assessments and Procedures 
Before any study procedures are performed, all potential patients will sign an ICF. Additional 
procedural details related to the ICF are provided in Section 9.3.
Study procedures and their timing are summarized in the Schedule of Events (Table 13-1).
Data handling for analysis of Schedule of Events performed outside of the allotted time 
window will be discussed and agreed upon on a by-patient basis in the blinded data review 
meeting, with the report finalized before database lock. 
6.1 Efficacy Assessments 
6.1.1 Bone Mineral Density 
Bone mineral density will be assessed by DXA scan at the time points specified in the 
Schedule of Events (Table 13-1), using validated instruments. All DXA scans will be 
analyzed by the central imaging vendor. The same DXA instrument shall be used for all study 
procedures for each patient during the study. If for unforeseeable reasons the same scanner is 
no longer available, the study site should follow the central imaging provider’s guidance on 
selecting an appropriate replacement scanner and follow a phantom scanning process to 
quantify any calibration differences. All DXA scans of lumbar spine, total hip, and femoral 
neck BMD will be submitted to and analyzed by the central imaging vendor. 
For lumbar spine DXA scan, L1 to L4 will be measured, only excluding vertebrae that are 
affected by local structural change or artefact, using at least 2 vertebrae for diagnostic 
classification. Anatomically abnormal vertebrae may be excluded from analysis if they are 
clearly abnormal and nonassessable within the resolution of the system and using a 
1.0 T-score difference between vertebra in question and adjacent vertebrae as a guideline in 
identifying vertebrae for exclusion (ISCD 2019). 
For femur DXA scan, 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 patient fractures the hip that has been scanned 
during the study up to the time of fracture, no further scans will be obtained for the affected 
location. 
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6.1.1.1 Screening Bone Mineral Density Assessment 
To determine eligibility based on BMD T-score, lumbar spine DXA scans will be analyzed.
To be eligible for the study, patients must have at least 3 evaluable vertebrae at the lumbar 
spine (L1 to L4) and at least 1 evaluable hip by DXA scan assessed by the central imaging 
vendor. Patients with unilateral metal in hip will be allowed to enroll into this study and the 
contralateral hip will be used for evaluation. 
6.1.1.2 On-Study Bone Mineral Density Assessment 
Bone mineral density changes for individual patients will be monitored during the study per 
the time points specified in the Schedule of Events (Table 13-1). Investigators will be alerted 
if a patient experiences a BMD loss from baseline of 7% or more at the lumbar spine or total 
hip. 
6.1.2 Incidence of Fracture 
To increase the potential of therapeutic intervention to prevent vertebral fractures, the lateral 
spine X-ray will be performed at screening, Weeks 26 and 52, and also could be performed as 
required for confirmation of suspected fractures. All lateral spine X-rays will be assessed at a 
central imaging center. Any new fractures confirmed by the central imaging vendor will be 
recorded as an adverse event. If necessary to support the patient’s medical care, these X-rays 
could be read locally; however, only fractures confirmed by the central imaging center will 
be considered for the analysis. 
A new vertebral fracture is defined as an increase of at least one grade in any vertebra from 
T4 to L4 that was normal at screening (Cummings et al., 2009). The vertebral fracture will be 
assessed by semi-quantitative grading at a central imaging vendor (Genant et al., 1993): 
 
Grade 0 = no fracture. 
 
Grade 1 = mild fracture, 20% to 25% reduction in vertebral height (anterior, middle, 
or posterior). 
 
Grade 2 = moderate fracture, greater than 25% to 40% reduction in any height. 
 
Grade 3 = severe fracture, greater than 40% reduction in any height. 
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Information about a new nonvertebral fracture (eg, details regarding the type of fracture and 
other pertinent data) and level of trauma causing the fracture will be recorded during the 
study. A copy of other diagnostic image and/or radiology report, surgical report, or discharge 
summary will be included in the patient’s individual source documents and 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 will be submitted to the central imaging vendor. 
6.2 Safety Assessments
Safety will be assessed through the collection and evaluation of AEs, including TEAEs, 
SAEs, AESIs, clinical laboratory assessments, physical examinations, vital sign 
measurements, and ECGs.
6.2.1 Adverse Events 
6.2.1.1 Definitions 
6.2.1.1.1 Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to the study treatment or their clinical significance.
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to the study treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medical product, whether or not 
considered related to the study treatment. 
In accordance with the above definition, AEs may include: 
 Worsening (change in nature, severity, or frequency) of conditions (except for 
osteoporosis) present at the onset of the study 
 Condition detected or diagnosed after informed consent even though it may have been 
present prior to the start of the study 
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An AE does not include: 
Laboratory results of the disease being studied, medical or surgical procedures (eg, 
surgery, endoscopy, tooth extraction, transfusion) but rather the condition that leads to 
the procedure is an adverse event.
 Pre-existing diseases or conditions present or detected prior to signing the ICF that 
does not worsen. 
 Anticipated day-to-day fluctuations of pre-existing diseases or conditions present or 
detected at the start of the study that do not worsen as per investigator. 
 Situations where an untoward medical occurrence has not occurred 
(eg, hospitalization for elective surgery, social and/or convenience admissions). 
Patients will be instructed to contact the investigator at any time after randomization if any 
symptoms develop. 
A TEAE is defined as any event absent before exposure to the study treatment or any event 
already present that worsens in either intensity or frequency after exposure to the study 
treatment. 
6.2.1.1.2 
Adverse Drug Reaction 
An ADR is defined as any noxious and unintended responses to study treatment, related to 
any dose administered. 
6.2.1.1.3 
Unexpected Adverse Drug Reaction 
An unexpected ADR is defined as an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, IB for an unapproved investigational 
medicinal product). 
6.2.1.1.4 Serious Adverse Events 
An SAE is defined as any event that 
 results in death
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 is immediately life-threatening* 
 requires inpatient hospitalization or prolongation of existing hospitalization** 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient or may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
* The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it was more severe. 
**“Inpatient hospitalization” does not imply that the patient must have had an overnight stay 
in the hospital. If the patient was admitted to the hospital for less than a day for the purpose 
of treatment or observation, the definition of “Inpatient hospitalization” is met, provided the 
patient is admitted solely for treatment of the event and not admitted for any other reasons 
including, rehabilitation, hospice care, respite care (eg, caregiver relief), skilled nursing 
facilities, nursing homes, social reasons, ease of compliance, day care procedures, or for 
medical or hospital records (insurance reimbursement) purpose. Although, brief treatment in 
an outpatient clinic or emergency department does not constitute “inpatient hospitalization”, 
depending on the intervention/treatment required for the event, it may satisfy the criteria of 
inpatient hospitalization to be reported as an SAE. 
Events NOT to be reported as SAEs are hospitalizations for the following: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
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 Treatment, which was elective or preplanned, for a pre-existing condition that is 
unrelated to the indication under study and did not worsen 
 Admission to a hospital or other institution for general care due to social or economic 
reasons (eg, no access to local ambulatory medical care) 
6.2.1.1.5 Suspected Unexpected Serious Adverse Reaction 
Suspected Unexpected Serious Adverse Reactions are SAEs having a reasonable possibility 
of a causal relationship with the study treatment, the nature or severity of which is not 
consistent with the applicable product information (eg, IB or approved product labels). 
6.2.1.1.6 Adverse Events of Special Interest 
An AESI (serious or nonserious) is defined as an AE or SAE of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor/sponsor representative could be 
appropriate (ICH E2F; CIOMS VI).
The following AEs are considered as AESIs: 
Treatment-related hypersensitivity/allergic reaction
All AEs related to hypersensitivity/allergic reactions including anaphylaxis after study 
treatment administration will be reported. Symptoms include but not limited to hypotension, 
dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria, will be 
reported.  
Anaphylactic Reactions
Anaphylaxis will be identified according to Sampson criteria (Sampson et al., 2006). 
Anaphylaxis is likely when any 1 of the 3 criteria are fulfilled. 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following: 
a.
Respiratory compromise (eg, dyspnea, wheeze or bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia) 
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b.
Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a.
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b. 
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia) 
c. 
Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], 
syncope, incontinence) 
d. 
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to 
several hours): 
a. 
Adults: Systolic blood pressure of less than 90 mmHg or greater than 30% 
decrease from that person’s baseline.
Serious Infections 
All AEs related to serious infections including but not limited to urinary tract infection, upper 
respiratory tract infections, skin infections including but not limited to erysipelas and 
cellulitis, abdomen infection and ear infection will be reported. 
Hypocalcemia 
All AEs related to hypocalcemia include but not limited to asymptomatic hypocalcemia, 
paresthesia or muscle stiffness, twitching, spasms and muscle cramps, QT interval 
prolongation, tetany, seizures and altered mental status will be reported.  
Osteonecrosis of the jaw 
All AEs related to osteonecrosis of the jaw include but not limited to jaw pain, osteomyelitis, 
osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, and 
gingival erosion will be reported.  
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Atypical femoral fracture
All AEs related to atypical femoral fracture include but not limited to new or unusual thigh, 
hip, or groin pain will be reported.  
Dermatologic reactions 
All AEs related to dermatologic reactions include but not limited to dermatitis, eczema, and 
rashes will be reported 
All AESIs must be reported to the sponsor/sponsor representative immediately (ie, within 
24 hours) after site personnel first learn of the event. Further details on the reporting and 
management of AESIs are provided in the Safety Management Plan. 
6.2.1.2 Eliciting and Documenting Adverse Events 
Adverse events will be assessed from the time the patient signs the ICF until the EoS. 
If the investigator learns of any SAE, including a death, at any time after the EoS, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor/sponsor representative. 
At every study visit, patients will be asked a standard nonleading question to elicit any 
medically related changes in their well-being.  
In addition to patient observations, AEs identified from any study data (eg, laboratory values, 
physical examination findings, ECG changes) or identified from review of other documents 
that are relevant to patient safety will be documented on the AE page in the eCRF. 
Adverse events will be recorded in the patient’s medical records in accordance with the 
investigator’s normal clinical practice and on the AE page of the eCRF. Serious AEs that 
occur during the study must be documented in the patient’s medical record, on the AE/SAE 
page of the eCRF.
The investigator should attempt to establish a diagnosis of the event based on the signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE (and SAE if serious) and not the individual signs/symptoms. If a 
clinically significant abnormal laboratory finding or other abnormal assessment meets the 
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definition of an AE (and SAE if serious), then the AE/SAE page of the eCRF page must be 
completed as appropriate. A diagnosis, or clinical signs or symptoms if the diagnosis is 
unknown, rather than the clinically significant laboratory finding or abnormal assessment, 
should be used to complete the AE/SAE page. As additional information becomes available 
and a diagnosis is achieved, the signs/symptoms or abnormal finding verbatim should be 
updated on the eCRF. 
If no diagnosis is known and clinical signs or symptoms are not present, then the abnormal 
finding should be recorded on the AE/SAE page. 
6.2.1.2.1 Assessment of Severity 
The severity of an AE refers to the extent to which an AE affects the patient’s daily activities. 
The severity of the AE will be graded based on the NCI CTCAE v5.0, based on the following 
general guidelines (a semicolon [;] indicates “or” within each description): 
Grade 1: 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2: 
Moderate: minimal, local, or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living*
Grade 3: 
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living**
Grade 4: 
Life-threatening consequences: urgent intervention indicated 
Grade 5:
Death related to AE
* Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
** Self-care activities of daily living refer to bathing, dressing, and undressing, feeding self, 
using the toilet, taking medications, and not bedridden. 
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In the course of the study, if AEs are not covered in the NCI CTCAE occur the investigator 
will determine the severity of these adverse events as follows:
Mild:
Awareness of symptoms but easily tolerated
Moderate:
Discomfort enough to cause interference with usual activity
Severe: 
Incapacitating with inability to work or carry out usual activity 
Life-threatening
Immediate risk of death at the time of event
Death:
Results in death 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity. Adverse events characterized as intermittent 
do not require documentation of onset and duration of each episode. 
The SAE will not be closed out if it is of changing severity during the course. It will be 
reported with changes in the severity as it upgrades in follow-up reports such that each 
upgraded sequela will not be recorded as a new SAE, but continuation of same SAE and the 
serious and unexpected adverse reactions will be reported to the local regulatory 
authority/IEC within the stipulated timeline. Only the highest grade of severity will be 
considered for analysis purpose. 
6.2.1.2.2 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to the study treatment is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The investigator’s causality assessment should consider the potential etiologies for the 
observed AE. An AE may be related to study treatment, other concomitant medications, the 
underlying disease pathology, intercurrent illness, a procedure performed in the course of the 
study, or another reason. Among the potential etiologies, the investigator should decide based 
on the most likely causal relationship. When a causality assessment is provided for an SAE, 
it is important to include a rationale for the assessment so that a better understanding of the 
reported event can be compiled. The rationale should be accompanied by all available 
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supporting evidence, including relevant laboratory tests, histopathology evaluations, and the 
results of other diagnostic procedures. 
The relationship or association of the study treatment in causing or contributing to the AE 
will be characterized using the following: 
Unrelated: 
There is no association between the investigational product and the reported 
event.
Unlikely
Time to drug intake makes a relationship improbable. Another explanation is 
more likely such as disease, environment, or other medication.  
Possible: 
Treatment with the investigational product caused or contributed to the 
AE, ie, the event follows a reasonable temporal sequence from the time of 
drug administration or follows a known response pattern to the 
investigational product but could also have been produced by other factors. 
Probable:  
A reasonable temporal sequence of the event with drug administration exists 
and based upon the known pharmacological action of the drug, known or 
previously reported adverse reactions to the drug or class of drugs, or 
judgment based on the investigator’s clinical experience, the association of 
the event with the investigational product seems likely. The event disappears 
or decreases on cessation or reduction of the dose of investigational product.
Definite:
A definite causal relationship exists between drug administration and the AE, 
and other conditions (concurrent illness, progression/expression of disease 
state, or concurrent medication reaction) do not appear to explain the event. 
The event reappears or worsens if the investigational product is 
readministered. 
6.2.1.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF.  
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
Any fracture will be recorded as an AE/SAE/AESI (as applicable). All AEs will be followed 
to adequate resolution. The current version of MedDRA will be used to code all AEs. 
Any medical condition that is present at the time that the patient is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
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6.2.1.3.1 Reporting Serious Adverse Events 
Any AE that meets SAE criteria (Section 6.2.1.1) must be reported to 
immediately (ie, within 24 hours) after site personnel first 
learn of the event. Recurrent episodes, complications, or progression of the initial SAEs must 
be reported as follow-up to the original episode within 24 hours of the investigator 
knowledge. An SAE occurring at a different time interval should be reported separately as a 
new event. Serious AEs will be reported electronically via the eCRF. Paper SAE forms will 
be used as a back-up option, and the following contact information is to be used: 
Name of Department: 
The sponsor/sponsor representative has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety of an investigational 
product under clinical investigation. The sponsor/sponsor representative will comply with 
country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, IRB/IEC, and investigators. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information from the sponsor/sponsor representative will review and then file 
it as appropriate and will notify the IRB/IEC, if appropriate according to local requirements. 
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Clarification in Reporting of Deaths 
All patient deaths (regardless of relationship to study treatment) should be reported for 
patients on the study and recorded in the eCRF. If a patient dies after signing consent but 
before the first dose of the study treatment, this should also be recorded in the eCRF. Death is 
an outcome of an AE and not an AE in itself. All reports of patient deaths should include an 
AE term (other than “Death”) for the cause of the death. If an AE term is not provided, the 
investigator will be queried to obtain the cause of death. Only in the rare occurrence that no 
verbatim description of an AE can be obtained from the investigative site, the 
“Death-Unknown cause” will be used as the event term. 
6.2.1.3.2 Reporting Suspected Unexpected Serious Adverse Reactions 
The sponsor/sponsor representative will promptly evaluate all SUSARs and nonserious AEs 
of special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs/IECs, and applicable health 
authorities based on applicable legislation.
To determine reporting requirements for single AE cases, the sponsor/sponsor representative 
will assess the expectedness of these events using Bmab 1000 IB. 
The sponsor/sponsor representative will compare the severity of each SUSAR and the 
cumulative event frequency reported for the study with the severity and frequency reported in 
the applicable reference document, ie, Bmab 1000 IB, Prolia USPI/SmPC. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. 
6.2.1.4 Follow-Up of Patients Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, the event is considered to be stable, the AE returns to baseline status, or the 
patient is lost to follow-up. 
The investigator will administer appropriate treatment for the AE/SAE resolution. The 
investigator is responsible to ensure that follow-up includes any supplemental investigations 
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as may be indicated to elucidate as completely as practical the nature and/or causality of the 
AE/SAE. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
6.2.1.5 PFS Related Issues/ Adverse Events 
The PFS is used to inject Bmab 1000/Prolia. The unblinded site staff is responsible for the 
detection and documentation of PFS-related issues (eg, accidental needle stick injury, 
malfunction of injection mechanism). The PFS related AEs will be handled as mentioned in 
Section 6.2.1.2, 6.2.1.3, 6.2.1.4 and Table 6-1.
The unblinded site staff will promptly notify the unblinded study team as soon as possible (as 
per regulatory requirement) about any PFS related issues. Further details will be provided in 
the Pharmacy Manual.
The PFS related AEs will be assessed, from signing of ICF until the EoS, using the 
classification shown in below table.
Table 6-1 
Classification of Assessment of PFS Related Adverse Events
Unrelated 
There is no temporal association between the PFS and the reported event and event is 
clearly due to other causes (eg, concomitant medication, underlying disease) 
Unlikely 
Time to adverse event and use of PFS makes a relationship improbable. Another 
explanation is more likely such as disease, environment, or other medication  
Possibly 
The use of PFS has caused or contributed to the adverse event, ie, the event follows a 
reasonable temporal sequence from the time of the injection with PFS but could also have 
been produced by other factors 
Probably 
A reasonable temporal sequence of the event with the use of PFS exists and, based upon 
the known or previously reported complications following use of PFS, or judgment based 
on the investigators clinical experience, the association of the event with the PFS seems 
likely 
Definitely 
A definite causal relationship exists between the use of PFS and the adverse event, and 
other conditions (concurrent illness, progression/expression of disease state, or concurrent 
medication reaction) do not appear to explain the event 
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6.2.2 Clinical Safety Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected at the time 
points specified in the Schedule of Events (Table 13-1). Blood samples do not need to be 
performed in a fasting state unless required in the opinion of the investigator. If PD blood 
samples are also being collected at the same timepoint, the safety blood samples can be 
collected in the fasting state along with the PD blood samples. Clinical laboratory test 
samples will be analyzed at the central laboratory of safety testing. For management of 
emergency cases (AE/SAE), assessment can be performed at local laboratory. 
The following clinical laboratory analyses will be performed: 
Clinical chemistry:
Albumin, albumin-adjusted total serum calcium, ALP, ALT, AST, 
bicarbonate, blood urea nitrogen, calcium, chloride, total cholesterol, 
high-density lipoprotein cholesterol, FT3a, FT4a, low density 
lipoprotein cholesterol, creatine kinase–myocardial band isoenzyme, 
creatine phosphokinase, creatinine, gamma-glutamyl transferase, 
glucose, lactate dehydrogenase, triglycerides, magnesium, 
phosphates, potassium, sodium, bilirubin (total, direct), total protein, 
uric acid, troponin Ib, serum 25-OH vitamin D, TSHc, and intact 
parathyroid hormone.  
a. FT3 and FT4 are required only at screening. 
b. Troponin I should be tested only if clinically relevant (at 
investigator’s discretion). 
c.
TSH should be tested at screening and if clinically relevant (at 
investigator’s discretion) at any time during the study. 
Hematology: 
Hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential count, absolute neutrophil count, lymphocyte count, 
and platelet count. 
Urinalysis:
Color, pH, specific gravity, glucose, ketones, leukocytes, nitrite, 
protein, bilirubin, urobilinogen, occult blood, and microscopic 
examination. 
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Additional clinical laboratory evaluations will be performed at other times if judged to be 
clinically appropriate or if the ongoing review of the data suggests a more detailed 
assessment of clinical laboratory safety evaluations is required.
Clinical monitoring of albumin-adjusted total serum calcium, serum 25-OH vitamin D, and 
mineral levels (magnesium, phosphate), and any signs and symptoms of hypocalcemia will 
be closely sought and adequately treated at the investigator’s discretion if it occurs. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, radiological scans, vital sign measurements), including those 
that worsen from baseline or are clinically significant in the medical and scientific judgment 
of the investigator are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the patient’s 
condition, are not to be reported as AEs or SAEs. 
The investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study. If the laboratory reports are not 
transferred electronically, the values must be filed with the source information (including 
reference ranges). In most cases, clinically significant abnormal laboratory findings are those 
that are not associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the patient’s condition. 
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 or medical monitor. 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 notified. 
All protocol-required laboratory assessments must be conducted in accordance with the 
laboratory manual and the Schedule of Events (Table 13-1). If laboratory values from 
nonprotocol-specified laboratory assessments performed at the institution’s local laboratory 
require a change in patient management or are considered clinically significant by the 
investigator (eg, SAE or AE or dose modification), then the results must be recorded in the 
eCRF. 
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6.2.2.1 Hepatitis B Virus, Hepatitis C Virus, Human Immunodeficiency 
Virus, and SARS-CoV-2 
At screening, HBsAg, HBsAb, and HBcAb will be assessed in all patients as specified in 
Table 6-2.
Table 6-2 
Eligibility Based on Serologic Markers for Hepatitis B Infection
Test Results 
Eligibility
HBsAg 
HBcAb
HBV DNA
+ 
+/– 
Not applicable 
Not eligible 
– 
+ 
+ 
Not eligible 
– 
Eligible 
– 
– 
Not applicable 
Eligible 
Abbreviations: HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. 
If the HBsAg test result is positive, the patient will be excluded from the study. If a patient 
has HBsAg negative and HBcAb positive, an HBV DNA test will be performed at screening. 
If the HBV DNA test result is positive, the patient will be excluded from the study; if the 
HBV DNA test result is negative, the patient can be included in the study. Hepatitis B 
analysis will be performed at the central laboratory of safety testing. 
At screening, hepatitis C antibody and HIV will be assessed in all patients. If the HCV test 
results is positive, HCV RNA will be performed at screening. If the HCV RNA test result is 
positive, the patient will be excluded from the study; If the HCV RNA test result is negative, 
the patient can be included in the study at the investigator’s discretion. Further evaluation for 
the patients who are enrolled based on HCV RNA test can be done depending on the 
investigator’s discretion during the study. If the HIV test result is positive, the patient must be 
excluded from the study. Hepatitis C and HIV analysis will be performed at the central 
laboratory of safety testing. 
At the screening visit, a COVID-19 test will be performed as per site and/or local regulatory 
guidelines. Patients who have a COVID-19 positive test result and were asymptomatic or 
mildly symptomatic will be allowed to be rescreened as described in Section 4.2.5. 
Systematic COVID-19 screening tests will be performed locally based on the site guidelines 
and on the investigator’s discretion throughout the study period. If COVID-19 is confirmed 
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after randomization, the investigator will discuss case-by-case with the sponsor and/or 
medical monitor. If the patient has had contact with COVID-19 infected patients within 14 
days following any site visit, the investigator will re-assess the visit schedule following the 
site and/or local regulatory guidelines. 
6.2.2.2 Follicle-Stimulating Hormone 
Women of childbearing potential will not be eligible for enrolment in this study. To confirm 
postmenopausal status, FSH levels will be measured at screening, which should be 
 mIU/mL with at least 12 consecutive months since spontaneous amenorrhea. Note: 
Women with surgical menopause will not have their postmenopausal status confirmed with 
FSH test but confirmation will be via their medical history.
6.2.3 Physical Examinations 
Investigators should carefully evaluate patients for any indication of injection site reaction, 
hypersensitivity/allergic reactions, infection, hypocalcemia, osteonecrosis of jaw, atypical 
femoral fracture, and dermatologic reactions and treatment should be indicated in accordance 
with the investigator’s medical judgment. Especially, a thorough oral examination (including 
mouth, gums, teeth, tongue) should be performed. Physical examination will be performed at 
the time points specified in the Schedule of Events (Table 13-1). 
Information about the physical examination findings will be recorded by the investigator or 
designee in the eCRF and source documents. Any abnormalities will be recorded in the 
source documents. Clinically significant findings and illnesses reported after signing the ICF 
that meet the definition of an adverse event will be recorded in the eCRF and source 
documents. 
A complete physical examination will include, at a minimum, oral examination and 
assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems. 
Height and weight will also be measured and recorded. The complete physical examination 
will be performed at screening, baseline (Day 1), and Weeks 26, 52, and 78. Abbreviated, ie, 
sign/symptom-directed examination will be performed at other visits as specified in the 
Schedule of Events (Table 13-1). Investigators should pay special attention to clinical signs 
related to previous serious illnesses. 
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6.2.4 Vital Signs 
Vital signs will be measured at scheduled visits as indicated in the Schedule of Events 
(Table 13-1). Body temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed. Blood pressure and pulse measurements will be assessed after 5 minutes of rest 
(sitting), preferably with a completely automated device. Blood pressure and pulse 
measurements should be preceded by at least 5 minutes of rest for the patient in a quiet 
setting without distractions (eg, television, cell phones). On the dosing day visits, vital signs 
will be assessed prior to dosing. All measurements will be recorded in the eCRFs and source 
documents. 
6.2.5 Electrocardiograms 
All scheduled 12-lead ECGs will be performed at the study site after the patient has rested 
quietly for at least 5 minutes in a supine position. A 12-lead ECG will be performed at the 
time points specified in the Schedule of Events (Table 13-1) and if the patient experienced 
cardiac symptoms during study treatment administration. If following the ECG review by the 
investigator, there are any ECG findings that would indicate cardiac insufficiency or 
QT/QTcF prolongation, the patient will be referred to a cardiologist to confirm the 
abnormality. The investigator will then report the event in the source documents and the 
eCRF. Regardless of the 12-lead ECG result, further evaluation with a cardiologist can be 
done depending on the investigator’s discretion. 
6.2.6 Other Safety Assessments 
6.2.6.1 Medical History, Disease History, and Demographic Information 
The medical history (general medical history and disease medication history), disease history 
of postmenopausal osteoporosis, fracture history, and demographic information including 
gender, age, ethnicity, race, weight, and body mass index (kg/m2) at screening (Visit 1) will 
be recorded in the patient’s eCRF and the source documents. 
6.2.6.2 Injection Site Reaction Monitoring 
Injection site reactions will be assessed within 1 hour of the end of each study treatment 
administration, as specified in the Schedule of Events (Table 13-1). Injection site reaction will 
be assessed based on CTCAE v5.0. 
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Details will be recorded in both the source documents and the eCRF. 
6.2.6.3 Hypersensitivity/Allergic Reaction Monitoring
Hypersensitivity reactions will be assessed prior to the study treatment administration (within 
approximately 15 minutes) and 1 hour (±10 minutes) after each study treatment 
administration, as specified in the Schedule of Events (Table 13-1). If patients have signs and 
symptoms of hypersensitivity/allergic reactions at home (hives, difficulty breathing, or 
swelling of face, eyes, lips, or mouth or any symptoms of cardiac origin), patients or 
caregivers should be advised to call the study site or get immediate help. 
In addition, hypersensitivity will be monitored by routine continuous clinical monitoring 
including patient-reported signs and symptoms. In case of hypersensitivity, emergency 
medication and equipment, such as adrenaline, antihistamines, corticosteroids, and 
respiratory support including inhalational therapy, oxygen, and artificial ventilation must be 
available and any types of ECG can be performed. If the patient experiences any 
hypersensitivity signs and symptoms outside the study site, the patient can visit the study site 
for further assessment.
For patients who experience or develop life-threatening treatment-related anaphylactic 
reactions, study treatment must be stopped immediately and succeeding doses need to be 
discontinued. 
Details will be recorded in both the source documents and the eCRF. 
6.2.6.4 New York Heart Association Functional Classification 
At screening, patients who have history of heart failure will be assessed for the presence of 
congestive heart failure according to the NYHA functional classification. Patients with 
congestive heart failure of class III or IV chronic heart failure will be excluded from the study. 
Results will be recorded in both the eCRF and source documents. 
6.3 Pharmacokinetics 
Pharmacokinetic blood samples for the determination of serum concentration of denosumab 
will be collected from patients from both study groups (Bmab 1000 and Prolia) at the time 
points specified in the Schedule of Events (Table 13-1). Additionally, the blood samples for 
method validation will also be collected on Day 1 (pre-dose). 
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If the blood sample is unable to be analyzed or is missing at a certain time point, some blood 
samples collected for PD or immunogenicity assessment at the same time point can be used 
for PK assessment after discussion and agreement from the sponsor. 
Actual sampling times for each patient will be recorded in the patient’s eCRF and individual 
source documents. 
Further details about PK blood sampling collection, storage, and sample processing 
specification are provided in the laboratory manual. 
6.4 Pharmacodynamics and Biomarkers
Concentrations of the bone turnover markers (CTX and PINP) will be measured from fasting 
serum samples at the time point specified in the Schedule of Events (Table 13-1). Patients 
will be required to refrain from intense physical activity in the 48-hour period prior to sample 
collection, to fast overnight for 8 hours prior to assessment, not to take calcium supplement 
prior to sample collection (to be taken after sample collection), and to visit the study center in 
the morning for PD assessment. Actual sampling times for each patient will be recorded in 
the patient’s eCRF and individual source documents. 
Further details about PD blood sampling collection, storage, and sample processing 
specification are provided in the laboratory manual.
6.4.1 Pharmacodynamic Endpoints 
Serum concentrations of CTX and P1NP will be assessed at the time points specified in the 
Schedule of Events (Table 13-1).
The following PD parameters will be estimated for sCTX using noncompartmental methods, 
actual sampling times, and absolute (unadjusted) sCTX concentrations, as appropriate: 
Cmin
the minimum concentration (which represents the maximum PD 
effect) 
Tmin 
the time of occurrence of the minimum concentration 
AUEC 
the area under the effect curve, calculated using absolute data 
(without baseline-adjustment) using the linear trapezoidal rule 
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In addition, the following PD parameters will be estimated for sCTX using 
noncompartmental methods, actual sampling times, and percent reduction from baseline 
sCTX values, as appropriate:
Imax
maximum % inhibition
TImax
the time of occurrence of maximum % inhibition
AUIC
the area under the % inhibition curve, calculated using percent 
reduction from baseline data and the linear trapezoidal rule 
6.5 Immunogenicity Assessments
The immunogenicity of Bmab 1000 and Prolia will be assessed by ADA and NAb test in a 
validated immunoassay. Blood samples for immunogenicity assessments will be collected at 
the time points specified in the Schedule of Events (Table 13-1). Additionally, the blood 
samples for method validation will also be collected on Day 1 (pre-dose). 
If the blood sample is unable to be analyzed or is missing at certain time point, some blood 
samples collected for PK or PD assessments at the same time point can be used for 
immunogenicity assessment after discussion and agreement from the sponsor.  
Blood samples for immunogenicity for patients with immune-related AEs will be obtained on 
onset date (within 24 hours after study treatment administration) of immune-related AEs (eg, 
rash, pruritus), if possible, or blood sample can be used if it was obtained at the same date of 
study treatment administration. 
Analysis will be performed at the central laboratory. 
Further details about immunogenicity blood sampling collection, storage, and sample 
processing specification are provided in the laboratory manual. 
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7 Statistical Considerations 
The statistical analysis will be performed using SAS software Version 9.4 or later, with PD 
parameters estimated using Phoenix WinNonlin software Version 8.0 or later. The statistical 
methods for this study will be described in a detailed SAP, which will be finalized and signed 
off before database lock. Changes from analyses planned in the protocol will be documented 
in the statistical analysis plan.
7.1 
Estimands and Intercurrent Events 
7.1.1 Intercurrent Events 
The following intercurrent events are relevant in the treatment of postmenopausal women 
with osteoporosis by SC injection of study treatment (Bmab 1000 and Prolia) every 6 
months: 
Table 7-1 
Intercurrent Event Types
Label 
Intercurrent Event Type 
ICE1 (Discontinue - related) 
Treatment discontinuation for reasons related to study treatment 
(tolerability) or worsening of osteoporosis (lack of efficacy) (see 
Section 4.2.1 for further details) 
ICE2 (Discontinue - unrelated) 
Treatment discontinuation for unrelated reasons (as detailed in 
Section 4.2.1) such as logistical issues or other emerging conditions which 
require treatment 
ICE3 (Dosing deviation) 
Missing a dose or error in delivering dose (note this treatment is 
administered with SC denosumab injections every 6 months) 
ICE4 (Death) 
Death due to any cause in this elderly population 
ICE5 (Medications affecting 
bones) 
Administration of alternative osteoporosis medications or medications 
affecting bone health (except vitamin D and calcium supplements 
considered separately in ICE6) 
ICE6 (Supplements) 
Adjustments to vitamin D or calcium supplements 
ICE7 (ADAs) 
Formation of ADAs 
Abbreviations: ADA, anti-drug antibody; ICE, intercurrent event; SC, subcutaneous 
In addition, food and intense physical activity can impact sCTX and the sample for this 
endpoint should be collected after 8 hours of fasting and no intense physical activity in the 
48-hour period prior to sample collection.
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7.1.2 Estimands
Table 7-2 presents the key estimands most important to regulatory decision making with rationale for strategies to address intercurrent 
events.
Table 7-2 
Key Estimands with Rationale for Strategies to Address Intercurrent Events
Estimand 1a-EMA (Co-primary: 
Efficacy)  
Estimand 1a-US FDA (Efficacy) 
Estimand 1b-EMA (Co-primary: PD) 
Estimand Description 
(attributes specified in detail 
below) 
Difference in means 
(Bmab 1000 – Prolia) in % change 
from baseline in lumbar spine BMD 
by DXA after 52 weeks in 
postmenopausal womena with 
osteoporosis treated with SC 
injections every 6 months assuming 
that all women receive 2 doses 
without any errors or deviations in 
dosing and without receipt of any 
other medications affecting bones 
except for vitamin D and calcium 
supplements. 
Difference in means 
(Bmab 1000 – Prolia) in composite 
endpoint of % change from baseline in 
lumbar spine BMD by DXA after 
52 weeks (where % change from 
baseline of zero is taken for anyone 
who dies) in postmenopausal womena
with osteoporosis treated with SC 
injections every 6 months irrespective 
of discontinuation of treatment for any 
reason, errors or deviations in dosing 
and whether any other osteoporosis 
medications are taken. 
Ratio of geometric means 
(Bmab 1000/Prolia) in AUEC in (fasted) 
sCTX up to 26 weeks in postmenopausal 
womena with osteoporosis treated with a 
SC injection without any dosing error 
and no receipt of any other medications 
affecting bones except for vitamin D and 
calcium supplements. 
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Estimand 1a-EMA (Co-primary: 
Efficacy)  
Estimand 1a-US FDA (Efficacy) 
Estimand 1b-EMA (Co-primary: PD) 
Treatment Conditions of 
Interest
Two doses of Bmab 1000 versus 
Prolia (without receipt of any other 
medications affecting bones except 
for vitamin D and calcium 
supplements) 
Up to two doses of Bmab 1000 versus 
Prolia (irrespective of any other 
medications) 
One dose of Bmab 1000 versus Prolia 
(without receipt of any other medications 
affecting bones except for vitamin D and 
calcium supplements) 
Target Population 
Postmenopausal women with osteoporosis 
Endpoint
Percentage change from baseline at 
Week 52 in lumbar spine BMD by 
DXA 
Composite endpoint of percentage 
change from baseline at Week 52 in 
lumbar spine BMD by DXA (and 
taking a value of zero for someone who 
dies) 
AUEC calculated using absolute sCTX 
data (without baseline-adjustment) and 
actual sampling times using the linear 
trapezoidal rule to Week 26. Samples 
should be collected after 8 hours of 
fasting and no intense physical activity in 
48-hour period prior to PD sample 
collection. 
Population Level Summary 
Difference between treatments in population mean % change from baseline 
BMD at Week 52 (Bmab 1000 / Prolia) 
Ratio of geometric means 
(Bmab 1000/Prolia)
ICEs and Strategies to Handle ICEs
ICE1 (Discontinue - related)
Hypothetical
Treatment policy
Not applicable (endpoint is measured 
before the second dose) 
ICE2 (Discontinue - unrelated)
Hypothetical
Treatment policy
Not applicable (endpoint is measured 
before the second dose) 
ICE3 (Dosing deviation)
Hypothetical
Treatment policy
Hypothetical
ICE4 (Death)
Hypothetical
Composite
Hypothetical
ICE5 (Medications affecting 
bones) 
Hypothetical 
Treatment policy 
Hypothetical 
ICE6 (Supplements)
Treatment policy
Treatment policy
Treatment policy
ICE7 (ADAs)
Treatment policy
Treatment policy
Treatment policy
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Estimand 1a-EMA (Co-primary: 
Efficacy)  
Estimand 1a-US FDA (Efficacy) 
Estimand 1b-EMA (Co-primary: PD) 
Rationale of Strategies to 
Handle ICEs
Estimand 1a-EMA (Co-primary) 
utilizes a mostly hypothetical 
approach and so is sensitive to pick up 
differences between treatments which 
will enable to demonstrate 
equivalence. The hypothetical strategy 
requires statistical modeling to 
estimate the difference that might 
exist in the scenario that those ICEs 
do not occur. 
Estimand 1a-US FDA using a 
treatment policy strategy which targets 
the comparative effectiveness close to a 
real-world setting. This requires 
follow-up of patients to measure BMD 
at Week 52 irrespective of whether 
they have taken other osteoporosis 
medication or whether they 
discontinued treatment for any reason. 
Estimand 1b-EMA (Co-primary PD) 
utilizes a mostly hypothetical approach 
and so is sensitive to pick up differences 
between treatments. The hypothetical 
strategy requires statistical modeling to 
estimate the difference that might exist in 
the scenario that those ICEs do not occur. 
It is anticipated that the occurrence of each ICE will be balanced between groups since the biosimilar treatment, Bmab 1000, 
should have similar properties to Prolia. It should be noted that Prolia has a good safety profile, and it is anticipated tha
of patients will have tolerability issues or death during the year after the first dose. 
Note: T
ICE has not been specifically mentioned in the estimand description and will be ignored in estimation approaches. 
Abbreviations: ADA, anti-drug antibody; AUEC, area under the effect curve; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; ECG, 
electrocardiogram; EMA, European Medicines Agency; FDA, Food and Drug Administration; ICE, intercurrent event; PD, pharmacodynamic; sCTX, serum C-
terminal telopeptide of Type 1 collagen 
Note: The screening BMD assessment will be taken as the baseline BMD assessment 
a.
Women should not have been previously treated with denosumab but may have had prior treatment with bisphosphonates and will be co-administered 
vitamin D and calcium supplements 
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7.1.2.1 Choice of Primary and Key Secondary Estimands 
The three estimands described above (Table 7-2) are as per the recommendations from 
regulatory agencies.
Estimand 1a-US FDA, using a treatment policy strategy (targeting the comparative 
effectiveness close to a real-world setting), will be considered as primary in the submission to 
the US FDA but key secondary for other submissions. 
In addition, EMA required addition of the Co-primary Estimand 1b-EMA (Co-primary PD). 
Thus, submissions will be tailored as follows with Estimand 1a-US FDA considered the 
primary estimand for US FDA submission and Co-primary Efficacy and PD estimands for 
EMA. 
Estimand
US FDA
EMA  
Estimand 1a-EMA (Co-
primary Efficacy)
Key secondary
Co-primary 
Estimand 1a-US FDA 
(Efficacy)
Primary
Key secondary 
Estimand 1b-EMA (Co-
primary PD)
Key secondary
Co-primary 
7.2
Statistical Hypothesis
The statistical hypothesis associated with the difference in treatments for the primary efficacy 
analysis of % change from baseline in lumbar spine BMD by DXA at Week 52 is:  
H0: (µBmab 1000 - µProlia –1.45%) or (µBmab 1000 - µProlia 
 
H1: –
Bmab 1000 - µProlia 
 
where µBmab 1000 and µProlia denotes the true mean % change from baseline in lumbar spine 
BMD by DXA at Week 52 for Bmab 1000 and Prolia, respectively. 
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The statistical hypothesis associated with the difference in treatments for the analysis of 
sCTX AUEC (from Day 1 to Day 183) is: 
H0: ( Bmab 1000/ Prolia
Bmab 1000/ Prolia
H1
Bmab 1000/ Prolia 
 
where Bmab 1000 and Prolia denotes the true geometric mean sCTX AUEC for Bmab 1000 and 
Prolia, respectively. 
7.3 Sample Size Determination 
The initial sample size calculation is based on the primary endpoint, percent change from 
baseline in lumbar spine BMD by DXA at Week 52.
Equivalence will be established if the 95% CI of the difference (T-R) in mean percent change 
in lumbar spine BMD from baseline at Week 52 is within equivalence margin of (±1.45%). 
Equivalence margin is derived from meta-analysis of previous similar studies (Bone et al., 
2008, Cummings et al., 2009, McClung et al., 2006) which gave the pooled denosumab 
treatment effect 
 Based on the lower bound of the 95% CI, 
a 1.45% margin will preserve 70% of the treatment effect 
 Assuming that the 
treatments are equally effective and that the common SD for percent change from baseline in 
lumbar spine BMD at Week 52 is 4.5, a sample size of 204 patients per treatment group (total 
408 patients) ensures a power of minimum 80% with 2.5% level of significance. Considering 
a dropout of 15%, the total sample size required is 480 patients (240 per treatment group). 
Note that the US FDA require a 90% CI to establish equivalence which provides more power 
for this sample size (this will be reflected in the efficacy analyses). 
Since sCTX is also a key endpoint (considered Co-primary by EMA), the power of 95% CI 
falling within standard equivalence limits of 80.00%-125.00% will be considered. Thus, if 
Bmab 1000 achieves a true inhibition level in the region of 85% (as expected), giving rise to 
sCTX levels around 15% of baseline, meeting these limits would equate to 80%-125% of 
15% (ie, 12% to 18.75%), which would give confidence that Bmab 1000 preserves much of 
the Prolia inhibition rate and, on average, achieves 81.25% to 88% inhibition over a 6-month 
period. The current sample size has high power for the sCTX AUEC endpoint; 204 evaluable 
patients/group with a margin of 80%-125% and between-patient CV of 45% would give 
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>95% power to demonstrate similarity for the sCTX endpoint (using 95% CI equivalent to 2 
one-sided tests at 2.5% level). 
7.4 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Similar analysis set will be defined in the SAP for the transition phase. 
7.4.1 Full Analysis Set 
The FAS will consist of all randomized patients who meet the eligibility criteria and receive 
at least one dose of study treatment. Patients from the FAS will be analyzed under the 
treatment as randomized. This will be used as the analysis dataset for estimation of Estimand 
1a-US FDA (Efficacy). 
7.4.1.1 Modified Full Analysis Set 
The term mFAS will be used to define the analysis data set which includes a data record at 
each time point for all patients in the FAS but excludes data observed after the first 
occurrence of those intercurrent events where a hypothetical strategy is taken (eg, missing a 
dose, errors or deviations in dosing, or receipt of any other osteoporosis medication or 
medication affecting bone health). Data in the mFAS will be analyzed under the treatment as 
randomized and used as the primary analysis data set for estimation of Estimand 1a-EMA 
(Co-primary Efficacy) and Estimand 1b-EMA (Co-primary PD) and other efficacy, and PK 
analyses. For PD, data points within 8 hours of food-intake or 48-hours of intense physical 
activity will not be used. 
7.4.2 Safety Analysis Set 
The SAF will consist of all randomized patients who received at least one administration of 
study treatment. The SAF will be used for all safety and immunogenicity analyses. In the 
SAF, patients will be analyzed per the actual treatment received. 
7.5 Description of Subgroups to Be Analyzed 
The following subgroups will be explored for both (co-)primary endpoints: 
 Geographical region (US, Europe) 
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 Prior use of bisphosphonate treatment (Yes, No) 
 
 
 Selected baseline characteristics
Further details will be provided in the statistical analysis plan. 
7.6 Statistical Analysis Methodology
Continuous variables will be summarized using the mean, SD, median, minimum value, and 
maximum value. Categorical variables will be summarized using frequency counts and 
percentages. Data will be listed in data listings.
Details of the statistical analyses, methods, and data conventions are described in the 
statistical analysis plan and will be finalized and signed off before database lock. 
The majority of the CIs presented will be 95% (two-sided) CIs. For the primary efficacy and 
PD endpoints (for the EMA), equivalence is demonstrated if both the 95% CIs fall entirely 
within predefined margins; this approach is equivalent to two one-sided tests at the 2.5% 
significance level for each endpoint. For the primary efficacy for the US FDA, equivalence is 
demonstrated if the 90% CI falls entirely within predefined margins; this approach is 
equivalent to two one-sided tests at the 5% significance level. 
7.6.1 General Considerations 
Data collected in this study will be presented using summary tables, patient data listings and 
figures. For ordinal-scaled variables, a combination of presentations may be employed as 
appropriate: frequency and percentage of observations within a category and means and SDs 
of the scores of the categories. For categorical and ordinal variables, percentages will be 
calculated based on the N of the patient level analysis set (FAS or SAF) and number of 
patients with missing data will also be included. 
After the transition is complete, 2 sets of descriptive statistics will be presented to explore:
1) The single transition from Prolia to Bmab 1000 compared to continuing on Prolia 
focusing on the transition period from Week 52 to Week 78 
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2) Data from first dose through to Week 78 of Bmab 1000 throughout versus Prolia 
throughout.  
7.6.2 Overview of Statistical Methods: Estimation of Estimands and 
Sensitivity Analyses 
Table 7-3 presents a summary of statistical methods including sensitivity analyses.
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Table 7-3 
Summary of Statistical Methods, Including Sensitivity Analyses 
Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis 
Set 
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
Estimand 1a-
EMA (Co-
primary 
Efficacy) 
Difference in means (Bmab 
1000 – Prolia) in % change 
from baseline in lumbar spine 
BMD by DXA after 52 weeks 
in postmenopausal womena
with osteoporosis treated with 
SC injections every 6 months 
assuming that all women 
receive 2 doses without any 
errors or deviations in dosing 
and without receipt of any 
other medications affecting 
bones except for vitamin D and 
calcium supplements.
mFAS mFAS removes data 
occurring after ICEs for 
which the hypothetical 
strategy is used (keeping 
all patients in the FAS). 
For sensitivity [i], MI 
under MAR [ii] delta 
applied to imputation in 
the tipping point 
approach 
MMRM of % change from 
baseline in BMD at Weeks 
26 and 52 including terms 
for randomization strata, 
visit by treatment, baseline 
BMD (as a covariate). The 
estimated mean difference 
in % change from baseline 
in BMD will be presented 
with 95% CI at each time 
point, and the result at 
Week 52 compared to 
margins of [–1.45, 1.45]. 
[i] MI under MAR approach will be applied to the 
mFAS (see Section 7.6.3.5 for details). 
% change from baseline BMD at timepoints up to 
Week 52 from each multiply imputed data set will 
be analyzed by ANCOVA and results pooled 
using Rubin’s method.  
[ii] MI under MAR will be used to impute 
missing data where a penalty will be added to the 
imputed % change from baseline values.  This 
will be a delta for Bmab 1000, of –1.45 and 1.45 
(see Section 7.6.3.5.1 for further details). 
[iii] Supplementary: MMRM analysis of log-
transformed data (see Section 7.6.3.7). 
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Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis 
Set
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
Estimand 1a-
US FDA 
(Efficacy) 
Difference in means 
(Bmab 1000 - Prolia) in 
composite endpoint of % 
change from baseline in lumbar 
spine BMD by DXA after 
52 weeks (where % change 
from baseline of zero is taken 
for anyone who dies) in 
postmenopausal womena with 
osteoporosis treated with SC 
injections every 6 months 
irrespective of discontinuation 
of treatment for any reason, 
errors or deviations in dosing 
and whether any other 
osteoporosis medications are 
taken. 
FAS
The composite endpoint 
defines % change from 
baseline of zero for 
anyone who dies. 
Observed data analyzed 
without any imputation or 
removal of data points
Missing data imputed under 
MI MAR approach 
(Section 7.6.3.5) and 
penalties added to reflect 
non-inferiority and non-
superiority nulls 
(Section 7.6.3.1). 
ANCOVA of % change 
from baseline in BMD at 
Weeks 26 and 52 and 
including terms for 
randomization strata, 
treatment, baseline BMD 
(as a covariate). Results 
pooled using Rubin’s 
method and two one-sided 
tests. 
The estimated mean 
difference in % change 
from baseline in BMD will 
be presented with 90% CI 
for each delta. 
Not required since sensitivity included in other 
estimands that are explored. 
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Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis 
Set
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
Estimand 1b-
EMA (Co-
primary: PD) 
Ratio of geometric means 
(Bmab 1000/Prolia) in AUEC 
in sCTX up to 26 weeks in 
postmenopausal womena with 
osteoporosis treated with a SC 
injection without any dosing 
error and no receipt of any 
other medications affecting 
bones except for vitamin D and 
calcium supplements.
mFAS
No imputation will be 
performed 
Log-transformed AUEC 
will be analyzed using an 
ANCOVA model with 
baseline log sCTX and 
baseline eGFR as covariates 
and treatment group and 
stratification factors as 
fixed effects 
sCTX AUEC will be transformed to standardize 
the AUEC by the number of days (ie, divided by 
183-1=182), then divided by baseline sCTX prior 
to log transformation. ANCOVA analysis will 
give the same 95% CI for geometric mean ratio as 
the primary analysis, but the geometric means can 
be transformed to represent a % inhibition scale. 
Supplementary: A MMRM analysis will be 
performed to estimate the mean % reduction 
(interpreted as % inhibition) of each treatment 
and mean difference at each time point with 
95% CI. In addition, this same model will be used 
to estimate the overall % inhibition to 6 months 
for each treatment group and the mean difference 
with 95% CI. 
Abbreviations: ANCOVA, analysis of covariance; AUEC, area under the effect curve; BMD, bone mineral density; CI, confidence interval; DXA, dual-energy X-
ray absorptiometry; FAS, full analysis set; ICE, intercurrent event; mFAS, modified full analysis set; MAR, missing at random; MI, multiple imputation; 
MMRM, mixed model for repeated measures; PD, pharmacodynamic; sCTX, serum carboxy-terminal cross-linking telopeptide of Type 1 collagen; SC, 
subcutaneous 
Note: The screening BMD assessment will be taken as the baseline BMD assessment. 
a. 
Women should not have been previously treated with denosumab but may have had prior treatment with bisphosphonates and will be co-administered 
vitamin D and calcium supplements. 
 
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7.6.3 Analysis of Primary Efficacy Endpoints 
7.6.3.1 Main Estimation of Estimand 1a-US FDA (Efficacy) 
In order to estimate Estimand 1a-US FDA, an ANCOVA model will be fitted to the 
composite percent change from baseline in lumbar spine BMD at Week 52 on FAS 
multiply imputed data sets including terms for randomization strata, treatment, and 
baseline BMD included as a continuous covariate. Rubin’s method will be used to pool 
results. 
Multiple imputation will be used to produce 30 multiply imputed data sets so that any 
missing BMD data at Week 52 are imputed under MAR, by treatment (see Section 7.6.3.5). 
A penalty (delta of –1.45 and 1.45) will be applied to imputed values for the BMab 1000 
group reflecting the noninferiority and non-superiority null hypotheses (H0) respectively 
and two separate one-sided tests at alpha=0.05 conducted (Tests 1 and 2 below, 
respectively): 
Test 1: for non-inferiority (delta =–1.45): 
H0: µBMab 1000 - µProlia 
–1.45% 
H1: –
BMab 1000 - µProlia
 
Test 2: for non-superiority (delta =1.45): 
H0: µBMab 1000 - µProlia  +1.45% 
H1: µBMab 1000 - µProlia
where µBmab 1000 and µProlia denotes the true mean % change from baseline in lumbar spine 
BMD by DXA at Week 52 for Bmab 1000 and Prolia, respectively. The estimated mean 
difference in percent change from baseline in lumbar spine BMD will be presented with 
90% CI for each delta. The two one-sided tests of alpha=0.05 are equivalent to showing 
that each 90% CI falls within predefined equivalence margins of [–1.45%, 1.45%]. If these 
criteria are met, equivalence will be concluded for the US FDA submission. 
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7.6.3.2 Main Estimation of Estimand 1a-EMA (Co-primary Efficacy) 
For the primary efficacy analysis, an MMRM will be fitted to the % change from baseline 
in lumbar spine BMD at Week 26 and Week 52 on the mFAS. The MMRM will include 
terms for randomization strata, visit by treatment, and baseline BMD included as a 
continuous covariate. The repeated measures on patients will be modeled with an 
unstructured covariance structure. 
The estimated mean difference in % change from baseline in lumbar spine BMD will be 
presented with 95% CI at each time point. 
If at Week 52, the 95% CI falls within predefined equivalence margins of  
[–1.45%, 1.45%], equivalence will be concluded for the EMA submission. 
Note: The main analysis method is on the mFAS and therefore does not use data after any 
dosing errors, treatment discontinuation or receipt of any other medications affecting bone 
health (except for supplements). 
7.6.3.3 Main Estimation of Estimand 1b-EMA (Co-primary PD) 
Comparability of sCTX levels between Bmab 1000 and Prolia will be assessed by fitting 
an ANCOVA to AUEC data on a log scale (mFAS) to give the ratio of geometric means 
with 95% CI. Logged pre-dose sCTX concentrations will be fitted as a covariate since 
baseline-adjustment is not included in the AUEC calculation, baseline eGFR will be 
included as a covariate since renal function is known to affect sCTX levels, and treatment 
group and all stratification factors will be fitted as fixed effects. Comparability between 
Bmab 1000 and Prolia will be concluded if the 95% CI around the geometric mean ratios 
for AUEC lie entirely within 80.00% - 125.00%.
7.6.3.4 Sensitivity Analysis for Estimand 1a-EMA (Co-primary Efficacy)  
A sensitivity approach will be performed the mFAS (targeting Estimand 1a-EMA) in a 
similar approach using penalties to the main analysis on FAS (targeting Estimand 1a-US 
FDA): 
Multiply imputed data sets will be produced on mFAS under MAR as explained in 
Section 7.6.3.5. The percent change from baseline in lumbar spine BMD will be calculated 
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as a post processing step from BMD values and analyzed by ANCOVA. Results will be 
pooled using Rubin’s method. 
In addition, the robustness of the results in both of the one-sided hypotheses will be 
assessed by adding penalties (delta of –1.45 and 1.45) to all imputed values in the BMab 
1000 group (Section 7.6.3.5.1).
7.6.3.5 Multiple Imputation Model Under Missing at Random
Multiple imputation will be used to produce 30 multiply imputed data sets so that any 
missing BMD data at Week 26 or Week 52 are imputed under MAR, by treatment. This 
approach will be applied to mFAS (for sensitivity aligned to Estimand 1a-EMA, excluding 
data after relevant intercurrent events and treating it as missing) and also to FAS (for the 
main estimation of Estimand 1a-US FDA).
The MI approach will comprise of 2 steps by analysis set and treatment group: 
1. Any intermittent missing data at Week 26 (eg, where Week 0 and Week 52 data are 
available) will be imputed using a Markov Chain Monte Carlo approach, using the 
impute = monotone option in SAS Version 9.4 (or higher) PROC MI. 
2. A single imputation will be performed on each of the 30 multiply imputed data sets 
from Step 1. This step will use a monotone regression approach. 
The MI model will include continuous terms for age, body mass index, BMD at Week 0, 
Week 26 and Week 52, total number of doses received. 
Full details of the MI models will be provided in the statistical analysis plan.
7.6.3.5.1 
Penalties for Non-Inferiority and Non-Superiority 
A penalty (delta) will be added to the imputed percent change in BMD values from MI 
assuming MAR in the Bmab 1000 group only. This approach is a sensitivity for Estimand 
1a-EMA conducted on mFAS and the main estimation approach for Estimand 1a-FDA 
conducted on the FAS. 
A penalty will be added to the Week 52 imputed percent change from baseline in lumbar 
spine BMD values (but not to data observed) for the Bmab 1000 group only. Note this 
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applies to missing data and to data removed as irrelevant for the hypothetical Estimand 1a-
EMA. It will consider delta of –1.45 and 1.45 representing values under the non-
superiority null and non-inferiority null, respectively.  ANCOVA is performed for each 
multiply imputed dataset at each delta level and then the result will be pooled using 
Rubin’s method. 
Note: That both positive and negative values of delta are tested in order to stress test 
whether the 90% CI and 95% CI for the mean difference in percent change meets each of 
the lower and upper bounds of the equivalence margins of [–1.45, 1.45]. 
Further exploratory analysis may be described in the SAP to investigate a penalty applied 
only where treatment (ie, 2nd dose) was discontinued for related reasons or other alternative 
medications received. 
7.6.3.6 Sensitivity and Supplementary Analyses of Estimand 1b-EMA 
(Co-primary PD) 
Sensitivity: sCTX AUEC will be transformed to standardize the AUEC by the number of 
days (ie, divided by 183-1=182), then divided by baseline sCTX. In doing so, a resulting 
value of 0.15 would indicate an overall 85% reduction from baseline (ie, 85% inhibition), 
hence an ANCOVA analysis of log-transformed value (adjusted for time and baseline) will 
give the same 95% CI for geometric mean ratio as the primary analysis, but the geometric 
-ratio)] to represent a percent inhibition scale. 
Supplementary: An MMRM analysis using all relevant unlogged percent reduction sCTX 
data will be performed to estimate the mean percent reduction (interpreted as percent 
inhibition) of each treatment and mean difference at each time point with 95% CI. The 
model will include baseline sCTX and treatment by time point interaction and allow for 
variability to be different at each time point. In addition, this same model will be used to 
estimate the overall % inhibition to 6 months for each treatment group and the mean 
difference with 95% CI. Specifically, AUEC is a weighted mean percent inhibition; if we 
assume nominal sampling days of 1, 3, 15, 29, 85, 141, 162 and 183 then the weights 
(based on linear trapezoidal rule) would be 1, 7, 13, 35, 56, 38.5, 21 and 10.5, respectively, 
with divisor of 182 to standardize by overall time (calculated using ESTIMATE statement 
in PROC MIXED in SAS). 
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A sensitivity analysis using LOCF will be performed as requested by PMDA.
7.6.3.7 Supplementary Analysis for Estimand 1a-EMA (Co-primary 
Efficacy) 
In order to investigate assumptions of normality, the log-transformed BMD as a ratio of 
baseline will be analyzed in a similar MMRM model to the main analysis but with baseline 
covariate as the log BMD (using the mFAS). The least squares mean and difference will be 
back-transformed to present geometric mean ratios of baseline, and 95% CI for the ratio of 
geometric means (Bmab 1000/Prolia). Residual plots will be produced and compared to the 
main analysis.
7.6.4 Analysis of Secondary Efficacy Endpoints 
7.6.4.1 Secondary BMD Endpoints 
An MMRM as per the main estimation of Estimand 1a-EMA (Co-primary Efficacy) (see 
Section 7.6.3.2) will be used to estimate the mean percent change from baseline and 
difference between treatments for the mFAS in:
 Lumbar spine BMD after 26 weeks 
 Hip BMD after 26 and 52 weeks 
 Femoral neck BMD after 26 and 52 weeks 
Similarly, ANCOVA on composite endpoint of percent change from baseline for FAS as 
per main estimation of Estimand 1a-US FDA (Efficacy) will be performed (see 
Section 7.6.3.1) but without the penalty being applied. 
7.6.4.2 Analyses of BMD After Transition 
BMD percentage change from baseline and percentage change at Week 78 from Week 52 
will be summarized by treatment for lumbar spine, hip, and femoral neck BMD by DXA. 
Statistical analyses to present 95% CIs will be performed on Week 78 lumbar spine BMD 
in 2 separate analyses which will be considering either original baseline or Week 52 
baseline as a covariate. Further details will be given in SAP.
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7.6.4.3 Summary of Fractures 
Any incidence of fractures up to and including Week 52 and from Week 52 to Week 78 will 
be summarized with descriptive statistics.
7.6.5 Analyses of Secondary Pharmacodynamic Endpoints 
Serum C-terminal telopeptide of Type 1 collagen and P1NP concentrations will be listed, 
summarized with descriptive statistics by treatment and visit, and presented graphically, as 
appropriate. 
Cmin for sCTX will be analyzed in a similar manner to sCTX AUEC (see Section 7.6.3.3) 
as a secondary PD endpoint on mFAS. In addition, PD parameters estimated for sCTX 
using change from baseline observations (ie, Imax and AUIC) will be analyzed in a similar 
manner to sCTX AUEC (see Section 7.6.3.3) as additional secondary PD endpoints on 
mFAS. 
Following the transition period, serum concentrations of CTX and P1NP at Week 78 will 
be summarized for those transitioning to Bmab 1000 and those continuing on Bmab 1000, 
compared to those continuing on Prolia. 
7.6.6 Analyses of Secondary Pharmacokinetic Endpoints 
Serum denosumab concentrations will be listed and summarized with descriptive statistics 
at each visit. Pharmacokinetic parameter estimation and formal statistical analyses of PK 
data are not planned in this study; however, population PK and/or PK/PD modeling may be 
performed and reported separately from the main clinical study report, if deemed 
necessary.
Following the transition period, serum concentrations up to Week 78 will be summarized. 
7.6.7 Analyses of Secondary Immunogenicity Endpoints 
Incidence and titer of anti-drug antibody, incidence of neutralizing antibody up to Week 52 
will be summarized by treatment and timepoints as shown in the Schedule of Events 
(Table 13-1).
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Similar summaries will be presented for the transition period, split by Week 52 serostatus, 
to compare the transition to Bmab 1000 against continuing on Prolia. 
7.6.8 Safety Analyses 
7.6.8.1 Adverse Events 
Treatment-emergent adverse events and serious adverse events recorded during the study 
will be summarized by system organ class, preferred term, and treatment, and will include 
the total number of events with number and percentage of patients with AEs. Adverse 
events and medical history will be coded using the most current version of MedDRA. 
Summaries of the number and percentage of patients (and number and percentage of 
events) for study treatment-related AEs, SAEs, AEs with an outcome of death, and AEs 
leading to discontinuation of the study treatment will be provided by treatment. 
Incidence and grade of AESI including treatment-related hypersensitivity/allergic reaction, 
serious infections, hypocalcemia, osteonecrosis of the jaw, atypical femoral fracture, and 
dermatologic reactions from baseline (Day 1) through the EoS will be summarized by 
treatment group. 
7.6.8.2 Clinical Laboratory Assessments 
Clinical safety laboratory data will be summarized descriptively by treatment and 
scheduled visits. Descriptive statistics for continuous variables will be provided at 
scheduled visits together with a summary of changes from baseline for each parameter by 
treatment. Summaries of safety laboratory parameters will include the first meaningful 
measurement of each scheduled assessment, but repeat assessments done at the same study 
time point will not be included in summary calculations (unless performed to provide 
missing data). Laboratory data will also be listed by treatment, patient, and visit. Listings 
will include scheduled, unscheduled, and repeat evaluations. A listing of markedly 
abnormal values will be generated. Shift tables by treatment will be provided when 
appropriate. 
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7.6.8.3 Vital Signs 
Vital signs, including blood pressure, pulse rate, respiratory rate, and body temperature will 
be summarized by treatment at baseline and at each scheduled visit. Descriptive statistics 
for continuous variables will be provided at scheduled visits together with a summary of 
change from baseline for each parameter by treatment.
7.6.8.4 Physical Examination 
Abnormal physical examination findings that suggest a clinically significant worsening 
will be reported as adverse events and the number and percentage of patients with normal 
or abnormal results will be presented at scheduled visits by treatment. Clinically significant 
findings noted prior to signing of ICF will be recorded as medical history and the number 
and percentage of patients with clinically significant findings will be presented by 
treatment.
7.6.8.5 Electrocardiograms 
The number and percentage of patients with normal or abnormal or abnormal and clinically 
significant results will be presented at scheduled visits by treatment. Descriptive statistics 
for continuous variables will be provided at scheduled visits together with a summary of 
changes from baseline for each parameter by treatment.
The ECG data will also be presented in listings by patient and summarized by collection 
date and time.
7.6.8.6 Transition Safety
Safety following the third dose at Week 52 and up to and including Week 78 will be 
summarized in order to assess any risk of transition to Bmab 1000 versus continuing on 
Prolia. Additional safety data captured in the transition period for the group that receives 
Bmab 1000 throughout will also be summarized. 
Therefore, following completion of the transition period, summaries will be produced for 
incidence of TEAEs, deaths, and SAEs from the third dose to Week 78, and incidence of 
clinically significant changes in physical examinations, laboratory safety tests, ECG, and 
vital signs will also be summarized for the same period.
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7.6.9 Other Analyses 
The occurrence and time to intercurrent events will be considered and compared for the 
treatment groups. 
7.6.9.1 Demographic and Baseline Disease Characteristics 
If permitted by local regulation, the following demographic data will be summarized: age 
(in years, at the time of signing the ICF), race, ethnicity, height, weight, and body mass 
index. 
Demographics and baseline disease characteristics will be summarized descriptively by 
treatment.
Patient disposition will be summarized by treatment, including the reasons for 
discontinuation. The number of patients in each analysis set will be displayed by treatment. 
7.6.9.2 Medical History 
Medical history will be coded according to the latest version of MedDRA and will be 
summarized by system organ class and preferred term. 
7.6.9.3 Study Treatment Exposure 
Study treatment administrations will be summarized and listed by treatment in the main 
period and transition. 
7.6.9.4 Prior and Concomitant Medications 
The number and percentage of patients with prior and concomitant medications will be 
tabulated by ATC Classification System of WHO drug, preferred term, and treatment. A 
medication’s usage will be considered concomitant if it was started or continued after 
administration of the study medication. If the start date is missing, it will be assumed that 
the medication was used concomitantly. Details on handling partial dates (ie, year or only 
year and month) will be described in the statistical analysis plan. 
7.6.9.5 Vitamin D and Calcium Accountability 
Vitamin D and calcium use will be summarized and listed by treatment. 
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7.6.10 Protocol Deviations 
Protocol deviations will be summarized and listed. A separate listing for COVID-19 related 
protocol deviations will be prepared. 
7.7 Handling of Missing Data 
The extent of missing data and study withdrawal will be assessed via risk-based 
monitoring. Study procedures will be in place to minimize missing data for the primary 
endpoints; for example, patients who wish to withdraw from study treatment or take 
another osteoporosis medication will still be encouraged to attend Week 52 visit 
(Section 4.2.1).
The MMRM for Estimand 1a-EMA (Section 7.6.3.2) assume any missing data are MAR 
and the robustness of this assumption explored in sensitivity analyses (Section 7.6.3.4).
Reasons for discontinuation of treatment will be collected as far as possible so that 
sensitivity analysis can take account of reasons related to treatment or osteoporosis 
differently to those unrelated.
In addition, ANCOVA analyses will be applied to multiply imputed data sets where 
imputed values for the Bmab 1000 group, will be penalized by -1.45 (representing the non-
inferiority null) for testing whether it is non-inferior to Prolia and penalized by 1.45 
(representing the non-superiority null) for testing whether it is non-superior to Prolia (see 
Sections 7.6.3.1 and 7.6.3.5.1).
Where a hypothetical strategy is taken in the estimand, data will be excluded after the first 
occurrence of intercurrent event (eg, dosing error, or receipt of any other osteoporosis 
medication for Estimand 1a-EMA and Estimand 1b-EMA) and treated as missing.
If a different approach is required for handling missing data due to COVID-19 or other 
issues, it will be documented in the statistical analysis plan prior to unblinding. 
7.8 Interim Analyses 
No formal interim analyses of efficacy data are planned for this study. 
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There will be 2 main analysis points after each study period is complete: 
Double-blind active-controlled period: Analyses include data after all patients have 
received the Week 52 assessments (prior to the third administration of study 
treatment) or have terminated the study before Week 52. Analyses in the clinical 
study report will include all data up to and including the Week 52 visit. 
Transition period: Analyses up to transition period Week 78 will be reported in a 
Clinical Study Addendum after all patients have completed all final assessments 
and the complete database is locked.
An unblinding plan will give full details of who will be unblinded at Week 52 and how the 
flow of information is going to be handled. 
7.9 Independent Safety Review Committee 
An ISRC (see Section 3.1.1) will be appointed for this study. Further details will be 
provided in the ISRC Charter.
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8 Data Quality Assurance 
This study will be conducted according to the ICH E6(R2) risk and quality processes 
described in the applicable procedural documents. The quality management approach to be 
implemented in this study will be documented and will comply with the current ICH 
guidance on quality and risk management. The sponsor assumes accountability for actions 
delegated to other individuals (eg, CRO). 
8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees 
to maintain adequate case histories for the patients treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include diary cards, laboratory 
reports, ECG strips, etc. 
All eCRF information is to be filled in. If an item is not available or is not applicable, this 
fact should be indicated. Blank spaces should not be present unless otherwise directed. 
Investigative site personnel will enter patient data into eCRF. The analysis data sets will be 
a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable sponsor’s 
standards and data cleaning procedures to ensure the integrity of the data, eg, removing 
errors and inconsistencies in the data. Adverse event terms will be coded using MedDRA, 
an internal validated medical dictionary, and concomitant medications will be coded using 
WHO Drug. 
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9 Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an 
IRB/IEC before patients participate in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of patients, and any other 
written information regarding this study to be provided to the patient or the patient’s legal 
guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and 
of the IRB/IEC compliance with ICH harmonised tripartite guideline E6(R2): GCP will be 
maintained by the site and will be available for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status 
of the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to patients. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
9.3 Patient Information and Consent
A written informed consent in compliance with all applicable regulatory requirements, ICH 
GCP, and ethical principles that have their origin in Declaration of Helsinki shall be 
obtained from each patient before entering the study or performing any unusual or 
nonroutine procedure that involves risk to the patient. If applicable, an informed consent 
template may be provided by the sponsor to investigative sites. If any institution-specific 
modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by the sponsor or its designee or both before IRB/IEC submission. 
Once reviewed, the consent will be submitted by the investigator to his or her IRB/IEC for 
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review and approval before the start of the study. If the ICF is revised during the course of 
the study, all active patients must be reconsented by signing the revised form. 
Before recruitment and enrollment, each prospective patient or his or her legal guardian 
will be given a full explanation of the study, be allowed to read the approved ICF, and have 
any questions answered. Once the investigator is assured that the patient/legal guardian 
understands the implications of participating in the study, the patient/legal guardian will be 
asked to give consent to participate in the study by signing the ICF. The authorized person 
obtaining the informed consent also signs the ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research (if applicable) and explain/address the 
exploratory research portion of the study. Patient medical records need to state that written 
informed consent was obtained. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed 
original form to the patient or legal guardian. 
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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of 
the study but may be subject to change based on industry and government standard 
operating procedures, working practice documents, or guidelines. Changes will be reported 
to the IRB/IEC but will not result in protocol amendments.
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in 
a manner designed to maintain patient confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the 
written permission of the patient (or the patient’s legal guardian), except as necessary for 
monitoring and auditing by the sponsor, its designee, the IRB/IEC, or other applicable 
regulatory agencies.
The investigator and all employees and co-workers involved with this study may not 
disclose or use for any purpose other than performance of the study any data, record, or 
other unpublished, confidential information disclosed to those individuals for the purpose 
of the study. Prior written agreement from the sponsor or its designee must be obtained for 
the disclosure of any said confidential information to other parties. 
10.2 Data Protection 
All personal data collected related to patients, investigators, or any person involved in the 
study, which may be included in the sponsor’s databases, shall be treated in accordance 
with local data protection law. 
Data collected must be adequate, relevant, and not excessive, in relation to the purposes for 
which they are collected. Each category of data must be properly justified and in line with 
the study objective. 
10.3 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor 
to submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigator must provide to the sponsor a commitment to 
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promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor the CRO is financially responsible for further testing or treatment 
of any medical condition that may be detected during the screening process. In addition, in 
the absence of specific arrangements, neither the sponsor nor the CRO is financially 
responsible for further treatment of the patient’s disease.
10.4 Investigator Documentation 
Prior to the beginning the study, the investigator will be asked to comply with ICH E6(R2) 
Section 8.2 and Title 21 of the CFR by providing all essential documents. 
10.5 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of patients begins, as 
per local requirements.
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
10.6 Adverse Events and Study Report Requirements 
The investigator agrees to submit reports of SAEs to the sponsor and/or IRB/IEC 
according to the timeline and method outlined in the protocol. In addition, the investigator 
agrees to submit annual reports to the study site IRB/IEC as appropriate. 
10.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
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10.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study treatment (Bmab 1000). These 
documents should be retained for a longer period; however, if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to 
be retained. No records may be transferred to another location or party without written 
notification to the sponsor. 
10.9 Publications and Results Disclosures 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which 
it will be submitted, and other related issues. The sponsor has final approval authority over 
all such issues.
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 
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11 Study Management 
The study administrative structure will include sponsor representatives, CRO, third-party 
vendors, laboratories, and other personnel as per the requirements of the study. 
11.1 Monitoring 
11.1.1 Monitoring of the Study 
This study will be monitored according to an approved monitoring plan based on the 
objectives, purpose, design, and complexity of the study. The investigator will allocate 
adequate time for all monitoring visits and between visits to facilitate the requirements of 
the study and study timelines. The investigator will also ensure that the monitor or other 
compliance or quality assurance reviewer is given direct access to all study-related 
documents and study-related facilities (eg, pharmacy, diagnostic laboratory), phone, fax, 
and internet and has adequate space to conduct the monitoring visit. Site monitoring is 
conducted to ensure that the rights of patients are protected, that the study is implemented 
in accordance with the protocol and/or other operating procedures, and that the study uses 
high quality data collection processes. The monitor will evaluate study processes based on 
the sponsor or designee standards, ICH E6, and all applicable, regulatory guidelines. 
11.1.2 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, 
representatives of the sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the sponsor and CRO of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in the required procedures defined in this protocol, except those necessary to 
remove an apparent, immediate hazard to the patient, must be reviewed and approved by 
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the sponsor or designee. Amendments to the protocol (including emergency changes) must 
be submitted in writing to the investigator’s IRB/IEC and to the regulatory authorities 
where required, along with any applicable changes to the ICF, for approval before patients 
can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol or 
to local regulations or ICH GCP guidelines that may or may not result in a significant, 
additional risk to the patient or impacts the integrity of study data. 
The investigator or designee must document and explain in the patient’s source 
documentation any deviation from the approved protocol. The investigator may implement 
a deviation from, or a change of, the protocol to eliminate an immediate hazard/safety risk 
to study patients without prior IRB/IEC approval. As soon as possible after such an 
occurrence, the implemented deviation or change, the reasons for it, and any proposed 
protocol amendments should be submitted to the IRB/IEC for review and approval, to the 
sponsor for agreement, and to the regulatory authorities, where required. 
In order to keep deviations from the protocol to a minimum, the investigator and relevant 
site personnel will be trained in all aspects of study conduct by the sponsor/sponsor 
representative. This training will occur either as part of the investigator meeting or site 
initiation. Ongoing training may also be performed throughout the study during routine site 
monitoring activities.
11.3 Study or Study Site Termination 
Although the sponsor has every intention of completing the study, the sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons.
The sponsor may suspend or stop the study at specific study sites due to (but not limited to) 
failure of the investigator to enroll patients into the study at an acceptable rate, failure of 
the investigator to comply with regulatory authority or ICH guidelines, or submission of 
knowingly false information. 
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The study can be paused/ continued/modified by the ISRC, based on the review of safety 
data (Refer Section 3.1.1 for details). 
The EoS is defined as the date on which the last patient completes the last visit (includes 
follow-up visit). 
If the study is prematurely terminated or suspended, the sponsor or investigator shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any CRO 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the patient and should 
assure appropriate patient therapy and/or follow-up. 
11.4 Clinical Study Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
final data are summarized and provided to the regulatory agency(ies) as required by the 
applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
reports in marketing applications (as applicable) meet the standards of the ICH harmonised 
tripartite guideline E3: Structure and content of clinical study reports. The primary CSR 
will be based on data up to Week 52 (with option of including transition period data if 
needed), this will be followed by the transition period CSR with applicable data (up to 
Week 78). 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results without giving individual patient level 
data. 
Upon completion of the final report, the sponsor will provide the investigator with the 
summary of the study results. The investigator is encouraged to share a summary of the 
results with the study patients, as appropriate. The study results will be posted on publicly 
available clinical trial registers, as per local requirements.
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12 References 
Bilezikian JP, Bikle D, Hewison M, et al. Mechanisms in Endocrinology: Vitamin D and 
COVID-19. Eur J Endocrinol. 2020;183:R133-R147. 
Bone HG, Bolognese MA, Yuen CK et al. Effects of denosumab on bone mineral density 
and bone turnover in postmenopausal women. J Clin Endocrinol Metab. 2008;93(6):2149-
57. 
Chang B, Quan Qi, Li Y et al. Treatment of osteoporosis with a focus on 2 monoclonal 
antibodies. Med Sci Monit. 2018;24:8758-8766. 
Cummings SR, San Martin J, McClung MR et al. Denosumab for prevention of fractures in 
postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-65. 
Formenti AM, Pedone E, Filippo LD, et al. Are women with osteoporosis treated with 
denosumab at risk of severe COVID-19? Endocrine. 2020;70(2):203-205. 
European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). 
(2012). Guideline on similar biological medicinal products containing monoclonal 
antibodies–non-clinical and clinical issues. London. EMA/CHMP/BMWP/403543/2010. 
Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
similar-biological-medicinal-products-containing-monoclonal-antibodies-non-
clinical_en.pdf 
European Medicines Agency (2021). Guidance on the Management of Clinical Trials During 
the COVID-19 (Coronavirus) Pandemic. Version 4. 04 February 2021. Available from: 
https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf 
FDA, Department of Health and Human Services (US). (2015). Guidance for Industry: 
Scientific considerations in demonstrating biosimilarity to a reference product. FDA. 
Available from: https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf
FDA Code of Federal Regulations Title 21 (regulation 21 CFR 320.38). (2019). Available 
from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=320.38
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Gittoes NJ, Criseno S, Appelman-Dijkstra NM, et al. Management of calcium metabolic 
disorders and osteoporosis. Eur J Endocrinol. 2020;183(2):G57-G65. 
Genant HK, Wu CY, van Kuijk C et al. Vertebral fracture assessment using a 
semiquantitative technique. J Bone Miner Res. 1993;8(9):1137-48. 
International Osteoporosis Foundation (IOF). 2nd edition of IOF compendium of 
osteoporosis.2019 [cited 12 November 2021] Available from: 
https://www.osteoporosis.foundation/sites/iofbonehealth/files/2020-01/IOF-Compendium-
of-Osteoporosis-web-V02.pdf
International Society for Clinical Densitometry (ISCD) [Internet] Adult positions – 
Indications for bone mineral density (BMD) testing; 2019 [cited 2021 Nov 10]. 
Available from: https://iscd.org/learn/official-positions/adult-positions/
Ji M, Yu Q. Primary osteoporosis in postmenopausal women. Chronic Dis Transl Med. 
2015;1(1):9-13 
Klibanski A, Adams-Campbell L, Bassford T, et al. Osteoporosis prevention, diagnosis, 
and therapy. JAMA. 2001;285:785-795.
McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with 
low bone mineral density. N Engl J Med. 2006;354(8):821-31. 
PMDA Guideline for the Quality, Safety and Efficacy Assurance of Follow-on Biologics 
(PFSB/ELD Notification No 0304007, 04 March 2009) [cited 2021 Aug 18]. 
Available from: https://www.pmda.go.jp/files/000153851.pdf
Prolia (denosumab) [package insert]. Amgen Inc. One Amgen Center Drive Thousand 
Oaks, California 91320-1799; May 2021. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125320s207lbl.pdf
Prolia (denosumab) [Summary of product characteristics]. Amgen Europe B.V., Minervum 
7061, 4817 ZK Breda, The Netherlands; October 2021. Available from: 
https://www.ema.europa.eu/en/documents/product-information/prolia-epar-product-
information_en.pdf
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Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition 
and management of anaphylaxis: Summary Report-Second National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin 
Immunol 2006;117(2):391-7. 
Tella SH and Gallagher JC. Prevention and treatment of postmenopausal osteoporosis. 
J Steroid Biochem Mol Biol. 2014;142:155-170. 
World Health Organization. (2009). Expert Committee on Biological Standardization. 
Guidelines on evaluation of similar biotherapeutic products. Available from: 
http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR
_WEB_22APRIL2010.pdf
World Health Organization. Q&A on Coronavirus Disease (COVID-19). 12 October 2020. 
Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/question-
and-answers-hub/q-a-detail/coronavirus-disease-covid-19
World Health Organization. Coronavirus Disease (COVID-19) Dashboard. 12 November 
2021. Available from: https://covid19.who.int/  
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13Appendices
13.1 Appendix: Schedule of Events 
Table 13-1 
Schedule of Events
 
Screening 
Double-Blind Active-Controlled Period (Part 1) 
Transition Period 
(Part 2) 
Early Study 
Withdrawala/ 
EoS
Visit 
 
 
 
 
 
7a 
8 
9 
10 
11 
12 
13 
Study Week 
-28 to -1 Wk0/ 
D1
Wk0/ 
D3
Wk2/ 
D15
Wk4/ 
D29
Wk12/ 
D85
Wk20/ 
D141
Wk23/ 
D162
Wk26/ 
D183
Wk38/
D267
Wk52/
D365
Wk56/ 
D393 
Wk64/
D449
Wk78/ 
D547 
Allowed Window 
 
 
±1D 
±2D 
±5D 
±5D 
±5D 
±7D 
±7D 
±7D 
±7D 
±7D
±7D 
±7D 
Study Month
-1
5
12
13
15
18
Informed consentb
X 
Eligibility check 
X 
X
c
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationd
X 
X 
Demographics, medical history, 
previous medication
X 
NYHA functional classification 
(in patients with heart failure)
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follicle-stimulating hormonee
X 
Height
X 
X 
X 
Body weight
X 
X 
X 
X 
X 
X 
X 
Physical examinationf
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsg
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGh
X 
X 
X 
X 
X 
X 
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Screening 
Double-Blind Active-Controlled Period (Part 1) 
Transition Period 
(Part 2) 
Early Study 
Withdrawala/ 
EoS
Visit 
 
 
 
 
 
7a 
8 
9 
10
11 
12
13
Study Week 
-28 to -1 Wk0/ 
D1
Wk0/ 
D3
Wk2/ 
D15
Wk4/ 
D29
Wk12/ 
D85
Wk20/ 
D141
Wk23/ 
D162
Wk26/ 
D183
Wk38/
D267
Wk52/
D365
Wk56/ 
D393 
Wk64/
D449
Wk78/ 
D547 
Allowed Window
±1D
±2D
±5D
±5D
±5D
±7D 
±7D
±7D
±7D
±7D
±7D
±7D
Study Month 
-1 
 
 
 
 
 
5 
 
 
12
13 
15
18
Safety/laboratory testi
X 
X 
X 
X 
X 
X 
X 
Albumin-adjusted total serum 
calciumj 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
Hepatitis B, C and HIV testk
X 
SARS-CoV-2l 
X 
As required 
Serum FT3/FT4/TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lateral spine X-raym
X 
X 
X 
Radiographyn 
 
As required 
DXA scano
X 
X 
X 
X 
Study treatment (Bmab 1000 or 
Prolia) administration
X 
X 
X 
Dispense patient diary
X 
Patient diary review of vitamin 
D and calcium intake
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypersensitivity/allergic 
reactionp, injection site reaction 
monitoringq
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
Calcium and vitamin D 
supplementr
 
Daily 
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Screening 
Double-Blind Active-Controlled Period (Part 1) 
Transition Period 
(Part 2) 
Early Study 
Withdrawala/ 
EoS
Visit 
 
 
 
 
 
7a 
8 
9 
10
11 
12
13
Study Week 
-28 to -1 Wk0/ 
D1
Wk0/ 
D3
Wk2/ 
D15
Wk4/ 
D29
Wk12/ 
D85
Wk20/ 
D141
Wk23/ 
D162
Wk26/ 
D183
Wk38/
D267
Wk52/
D365
Wk56/ 
D393 
Wk64/
D449
Wk78/ 
D547 
Allowed Window
±1D
±2D
±5D
±5D
±5D
±7D 
±7D
±7D
±7D
±7D
±7D
±7D
Study Month 
-1 
 
 
 
 
 
5 
 
 
12
13 
15
18
Blood sampling for denosumab 
PK
X
s,t
X 
X 
X 
X 
X
s
X 
X
s
X 
X 
X 
Blood sampling for 
immunogenicity (ADA and 
NAb) 
 
X
s,t 
 
X 
X 
X 
 
 
X
s 
X 
X
s 
X 
X 
X 
Blood sampling for PD testingu 
 
X
s
X 
X  
X 
X 
X 
X 
X
s 
X 
X
s 
 
 
X 
Adverse eventsv
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant medication
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ADA, anti-drug antibody; BMD, bone mineral density; COVID-19, Corona virus disease 2019; D, day; DXA, dual-energy X-ray 
absorptiometry; ECG, electrocardiogram; EoS, end-of-study; FT3, free tri-iodothyroinine; FT4, free throxine; HBV, hepatitis B virus; HCV, hepatitis 
C virus; HIV, human immunodeficiency virus; Nab, neutralizing antibody; NYHA, New York Heart Association; P1NP, procollagen Type 1 N-terminal 
propeptide; PK, pharmacokinetic; SARS-CoV-2; severe acute respiratory syndrome coronavirus 2; sCTX, serum C-telopeptide of Type 1 collagen; 
TSH, thyroid stimulating hormone; Wk, Week 
Note: Patients who early discontinue study treatment will be followed as described in Section 4.2.1. 
a.
For patients who discontinue the study early and do not wish to attend Week 26 and/or Week 52 as described in Section 4.2.1, all procedures 
specified for EoS visit Table 13-1will be performed at early withdrawal visit; however, DXA scan should be performed only if last DXA scan was 
not performed within 90 days prior to the early withdrawal visit. Lateral spine X-ray can be performed if clinically indicated. 
b.
Informed consent must be obtained before any study-related procedures are performed.
c.
Eligibility confirmation by investigator before randomization will be based on assessment of inclusion/exclusion criteria. 
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d.
Patients will be randomly assigned to 1 of 2 treatment groups (either Bmab 1000 or Prolia) on Day 1 prior to the study treatment administration. 
Second randomization will be performed prior to the study treatment administration on Week 52. Patients who are initially randomized to 
Bmab 1000 on Day 1 will continue to receive Bmab 1000. Patients who are initially randomized to Prolia on Day 1, will be re-randomized in a 
ratio of 1:1 to Bmab 1000 or Prolia. 
e. 
Not required for women with surgical menopause as their postmenopausal status will be confirmed via their medical history. 
f. 
A complete physical examination will include, at a minimum, oral examination and assessments of the cardiovascular, respiratory, gastrointestinal, 
and neurological systems and will be performed at screening, baseline (Day 1) and at Weeks 26, 52 and 78. Abbreviated, ie, sign/symptom-
directed physical examinations will be performed at other visits. 
g. 
Vital signs (blood pressure and pulse rate in a semi-supine position, body temperature, and respiratory rate) will be measured after 5 minutes of 
rest (sitting). On the dosing day visits, vital signs will be assessed prior to dosing. 
h.
All scheduled 12-lead ECGs must be performed at the study site after the patient has rested quietly for at least 5 minutes in the supine position. 
Regardless of the 12-lead ECG result, further cardiological evaluation can be conducted at the investigator’s discretion. 
i.
Safety laboratory tests include hematology, serum chemistry, and urinalysis. See Section 6.2.2 for the list of clinical laboratory tests.
j.
Blood samples for albumin-adjusted total serum calcium will be collected as a part of safety/laboratory tests when the sampling visits of serum 
calcium coincide with safety/laboratory tests. 
k. 
At screening, hepatitis B will be assessed in all patients. If a patient has HBsAg positive, the patient will be excluded from the study. If a patient 
has HBsAg negative and HBcAb positive, an HBV DNA test will be performed at screening. If the HBV DNA test result is positive, the patient 
will be excluded from the study. At screening, hepatitis C antibody will be assessed in all patients. If hepatitis C antibody test result is positive, an 
HCV RNA test will be performed at screening. If the HCV RNA test result is positive, the patient will be excluded from the study; If the HCV 
RNA test result is negative, the patient can be included in the study at the investigator’s discretion. HIV test will be assessed in all patients at 
screening. If the HIV test result is positive, the patient will be excluded from the study. 
l.
At the screening visit, a COVID-19 test will be performed as per site and/or local regulatory guidelines. Patients who have a COVID-19 positive 
test result and were asymptomatic or mildly symptomatic will be allowed to be rescreened as described in Section 4.2.5. Systematic COVID-19 
screening tests will be performed locally based on the site guidelines and on the investigator’s discretion throughout the study period. If 
COVID-19 is confirmed after randomization, the investigator will discuss case-by-case with the sponsor and/or medical monitor. 
m.
Lateral spine X-rays will be assessed by central imaging center. Lateral spine X-rays could be performed as required for confirmation of suspected 
fractures. 
n.
Radiography will be performed as required for confirmation of suspected fractures. Radiography will be analyzed at a central imaging vendor.
o.
BMD will be assessed by DXA using validated instruments. Assessment of lumbar spine, total hip, and femoral neck BMD assessments will be 
performed using the same DXA instrument for each patient throughout the study period. Assessments will be performed at a central imaging 
vendor. Note: The screening BMD assessment will be taken as the baseline BMD assessment. 
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p.
Hypersensitivity reactions will be assessed before the start of the study treatment administration (within approximately 15 minutes) and at 1 hour 
(± 10 minutes) after each study treatment administration. In addition, hypersensitivity will be monitored by routine continuous clinical monitoring 
including patient-reported signs and symptoms. In case of hypersensitivity, emergency medication and equipment, such as adrenaline, 
antihistamines, corticosteroids and respiratory support including inhalational therapy, oxygen and artificial ventilation must be available and any 
types of ECG can be performed. If the patient experiences any hypersensitivity signs and symptoms outside the study site, the patient can visit the 
study site for further assessment. 
q. 
Injection site reactions will be assessed within 1 hour of the end of each study treatment administration. 
r. 
All patients will be instructed to take daily supplementation containing calcium and vitamin D as described in Section 5.2.2. 
s. 
Blood sample for PK, PD, and immunogenicity should be collected up to 30 minutes prior to study treatment administration. 
t. 
Blood samples for PK and immunogenicity method validation will be collected up to 30 minutes prior to study treatment administration on Day 1. 
u. 
Blood sample for PD markers: this includes bone turnover markers, sCTX and P1NP. Samples will be collected in the morning with fasting of at 
least 8 hours and patients will be required to refrain from intense physical activity in the 48-hour period prior to sample collection. 
v.
Includes PFS related issues.
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13.2 Risk Assessment and Mitigation Plan due to COVID-19 
The novel SARS-CoV-2 was initially identified during an outbreak of atypical viral 
pneumonia cases of unknown cause in the People’s Republic of China in December 2019 and 
the disease caused by SARS-CoV-2 has been designated as COVID-19. On 11 March 2020, 
the WHO declared the SARS-CoV-2 infection outbreak a global pandemic and to date more 
than 5 million deaths have been reported globally (World Health Organization COVID-19 
Dashboard 2021).
Due to the global impact of the COVID-19 pandemic, the sponsor is taking proactive 
measures to guarantee that all site staff and patients involved in the trial are secure and the 
patients remain in the study until their last visit, with continuation of treatment during the 
study period. 
During COVID-19 pandemic, any potential measures or changes will be handled according 
to the local regulations. If the COVID-19 pandemic wanes off, there is no need to amend the 
protocol in terms of any specific information relating to COVID-19, including if some 
tests/procedures are not required anymore. 
Benefit and Risk Assessment on Study Population 
Considering the most common symptoms of COVID-19 are fever, dry cough, and tiredness 
(World Health Organization Q&A on COVID-19) and the irrelevance between cause of 
COVID-19 and osteoporosis disease itself, osteoporosis symptoms and disease itself have a 
low chance to deteriorate directly due to COVID-19. Furthermore, no high risk was seen for 
COVID-19 complications in women older than 50 years for postmenopausal or aromatase 
inhibitor-induced osteoporosis, and the patients are recommended to maintain the denosumab 
treatment for the management of osteoporosis during the COVID-19 outbreak 
(Gittoes et al., 2020). However, the irrelevance cannot be concluded since no studies have 
been conducted and there were a few research studies reporting the increased risk for 
respiratory infections following denosumab treatment (Formenti et al., 2020). 
Moreover, it has yet to be concluded that calcium and vitamin D, which is a protocol defined 
co-administration, may have beneficial effects to treat COVID-19. To date, it has been shown 
that the patients with osteoporosis may be protected from SARS-CoV-2 by vitamin D 
independently of the pharmacologic antiosteoporotic treatments (Bilezikian et al., 2020). 
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Basically, the quarantine of COVID-19 should be carried out based on the SOP of each site and 
local regulatory guidelines. Taking all these facts into consideration, the risks of COVID-19 
infection for each patient are not expected to increase by participating in this study. Yet due to 
the possibility of increasing the safety risk by being involved in the study, a systematic risk 
assessment will be conducted during the study by the sponsor through a sufficient discussion 
with the investigators. 
Mitigation Plans 
Study Treatment Management 
To cope better with the sudden imposition of movement restriction and/or increased shipment 
lead time due to frequent flight cancellation and limited staff at customs, sufficient study 
treatment will be supplied to cover patient visits for longer periods. Inter-country study 
treatment transfer using regional airways will be considered in case intercontinental flights 
are repeatedly cancelled. In addition, the sponsor will prepare site-to-site transfer of study 
treatment from nearby clinical sites in case an agile resupply is required (eg, more patients 
are enrolled at a site than anticipated but additional supplied study treatment is not sufficient 
to meet demand). Vitamin D and calcium supplements will also be supplied to patient's 
home. 
Rescheduling of Visit and Study Treatment Administration Schedule of Patients 
At the screening visit, a COVID-19 test will be performed as per site and/or local regulatory 
guidelines. Patients who have a COVID-19 positive test result and were asymptomatic or 
mildly symptomatic will be allowed to be rescreened as described in Section 4.2.5. 
Systematic COVID-19 screening tests will be performed locally based on the site guidelines 
and on the investigator’s discretion throughout the study period. If COVID-19 is confirmed 
after randomization, the investigator will discuss case-by-case with the sponsor and/or 
medical monitor. If the patient has had contact with COVID-19 infected patients within 14 
days following any site visit, the investigator will re-assess the visit schedule following the 
site and/or local regulatory guidelines. In the case of a patient who has contact with 
COVID-19 patient 14 days prior to screening and within the screening period up to 
randomization, the patient should not be enrolled in the study. If the patient has contact with 
COVID-19 patients within 14 days following any site visit, the investigator will re-assess the 
visit schedule following the site and/or local regulatory guidelines. 
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Investigators will promptly notify the sponsor if any unfavorable situation has occurred in 
relation to local COVID-19 status (eg, site shut down, lock down of city, cohort isolation, 
etc.). For sites where the patients are unable to travel or use public transportation, the sponsor 
will support the patients with alternative transportation or reimbursement for travel to ensure 
the visits can be made within the window or the visit can be proceeded at the earliest possible 
opportunity. Pre-approval is required for reimbursement. 
The patients require face-to-face interactions for study treatment administration. Therefore, 
in the event patients cannot visit the study center on the scheduled day for injection, the 
treatment schedule will be adjusted following Section 5.7. However, if study treatment 
administration cannot be carried out within an allowed visit window or a missed dose is 
expected, whether to continue with the subsequent study treatment will be discussed with the 
sponsor, ensuring the compliance with the trial protocol to such an extent that an ongoing 
benefit-risk assessment for the clinical trial and patients is still possible. 
Even if a study visit cannot be made, possible data will be continuously collected via a 
telephone call and during the next visit, if applicable. The investigator will keep following up 
with patients regarding any safety issues (AEs, concomitant medication) by telephone call 
before the patients visit the site.
Although the COVID-19 pandemic situation is likely to introduce more protocol deviations 
than under normal circumstances, protocol deviations will be managed in accordance with 
the standard procedures. The number and type of deviations will be monitored periodically to 
assess whether a protocol amendment or other modifications are needed. 
COVID-19 Vaccine  
The study indication, study treatment, and assessments are not expected to be impacted by 
vaccination. However, COVID-19 vaccine is prohibited within 14 days prior to and 14 days 
after study treatment administration on Day 1, Week 26, and Week 52. 
DXA Scan and X-ray Assessments
For BMD assessment, only validated bone densitometers will be allowed during the study, 
and the same DXA instrument shall be used for all study procedures for each patient during 
the study. However, in COVID-19 pandemic situation, if the patients are restricted in their 
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ability to travel to the sites and/or the sites are locked down, the alternative imaging centers 
can be considered to acquire the DXA scans. The alternative center should follow the central 
imaging provider’s guidance on selecting an appropriate replacement scanner and a phantom 
scanning process to quantify any calibration differences. All DXA scans will be submitted to 
and analyzed by the central imaging vendor. 
For vertebral fractures, the lateral spine X-ray will be performed at time points specified in 
Schedule of Events (Table 13-1) and may be performed in the alternative imaging centers in 
COVID-19 pandemic situation (site shut down, lock down of city etc.). The lateral spine 
X-ray for vertebral fracture as well as copies of other diagnostic image and related source 
documents should be submitted to the central imaging vendor for confirmation of fracture. 
And, if X-ray is necessary to support the patient’s medical care, the X-rays also could be read 
locally.
The nonvertebral fractures may be assessed by alternative imaging centers in COVID-19 
pandemic situation. The information about new nonvertebral fractures (eg, details regarding 
the type of fracture and other pertinent data) and level of trauma causing the fracture will be 
recorded from the alternative centers. A copy of other diagnostic image and/or radiology 
report, surgical report, or discharge summary will also be included in the patient’s individual 
source documents and should be submitted to the central imaging vendor for confirmation of 
fracture. For further details on the source documents for nonvertebral fractures, see 
Section 6.1.2.
Site Monitoring and Audit 
In cases where a monitoring visit cannot be performed because of the prevailing COVID-19 
situation, centralized monitoring will be performed by the sponsor and/or CRO as 
alternatives particularly if this acceptable by local regulations, for the sites where the first 
patient is randomized but the first monitoring visit is not performed. Manual data review on 
the eCRF will be performed and if any mistakes or deviations are observed, proper guidance 
will be provided to prevent them happening in the future. Sponsor and/or CRO will review 
the data entered in the eCRF continuously and ensure queries are raised and support the sites 
as necessary. If necessary, sponsor/CRO will create and review reports based on CRF data to 
check study progress for each patient as per protocol and perform management of sites in 
case of any noted deficiency. 
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Other potential measures will be taken to assure the safety and welfare of trial patients , 
maintaining compliance with GCP, and minimizing risks to trial integrity during the 
Any potential measures or changes will be handled according to the regulations.  
Audits are required to ensure quality assurance throughout the study period in order to 
evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable 
regulatory requirements. In cases where an audit cannot be performed due to the COVID-19 
pandemic situation, the sponsor will postpone audits or consider performing remote audits 
after careful consideration of the COVID-19 pandemic situation according to guidance on the 
management of clinical trials during the COVID-19 (coronavirus) Pandemic (European 
Medicines Agency 2021). Audits will be conducted only when permitted under national, local 
and/or organizational social distancing restrictions. 
Handling of Missing Data 
To assess any possible risks on data collection, data will be routinely reviewed according to 
centralized monitoring plan and risk based monitoring plan. After data collection, missing
data on the primary efficacy analysis due to COVID-19 will be analyzed as specified in 
Section 7.7 with other missing cases.
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13.3 Appendix: Protocol Amendment History 
Amendment 1 (13-Apr-2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC and Article 2(13) of Regulation (EU) No 536/2014 of the European 
Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
Major changes from Original Protocol (06-Jan-2022) to Amendment 1 (13-Apr-2022) are 
summarized in the following table. Additional minor changes to the protocol and changes to 
the synopsis are not listed but were applied, as applicable. Minor editorial or formatting 
changes are not included in this summary table. 
Section # and Name 
Description of Change 
Brief Rationale 
Title page, Signature page, 
Protocol Amendment 
Summary of Changes, and 
Header 
Updated the protocol version and date. 
Reflect the new version and date. 
Synopsis – Rationale 
Section 1.5 Study Rationale 
Clarified that: For EMA, the PD 
endpoint AUEC of sCTX from baseline 
to 26 weeks is considered as Co-primary 
endpoint, while, for US FDA, this 
endpoint is considered as a key 
secondary endpoint. 
To provide further clarity. 
Throughout Section 2 and 7 Changes to estimand labels with EMA 
and US FDA descriptors to add clarity 
on the purpose of each: Estimands 1a, 2, 
and 1b changed to 1a-EMA (Co-primary 
Efficacy), 1a-US FDA (Efficacy), and 
1b-EMA (Co-primary PD), respectively.
Regulatory feedback suggests that 
EMA and US FDA regulators are 
looking for different estimands as 
primary (or Co-primary). 
Synopsis - Objectives and 
Estimands 
Section 2.1 Primary 
Objectives, Endpoints, and 
Estimands 
Efficacy objective stated as primary for 
US FDA submission whilst efficacy and 
PD objectives are Co-primary for EMA. 
Furthermore, Estimand 1a-US FDA now
uses the treatment policy strategy for 
discontinuation from treatment for any 
reason. 
To address the US FDA 
recommendations to modify the 
primary estimand and clarify that only 
EMA require the Co-primary 
objectives. 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis - Study Design
Section 3.1.1 Independent 
Safety Review Committee, 
and Section 7.9 - 
Independent Safety Review 
Committee 
An Independent Safety Review 
Committee will be used for review of 
safety data to decide whether to 
pause/continue/modify the study. 
To address the US FDA 
recommendation to specify safety 
findings that would require study 
termination. 
Section 5.9 Intervention 
After the End of the Study or 
Treatment Discontinuation 
Clarified that anti-resorptive therapy 
will be provided to patients after the end 
of study or treatment discontinuation.
To address the US FDA 
recommendation to provide anti-
resorptive therapy upon end of study. 
Synopsis - Safety 
Assessments 
Section 6.2.1.3 Reporting 
Adverse Events 
Clarified that any fracture will be 
recorded as an AE/SAE/AESI (as 
applicable). 
To address the US FDA 
recommendation to record any fracture 
that occurs during the study as an AE. 
Section 6.2.1.5 PFS related 
Issues /Adverse Events 
Added the details about the assessment 
and reporting of PFS related issues/AEs 
To address the US FDA 
recommendation to include an 
assessment of PFS related AEs. 
Synopsis - (Co-)primary 
Efficacy Endpoint, 
Secondary BMD Endpoints. 
Section 7.1.2 Estimands, 
Table 7-2 Key Estimands 
with Rationale for Strategies 
to Address Intercurrent 
Events, Section 7.1.2.1 
Choice of Primary and Key 
Secondary Estimands, 
Synopsis Sample Size, 
Section 7.3 Sample Size 
Determination 
Clarified what would be considered as 
primary, Co-primary or secondary 
estimands for US FDA and EMA 
submissions. 
Furthermore, Estimand 1a-US FDA now 
uses the treatment policy strategy for 
discontinuation from treatment for any 
reason. 
To address the US FDA 
recommendations to modify the 
primary estimands such that the data 
collected should be close to a real-
world setting. 
Synopsis - Statistical 
Methods-Analysis Sets, 
Main Estimation of Estimand 
1a-EMA (Co-primary 
Efficacy), Main Estimation 
of Estimand 1a-US FDA 
(Efficacy) 
Section 7 Statistical Analysis 
Methodology 
Section 7.6.4.1 Secondary 
BMD Endpoints 
Clarified which analysis sets will be 
used for Estimand 1a-EMA, Estimand 
1a-US FDA, and Estimand 1b-EMA 
(Co-primary PD) analyses. 
 
Removed mFAS2 so that FAS is used 
instead for estimation of Estimand 1a-
US FDA.  Renamed mFAS1 as mFAS.  
Both 90% and 95% CIs will be 
presented for primary efficacy. 
To address the US FDA 
recommendations to modify the 
primary estimands such that the data 
collected should be close to a real-
world setting. 
Synopsis - Analyses of BMD 
After Transition and Section 
7.6.4.2 Analyses of BMD 
After Transition 
Added that 95% CIs will be presented 
for the analyses of BMD after transition.
To provide clarity that 95% CIs will be 
presented for this endpoint. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 13.1 Appendix: 
Schedule of Events, Table 
13-1 Schedule of Events 
Added a footnote to clarify about 
collection of PFS related issues 
To address the US FDA 
recommendation to include an 
assessment of PFS related AEs. 
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