A Randomised, Double Blind, Multicentre Phase III Study to Assess the Efficacy and Safety of RGB-14-P Compared to Prolia® in Women With Postmenopausal Osteoporosis
Phase: PHASE3
Conditions: Postmenopausal Osteoporosis
Sponsor: Gedeon Richter Plc.

Protocol Title: A Randomised, Double-blind, Multicentre Phase III Study to Assess the Efficacy and 
Safety of RGB-14-P Compared to Prolia® in Women with Postmenopausal Osteoporosis
Protocol number: RGB-14-101
ClinicalTrails.gov Identifier: NCT05087030
Date of protocol: 28-March-2023

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Title Page 
Protocol Title: 
A Randomised, Double-blind, Multicentre 
Phase III Study to Assess the Efficacy and 
Safety of RGB-14-P Compared to Prolia® in 
Women with Postmenopausal Osteoporosis 
Short Title:  
Comparative Efficacy and Safety Study of 
RGB-14-P and Prolia® in Women with 
Postmenopausal Osteoporosis 
Compound: 
RGB-14-P (test product) and  
Prolia® (reference product) 
Indication: 
Postmenopausal Osteoporosis 
Study Sponsor: 
Gedeon Richter Plc. 
1103 Budapest, Gyömrői út 19-21 
Hungary 
Protocol Number: 
RGB-14-101 
Study Phase: 
Phase III 
Regulatory Agency Identifying 
Number: 
IND 146025 
European Clinical Trials Database 
(EudraCT) Number: 
2020-006017-38 
Approval Date: 
Final Version 5.0 28Mar2023 
This clinical study will be conducted in accordance with the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Tripartite Guideline for Good Clinical Practice (GCP) 
E6(R2), the protocol and its amendments, the Declaration of Helsinki and with other applicable regulatory 
requirements. 
Confidentiality Statement 
This document contains confidential information of Gedeon Richter Plc.  Do not copy or distribute without written 
permission from the Sponsor. 
 
 

PPD
PPD

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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Version 
Date 
Non-Substantial Amendment 2; Global 
Amendment 
Final 5.0 
28 Mar 2023 
Substantial Amendment 3; Global 
Amendment 
Final 4.0 
19 Jan 2023 
Substantial Amendment 2; Global 
Amendment 
Final 3.0 
10 Jan 2022 
Substantial Amendment 1; Country 
Specific – United States 
Final 2.0 
03 Aug 2021 
Non-Substantial Amendment 1; 
Country Specific - Czech Republic 
Final 1.1 
20 July 2021 
Original Protocol 
Final 1.0 
10 March2021 
 
Non-Substantial Amendment 2 (28 Mar 2023) 
This amendment is considered to be non-substantial because it neither significantly impacts the 
safety or physical/mental integrity of participants nor the scientific value of the study 
Overall Rationale for the Amendment: 
The protocol is mainly amended to incorporate and implement responses and suggestions made 
by the United States (US) Food and Drug Administration (FDA). 
Non-Substantial Amendment 2 Summary of Changes: 
Section # and Name 
Description of Change 
Brief Rationale 
9.4.2 Estimands (Table 9-3) 
Text added to include the 
composite variable strategy of 
ICE Strategy. 
 
Text added to include and specify 
that robustness of the main 
estimator will be assessed by 
using two-dimensional tipping 
point analyses for FDA 
submission of Sensitivity 
Estimator. 
Amended following the 
suggestion from the US FDA. 
9.4.5 Handling of Missing Data 
Text added to clarify a sensitivity 
tipping point analysis will be 
conducted to assess the 
robustness of results, at both 
week 52 and week 78. 
Amended following the 
suggestion from the US FDA. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not been 
summarized. 
 
 

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Table of Contents 
 
Protocol Amendment Summary of Changes Table ......................................................................... 3 
Table of Contents ............................................................................................................................ 4 
1 
Protocol Summary .................................................................................................................... 9 
1.1 
Synopsis ................................................................................................................................ 9 
1.2 
Schema ............................................................................................................................... 14 
1.3 
Schedule of Activities (SoA) .............................................................................................. 16 
2 
Introduction............................................................................................................................. 21 
2.1 
Background......................................................................................................................... 22 
2.1.1 
Summary of Non-clinical Studies .................................................................................. 23 
2.1.2 
Summary of Clinical Studies .......................................................................................... 25 
2.2 
Benefit/Risk Assessment .................................................................................................... 25 
2.2.1 
Risk Assessment ............................................................................................................. 25 
2.2.2 
Benefit Assessment ......................................................................................................... 28 
2.2.3 
Overall Benefit: Risk Conclusion ................................................................................... 29 
3 
Objectives and Endpoints ....................................................................................................... 30 
4 
Study Design ........................................................................................................................... 31 
4.1 
Overall Design .................................................................................................................... 31 
4.2 
Scientific Rationale for Study Design ................................................................................ 33 
4.3 
Justification for Dose .......................................................................................................... 33 
4.4 
End of Study Definition...................................................................................................... 34 
5 
Study Population ..................................................................................................................... 35 
5.1 
Inclusion Criteria ................................................................................................................ 35 
5.2 
Exclusion Criteria ............................................................................................................... 36 
5.3 
Lifestyle Considerations and Restrictions .......................................................................... 40 
5.4 
Screen Failures ................................................................................................................... 40 
5.4.1 
Screening and Enrolment Log ........................................................................................ 41 
6 
Study Treatments .................................................................................................................... 42 
6.1 
Study Treatments Administered ......................................................................................... 42 
6.1.1 
Study Treatment Devices ................................................................................................ 43 
6.1.2 
Medical Device Events ................................................................................................... 43 

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6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 44 
6.3 
Measures to Minimise Bias: Randomisation and Blinding ................................................ 44 
6.3.1 
Randomisation ................................................................................................................ 44 
6.3.2 
Re-randomisation and Participant Subset in Transition Period ...................................... 45 
6.3.3 
Blinding and Breaking the Blind .................................................................................... 45 
6.4 
Investigational Medicinal Product Compliance ................................................................. 47 
6.5 
Prior and Concomitant Therapy ......................................................................................... 48 
6.5.1 
Prohibited Therapy ......................................................................................................... 49 
6.5.2 
Additional Study Treatments .......................................................................................... 50 
6.6 
Dose Modification .............................................................................................................. 51 
6.7 
Intervention After the End of the Study ............................................................................. 51 
7 
Discontinuation of Investigational Medicinal Product and Participant 
Discontinuation/Withdrawal from the Study .......................................................................... 52 
7.1 
Discontinuation of Investigational Medicinal Product, Participant 
Discontinuation/Withdrawal from the Study ...................................................................... 52 
7.2 
Loss of Participants to Follow-Up ...................................................................................... 53 
8 
Study Assessments and Procedures ........................................................................................ 55 
8.1 
Administrative Procedures ................................................................................................. 55 
8.1.1 
Informed Consent ........................................................................................................... 55 
8.1.2 
Participant Identification and Visit Reminder Card ....................................................... 55 
8.2 
Screening and Eligibility Assessments ............................................................................... 56 
8.2.1 
Eligibility Criteria ........................................................................................................... 56 
8.2.2 
Demography ................................................................................................................... 56 
8.2.3 
Medical and Surgical History ......................................................................................... 56 
8.2.4 
Prior and Concomitant Medications Review .................................................................. 56 
8.2.5 
Screening Assessment .................................................................................................... 57 
8.2.6 
Recommended Order of Assessments ............................................................................ 58 
8.3 
Efficacy Assessments ......................................................................................................... 58 
8.3.1 
Dual Energy X-ray Absorptiometry Measurement ......................................................... 58 
8.3.2 
Lateral Spine X-ray ........................................................................................................ 59 
8.3.3 
Fracture Assessment ....................................................................................................... 59 
8.4 
Safety Assessments ............................................................................................................. 60 
8.4.1 
Physical Examinations .................................................................................................... 60 
8.4.2 
Vital Signs ...................................................................................................................... 60 
8.4.3 
Electrocardiograms ......................................................................................................... 61 

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8.4.4 
Clinical Safety Laboratory Assessments ........................................................................ 61 
8.4.5 
Local Tolerance (Skin Examination) .............................................................................. 62 
8.5 
Adverse Events and Serious Adverse Events ..................................................................... 63 
8.5.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information ..................................................................................................................... 63 
8.5.2 
Method of Detecting Adverse Events and Serious Adverse Events ............................... 64 
8.5.3 
Follow-up of Adverse Events and Serious Adverse Events ........................................... 64 
8.5.4 
Regulatory Reporting Requirements for Serious Adverse Event ................................... 65 
8.5.5 
Pregnancy ....................................................................................................................... 66 
8.6 
Treatment of Overdose ....................................................................................................... 67 
8.7 
Immunogenicity Assessments ............................................................................................ 67 
8.8 
Serum Drug Concentration ................................................................................................. 68 
8.9 
Pharmacodynamics ............................................................................................................. 69 
8.10 Genetics .............................................................................................................................. 69 
8.11 Biomarkers ......................................................................................................................... 69 
8.12 Medical Resource Utilisation and Health Economics ........................................................ 69 
9 
Statistical Considerations........................................................................................................ 70 
9.1 
Statistical Hypotheses ......................................................................................................... 70 
9.2 
Sample Size Determination ................................................................................................ 71 
9.3 
Populations for Analyses .................................................................................................... 73 
9.4 
Statistical Analyses ............................................................................................................. 73 
9.4.1 
General Considerations .................................................................................................. 74 
9.4.2 
Estimands ....................................................................................................................... 74 
9.4.3 
Primary pharmacodynamic analysis ............................................................................... 77 
9.4.4 
Additional analyses ........................................................................................................ 77 
9.4.5 
Handling of Missing Data .............................................................................................. 79 
9.4.6 
Other Analyses ................................................................................................................ 80 
9.5 
Interim Analyses ................................................................................................................. 82 
9.6 
Data Monitoring Committee............................................................................................... 82 
10 Supporting Documentation and Operational Considerations ................................................. 83 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 83 
10.1.1 
Regulatory and Ethical Considerations .......................................................................... 83 
10.1.2 
Financial Disclosure ....................................................................................................... 83 
10.1.3 
Informed Consent Process .............................................................................................. 84 
10.1.4 
Data Protection ............................................................................................................... 84 

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10.1.5 
Dissemination of Clinical Study Data ............................................................................ 85 
10.1.6 
Data Quality Assurance .................................................................................................. 85 
10.1.7 
Source Documents .......................................................................................................... 87 
10.1.8 
Study and Site Start and Closure .................................................................................... 87 
10.1.9 
Publication Policy ........................................................................................................... 88 
10.1.10 Protocol Approval and Amendment ............................................................................... 89 
10.1.11 Liability and Insurance ................................................................................................... 89 
10.2 Appendix 2: Clinical Laboratory Tests ............................................................................... 91 
10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................... 93 
10.3.1 
Definition of Adverse Event ........................................................................................... 93 
10.3.2 
Definition of Serious Adverse Event .............................................................................. 95 
10.3.3 
Definition of Medical Device Events ............................................................................. 97 
10.3.4 
Recording and Follow-up of Adverse Event and Serious Adverse Event ...................... 97 
10.3.5 
Reporting of Serious Adverse Events ........................................................................... 102 
10.4 Appendix 4: Coronavirus Disease 2019 (COVID-19) Related Considerations ............... 107 
10.5 Appendix 5: Abbreviations and Trademarks .................................................................... 108 
10.6 Appendix 6: Protocol Amendment History ....................................................................... 111 
11 References............................................................................................................................. 120 
Investigator Agreement Page ...................................................................................................... 123 
List of Figures 
Figure 1–1: 
Study Design – Main Period only ......................................................................... 14 
Figure 1–2: 
Study Design – Main and Transition Period ......................................................... 15 

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List of Tables 
Table 1-1 
Schedule of Activities (SoA) – Main Period......................................................... 16 
Table 1-2 
Schedule of Activities (SoA) – Transition Period ................................................. 19 
Table 3-1 
Objectives and Endpoints ..................................................................................... 30 
Table 6-1 
Study Treatments Administered ............................................................................ 42 
Table 8-1 
Common Terminology Criteria for Adverse Events Injection Site Reaction 
Grading ................................................................................................................. 63 
Table 9-1 
Probability to Observe at Least One Participant with a Given Adverse Event ..... 72 
Table 9-2 
Populations for Analysis ....................................................................................... 73 
Table 9-3 
Summary of the primary and secondary estimands .............................................. 74 
Table 10-1 
Protocol-Required Laboratory Assessments ......................................................... 91 
 
 

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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A Randomised, Double-blind, Multicentre Phase III Study to Assess the Efficacy 
and Safety of RGB-14-P Compared to Prolia® in Women with Postmenopausal Osteoporosis 
Sponsor Protocol No.: RGB-14-101 
Study Phase: Phase III 
Sponsor: Gedeon Richter Plc. 
Rationale: 
Gedeon Richter Plc. is developing RGB-14-P (test product) as a biosimilar to Prolia® (reference 
product) by undertaking a global development programme.  The Sponsor is also developing 
RGB-14-X, as a proposed biosimilar to Xgeva®.  Following a step-wise approach subsequent to 
demonstrating high level of similarity between the proposed biosimilars RGB-14-P and 
RGB-14-X and the respective reference products Prolia® and Xgeva® at the quality and in vitro 
non-clinical levels, Gedeon Richter Plc., intends to demonstrate clinical comparability by 
performing comparative pharmacokinetic (PK)/pharmacodynamic (PD) study of RGB-14-X as 
well as a comparative efficacy and safety study between RGB-14-P and Prolia®.  Although the 
comparative PK/PD study will commence earlier, essentially the two studies will run in parallel. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
Efficacy 
To demonstrate similar efficacy and effect of 
RGB-14-P with US-licensed Prolia® on BMD at the 
lumbar spine at Week 52 in female participants with 
postmenopausal osteoporosis 
 
 
Efficacy 
%CfB in lumbar spine BMD at Week 52 
Pharmacodynamics 
To demonstrate similar pharmacodynamics (AUEC of 
%CfB in sCTX) of RGB-14-P with US-licensed 
Prolia® in female participants with postmenopausal 
osteoporosis (only required for EMA) 
Pharmacodynamics 
AUEC of %CfB sCTX0-m6 until Week 26 
(secondary for US FDA submission) 

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Objectives 
Endpoints 
Secondary 
Efficacy 
To provide additional comparative efficacy data of 
RGB-14-P with US-licensed Prolia® in female 
participants with postmenopausal osteoporosis 
 
 
Efficacy 
• 
%CfB in total hip BMD at Weeks 26, 52 and 78 
• 
%CfB in lumbar spine BMD at Weeks 26 and 78 
• 
%CfB in femoral neck BMD at Weeks 26, 52 
and 78 
• 
Vertebral fragility fracture incidence at Weeks 52 
and 78 
• 
Non-vertebral fragility fracture incidence at 
Weeks 52 and 78 
 
Pharmacodynamics 
To provide additional comparative pharmacodynamic 
data of RGB-14-P with US-licensed Prolia® in female 
participants with postmenopausal osteoporosis 
 
Pharmacodynamics 
• 
%CfB in serum P1NP at Weeks 4, 26, 52 and 78 
• 
%CfB in sCTX at Weeks 4, 26, 52 and 78 
Safety 
To compare the safety and tolerability of RGB-14-P 
with US-licensed Prolia® in female participants with 
postmenopausal osteoporosis 
Safety 
• 
AE, SAE, clinical laboratory safety assessments 
(haematology, clinical chemistry and urinalysis), 
vital signs, physical examination, ECG, injection 
site reaction and fracture assessment up to 
Week 78 
 
Immunogenicity 
To compare the immunogenicity of RGB-14-P with 
US-licensed Prolia® in female participants with 
postmenopausal osteoporosis 
Immunogenicity 
• 
Incidence of binding ADAs and NAbs at Weeks 0, 
2, 4, 26, 28, 30, 52, 54, 56 and 78 
• 
Titre determination of binding ADAs at Weeks 0, 
2, 4, 26, 28, 30, 52, 54, 56 and 78 
ADA = anti-drug antibody; AE = adverse event; AUEC = area under the effective curve; 
AUEC sCTX0-m6 = AUEC after the first dose until Day 183 of %CfB in serum type I collagen C-telopeptide; 
BMD = bone mineral density; %CfB = percent change from baseline; ECG = electrocardiogram; 
EMA = European Medicines Agency; FDA = Food and Drug Administration; NAbs = neutralising antibodies; 
P1NP = serum procollagen type 1 N-terminal propeptide; SAE = serious adverse event; sCTX0-m6 =  serum type I 
collagen C-telopeptide up to month 6; US = United States 
 
Overall Design: 
This is a randomised, double-blind, multicentre, multiple fixed-dose, 2-arm parallel-group study 
(Main Period) with a Transition Period to assess the efficacy, PD, safety, tolerability and 
immunogenicity of RGB-14-P compared to US-licensed Prolia® in participants with 
postmenopausal osteoporosis, in a comparative manner. 
Participants will attend a Screening Period within 35 days prior to first dosing.  Participants 
meeting eligibility criteria will enter into the Main Period of the study.  The Main Period 
(52 weeks) consists of Treatment Period 1 (26 weeks) and Treatment Period 2 (26 weeks).  The 
primary endpoint of the study is assessed at the end of the Main Period.  The Transition Period 
consists of Treatment Period 3 (26 weeks), the Transition Period will be applicable to a subset of 

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participants (see Figure 1–2).  Day 1 of Treatment Periods 2 and 3 are the same as Day 183 of 
the preceding Treatment Period.  Timepoints of ambulatory site visits for Treatment Periods 2 
and 3 are calculated from the Day 1 of the respective Treatment Period. 
All participants will receive the investigational medicinal product (IMP) on 2 occasions 
(Weeks 0 and 26), on Day 1 of Treatment Periods 1 and 2.  Participants continuing to the 
Transition Period will receive the IMP on a third occasion (Week 52), Day 1 of Treatment 
Period 3.  One Treatment Period will take 6 months (26 weeks, 183 days). 
Participants will attend ambulatory site visits on the following timepoints for efficacy, PD, 
immunogenicity and safety assessment as indicated in the Schedule of Activities (Table 1-1 and 
Table 1-2). 
Main Period: 
On Day 1 of Treatment Period 1, prior to dosing, participants will be randomised in a 1:1 ratio to 
receive either RGB-14-P or Prolia®.  Administration of IMP will take place on two occasions in a 
double-blinded manner (Main Period), on Day 1 of both Treatment Periods 1 and 2 (Weeks 0 and 
26). 
Visits during the Main Period: 
• Days 1, 8, 15, 30, 60, 90, 120 and 150 postdose during Treatment Period 1. 
• Days 1, 8, 15, 30 and 90 postdose during Treatment Period 2. 
An End-of-Study Visit is planned on Day 183 (Week 52) postdose during Treatment Period 2 for 
participants not continuing participation in Transition Period.  Please see Section 6.7 for 
additional information on the transition treatment for participants not continuing in Transition 
Period of study. 
Transition Period: 
On Day 1 of Treatment Period 3 (Week 52) a total of approximately 198 participants will enter 
the Transition Period.  A subset of approximately 132 participants continuing in the Transition 
Period who received Prolia® during the Main Period will be re-randomised 1:1 to receive either a 
dose RGB-14-P or Prolia® in a double-blinded manner.  A subset of approximately 
66 participants continuing in the Transition Period who received RGB-14-P during the Main 
Period will continue to receive a dose of RGB-14-P but will also follow the randomisation 
procedure to maintain blinding. 

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Visits during the Transition Period: 
• Days 1, 8, 15, 30 and 90 postdose during Treatment Period 3. 
An End-of-Study Visit is planned on Day 183 (Week 78) postdose during Treatment Period 3.  
Please see Section 6.7 for additional information on the transition treatment for participants at 
the end of study. 
The estimated duration of the clinical phase for participants in the Main Period from the 
Screening to the End-of-Study Visit is approximately 13 months and for participants continuing 
in the Transition period from the Screening Period until the End-of-Study Visit is approximately 
19 months. 
The primary outcome of this study is determined based on the results of the efficacy analysis at 
Week 52.  To evaluate the efficacy and safety of transitioning from Prolia to RGB-14-P 
anticipated in a real-world setting, the study will continue up to Week 78.  Details of the blinding 
strategy will be described in the Blinding Maintenance Plan. 
The Main Clinical Study Report will be completed based on the data obtained after all 
participants have completed the Week 52 study visit.  The data obtained in the Transition Period 
will be added as a Final Clinical Study Report. 
Disclosure Statement: 
This is a randomised, double-blind, multicentre, multiple fixed-dose, 2-arm parallel-group study 
with a double-blind transition period. 
Number of Participants: 
Approximately 434 women with postmenopausal osteoporosis are planned to be enrolled 1:1 
(217 participants per arm, including 17% drop-out) in the study to have 362 evaluable 
participants to evaluate the primary efficacy endpoint at 90% power during the Main Period.  
Participants will be stratified by previous use of bisphosphonates and geographical region. 
It is planned that 198 participants will continue to participate during the Transition Period, which 
should ensure to have 180 evaluable participants; approximately 66 participants will continue on 
the RGB-14-P arm, whereas approximately 132 participants initially assigned to the Prolia® arm 
will be re-randomised 1:1 whereby approximately 66 participants will continue to receive Prolia® 
and approximately 66 participants will be switched to RGB-14-P. 

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Intervention Groups and Duration: 
On Day 1 of Treatment Period 1, prior to dosing, participants will be randomised in a 1:1 ratio to 
receive either RGB-14-P or Prolia®. 
Main Period: Participants will receive subcutaneous injection of RGB-14-P or Prolia®, into the 
thigh, abdomen or upper arm, administered on Day 1 of Treatment Periods 1 and 2 (Weeks 0 
and 26). 
Transition Period: A subset of approximately 66 participants in the RGB-14-P dose group will 
follow the randomisation procedure and receive one subcutaneous injection of RGB-14-P, into 
the thigh, abdomen or upper arm, administered on Day 1 of Treatment Period 3 (Week 52).  A 
subset of approximately 132 participants in the Prolia® dose group will be re-randomised to 
receive a subcutaneous injection of RGB-14-P or Prolia®, into the thigh, abdomen or upper arm, 
administered on Day 1 of Treatment Period 3 (Week 52). 
 

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1.2 Schema 
Figure 1–1: 
Study Design – Main Period only 
 
 
Main Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dayc 
-35 to 0 
1d 
8 
15 
30 
60 
90 
120 
150 
1d, e 
8 
15 
30 
90 
183f 
 
Week 
-5 to 0 
0 
1 
2 
4 
8 
12 
17 
21 
26 
27 
28 
30 
38 
52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Period 1 
Treatment Period 2 
 
 
 
 
EOS = End-of Study; n = number of participants 
a. 
Test product 
b. 
Reference product 
c. 
Day(s) refer to days within Screening or Treatment Period 
d. 
Dosing Visits 
e. 
Day 1 of Treatment Period 2 is also Day 183 of the preceding treatment period. 
f. 
Participants who will continue to receive the investigational product during Treatment Period 3 will not have an End-of-Study visit on Week 52 but will proceed to Day 1 of 
Treatment Period 3 (Week 52), see Figure 1–2. 
 
RGB-14-Pa (n = 217) 
Screening 
and Informed 
Consent 
procedures 
Proliab = (n = 217) 
Randomisation 
Screening 
EOS 

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Figure 1–2: 
Study Design – Main and Transition Period 
 
 
Main Period 
Transition Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dayc 
-35 to 0 
1d 
8 
15 
30 
60 
90 
120 
150 
1d, e 
8 
15 
30 
90 
1d, e, f 
8 
15 
30 
90 
183 
Week 
-5 to 0 
0 
1 
2 
4 
8 
12 
17 
21 
26 
27 
28 
30 
38 
52 
53 
54 
56 
64 
78 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Period 1 
Treatment Period 2 
 
Treatment Period 3 
 
 
 
 
 
 
EOS = End-of Study; n = number of participants 
a. 
Test product 
b. 
Reference product 
c. 
Day(s) refer to days within Screening or Treatment Period 
d. 
Dosing Visits 
e. 
Day 1 of Treatment Periods 2 and 3 is also Day 183 of the preceding treatment period. 
f. 
Participants continuing to the Transition Period who previously received Prolia® during the Main Period will be re-randomised 1:1 to either receive RGB-14-P or Prolia® in a 
double-blinded manner.  Participants continuing to the Transition Period who received RGB-14-P during the Main Period will continue to receive a dose of RGB-14-P but 
will also follow the randomisation procedure to maintain blinding. 
 
Randomisation 
Screening 
Re-randomisation 
EOS 
Screening 
and Informed 
Consent 
procedures 
RGB-14-Pa(n = 217) 
RGB-14-Pa(n = 66) 
Proliab(n = 217) 
Proliab(n = 66) 
RGB-14-Pa(n = 66) 

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1.3 Schedule of Activities (SoA) 
Table 1-1 
Schedule of Activities (SoA) – Main Period 
Study Period 
Days (weeks after first IMP administration) 
Screeningb 
Treatment Period 1 
Treatment Period 2c 
Day(s)a 
(Week) 
-35 to 0 
(-5 to 0) 
 
1 
(0) 
8 
(1) 
15 
(2) 
30 
(4) 
60 
(8) 
90 
(12) 
120 
(17) 
150 
(21) 
1 
(26) 
8 
(27) 
15 
(28) 
30 
(30) 
90 
(38) 
183 
(52)c/ 
EOS/ 
ET 
Window Period (Days) 
 
 
± 1 
± 1 
± 3 
± 4 
± 4 
± 4 
± 4 
± 4 
± 1 
± 1 
± 3 
± 4 
± 4 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recording of Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
Assessment 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, Height, BMIe 
X 
Xd 
 
 
 
 
 
 
 
Xd 
 
 
 
 
X 
Randomisation 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Pre-visit Phone Callf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participant Identification and Visit 
Reminder Cardg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments 
Physical Examinationh 
X 
Xd 
X 
 
 
 
 
 
 
Xc 
 
 
 
 
X 
Haematology and Clinical Chemistry 
X 
Xd, i 
X 
Xj 
X 
 
X 
 
 
Xd, i 
X 
Xj 
X 
X 
X 
HBV, HCV and HIV Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisk 
X 
Xd 
 
 
 
 
 
 
 
Xd 
 
 
 
 
X 
12-lead ECG 
X 
Xd 
 
 
 
 
 
 
 
Xd 
 
 
 
 
X 
Vital Signsl 
X 
Xm 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
X 
X 
X 
X 
Local Tolerance (Skin Examination) 
 
Xn 
X 
 
 
 
 
 
 
Xn 
X 
 
 
 
 
Prior and Concomitant Medicationo 
 
 
Adverse Events 
 
 
Medical Device Eventsp 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Efficacy Assessment 
DXA Scan Assessment 
Xq 
 
 
 
 
 
 
 
 
Xr 
 
 
 
 
X 
Lateral Spine X-ray 
Xq 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Study Period 
Days (weeks after first IMP administration) 
Screeningb 
Treatment Period 1 
Treatment Period 2c 
Day(s)a 
(Week) 
-35 to 0 
(-5 to 0) 
 
1 
(0) 
8 
(1) 
15 
(2) 
30 
(4) 
60 
(8) 
90 
(12) 
120 
(17) 
150 
(21) 
1 
(26) 
8 
(27) 
15 
(28) 
30 
(30) 
90 
(38) 
183 
(52)c/ 
EOS/ 
ET 
Window Period (Days) 
 
 
± 1 
± 1 
± 3 
± 4 
± 4 
± 4 
± 4 
± 4 
± 1 
± 1 
± 3 
± 4 
± 4 
Immunogenicity Assessment/Serum Drug Concentration Assessment 
Immunogenicity (binding ADAs and 
NAbs) Sampling 
 
Xd 
 
X 
X 
 
 
 
 
Xd 
 
X 
X 
 
Xd 
Serum Drug Concentration Sampling 
 
Xd 
 
X 
X 
 
 
 
 
Xd 
 
X 
X 
 
Xd 
PD 
PD (Serum CTX) Samplings 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
Xd 
 
 
 
 
Xd 
PD (Serum P1NP) Samplings 
 
Xd 
 
 
X 
 
 
 
 
Xd 
 
 
 
 
Xd 
ADA = anti-drug antibody; BMI = body mass index; CTX = collagen C-telopeptide; DXA = dual energy x-ray absorptiometry; ECG = electrocardiogram; EOS = End-of-Study, 
ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IMP = investigational medicinal product; NAbs = neutralising 
antibodies; P1NP = procollagen type 1 N-terminal propeptide; PD = pharmacodynamic(s) 
a. 
Day(s) refer to days within Screening or Treatment Period. 
b. 
The Screening visit may be conducted over the Screening period (i.e., more than 1 day can be utilised for Screening during to the Screening period), if necessary, for logistical 
reasons. 
c. 
Participants who will continue to receive the IMP during Treatment Period 3 will not have an End-of-Study visit on Week 52 but will proceed to Day 1 of Treatment Period 3 
(Week 52), see Table 1-2.  Please see Section 6.7 for additional information on the transition treatment for participants not continuing in Transition Period of study. 
d. 
Procedure(s)/assessment/blood collection to be performed predose. 
e. 
Height will be measured without shoes at Screening and at all timepoints when BMI is measured. 
f. 
All participants will be contacted by phone 1 day prior to every visit for assessing coronavirus disease 2019 symptoms and signs and if they had any contact with a person 
who has tested positive for severe acute respiratory syndrome coronavirus 2.  During the pre-visit call participants will be reminded of fasting conditions for blood analysis (as 
applicable). 
g. 
At each visit participants will be provided with a participant identification and visit reminder card.  The Investigator must update the visit reminder card at each visit with the 
details for the next visit. 
h. 
A comprehensive physical examination will include an assessment of general appearance and a review of systems (head, eyes, ears, nose, mouth/oral cavity, throat/neck, 
thyroid, lymph nodes, dermatologic, respiratory, cardiovascular, gastrointestinal, extremities, musculoskeletal and neurologic systems). 
i. 
Additional local calcium testing predose may be performed according to local practice or at Investigator’s discretion. 
j. 
Albumin-adjusted serum calcium only. 
k. 
Sites will perform a urine dipstick.  In case of abnormal results, a urine sample may be sent to the central laboratory for full analysis if deemed necessary by the Investigator.  
See Appendix 2 (Section 10.2). 
l. 
Vital signs include measurement of blood pressure, pulse and body temperature.  Respiratory rate to be assessed at the discretion of the Investigator.  Systolic and diastolic 
blood pressure and pulse measurements will be assessed after the participant has been sitting for at least 5 minutes with back supported and both feet on the floor. 

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m. Assessments to be done predose and 1 hour postdose. 
n. 
Injection site reaction assessment should be done predose and approximately 1 hour postdose, during this 1 hour period (i.e., from dosing to the injection site assessment) the 
participant will stay in the clinic for general safety observation.  Any further assessment of the injection site or prolonged observation of the participant may be done at the 
discretion of the Investigator. 
o. 
Compliance with daily calcium and vitamin D intake will be monitored and assessed throughout the study. 
p. 
Information on medical device events (e.g., needle broken, dose not administered properly, syringe condition problem) and medical device events (device incident/deficiency) 
that caused adverse events or events that led to serious adverse events are to be reported by unblinded site staff in the Product Complaint Form and electronic case report form 
(adverse events and serious adverse events only) as described in the Addendum to Investigator Manual and the Product Complaint Procedure.  A medical device event related 
to Prolia® will qualify as a device incident and a medical device event related to RGB-14-P will qualify as a device deficiency.  See Sections 6.1.2 and 8.5. 
q. 
Dual energy X-ray absorptiometry and lateral X-ray imaging will be done during Screening to determine participant eligibility.  Dual energy X-ray absorptiometry and X-ray 
imaging should be acquired and submitted for central independent review at least 10 days prior to Randomisation. 
r. 
Dual energy X-ray absorptiometry must be performed before dosing at Week 26 and Week 52; however, it can be performed on the same day or in the days before dosing, but 
within the visit window. 
s. 
A minimum of 8 hours fasting is required prior to blood collection, samples have to be collected in the morning between a window of 7:30 and 10:00 a.m.  Participants should 
refrain from extensive physical exercise for 24 hours before blood collection. 
 

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Table 1-2 
Schedule of Activities (SoA) – Transition Period 
Study Period 
Days (weeks after first IMP administration) 
Treatment Period 3 
Day(s)a 
(Week) 
1 
(52)b 
8 
(53) 
15 
(54) 
30 
(56) 
90 
(64) 
183 (78) 
EOS/ 
ET 
Window Period (Days) 
± 4 
± 1 
± 1 
± 1 
± 3 
± 4 
General Assessments 
Inclusion/Exclusion Criteria Assessment for the 
Transition Period 
Xc 
 
 
 
 
 
Weight, Height, BMId 
Xc 
 
 
 
 
X 
Re-randomisation 
Xc 
 
 
 
 
 
IMP Administration 
X 
 
 
 
 
 
Pre-visit Phone Calle 
X 
X 
X 
X 
X 
X 
Participant Identification and Visit Reminder Cardf 
X 
X 
X 
X 
X 
X 
Safety Assessments 
Physical Examinationg 
Xc 
 
 
 
 
X 
Haematology and Clinical Chemistry 
Xc, h 
X 
Xi 
X 
X 
X 
Urinalysisj 
Xc 
 
 
 
 
X 
12-lead ECG 
Xc 
 
 
 
 
X 
Vital Signsk 
Xc 
X 
X 
X 
X 
X 
Local Tolerance (Skin Examination) 
Xl 
X 
 
 
 
 
Prior and Concomitant Medicationm 
 
Adverse Events 
 
Medical Device Eventsn 
X 
 
 
 
 
 
Efficacy Assessment 
DXA Scan Assessment 
Xo 
 
 
 
 
X 
Lateral Spine X-ray 
X 
 
 
 
 
X 
Immunogenicity Assessment/Serum Drug Concentration Assessment 
Immunogenicity (binding ADAs and NAbs) Sampling 
Xc 
 
X 
X 
 
X 
Serum Drug Concentration Sampling 
Xc 
 
X 
X 
 
X 
PD 
PD (Serum CTX) Samplingp 
Xc 
 
 
 
 
X 
PD (Serum P1NP) Samplingp 
Xc 
 
 
 
 
X 
ADA = anti-drug antibody; BMI = body mass index; CTX = collagen C-telopeptide; DXA = dual energy x-ray absorptiometry; ECG = electrocardiogram; EOS = End-of-Study, 
ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IMP = investigational medicinal product; NAbs = neutralising 
antibodies; P1NP = procollagen type 1 N-terminal propeptide; PD = pharmacodynamic(s) 
a. 
Day(s) refer to days within Screening or Treatment Period. 

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b. 
On Day 1 of Treatment Period 3 (Week 52) participants continuing to the Transition Period who received Prolia® during the Main Period will be re-randomised 1:1 to receive 
either a dose RGB-14-P or Prolia® in a double-blinded manner.  Participants continuing to the Transition Period who received RGB-14-P during the Main Period will continue 
to receive a dose of RGB-14-P but will also follow the randomisation procedure to maintain blinding. 
c. 
Procedure(s)/assessment/blood collection to be performed predose. 
d. 
Height will be measured without shoes at all timepoints when BMI is measured. 
e. 
All participants will be contacted by phone 1 day prior to every visit for assessing coronavirus disease 2019 symptoms and signs and if they had any contact with a person 
who has tested positive for severe acute respiratory syndrome coronavirus 2.  During the pre-visit call participants will be reminded of fasting conditions for blood analysis (as 
applicable). 
f. 
At each visit participants will be provided with a participant identification and visit reminder card.  The Investigator must update the visit reminder card at each visit with the 
details for the next visit. 
g. 
A comprehensive physical examination will include an assessment of general appearance and a review of systems (head, eyes, ears, nose, mouth/oral cavity, throat/neck, 
thyroid, lymph nodes, dermatologic, respiratory, cardiovascular, gastrointestinal, extremities, musculoskeletal and neurologic systems). 
h. 
Additional local calcium testing predose may be performed according to local practice or at Investigator’s discretion. 
i. 
Albumin-adjusted serum calcium only. 
j. 
Sites will perform a urine dipstick.  In case of abnormal results, a urine sample may be sent to the central laboratory for full analysis if deemed necessary by the Investigator.  
See Appendix 2 (Section 10.2). 
k. 
Vital signs include measurement of blood pressure, pulse and body temperature.  Respiratory rate to be assessed at the discretion of the Investigator.  Systolic and diastolic 
blood pressure and pulse measurements will be assessed after the participant has been sitting for at least 5 minutes with back supported and both feet on the floor. 
l. 
Injection site reaction assessment should be done predose and approximately 1 hour postdose, during this 1 hour period (i.e., from dosing to the injection site assessment) the 
participant will stay in the clinic for general safety observation.  Any further assessment of the injection site or prolonged observation of the participant may be done at the 
discretion of the Investigator. 
m. Compliance with daily calcium and vitamin D intake will be monitored and assessed throughout the study. 
n. 
Information on medical device events (e.g., needle broken, dose not administered properly, syringe condition problem) and medical device events (device incident/deficiency) 
that caused adverse events or events that led to serious adverse events are to be reported by unblinded site staff in the Product Complaint Form and electronic case report form 
(adverse events and serious adverse events only) as described in the Addendum to Investigator Manual and the Product Complaint Procedure.  A medical device event related 
to Prolia® will qualify as a device incident and a medical device event related to RGB-14-P will qualify as a device deficiency.  See Sections 6.1.2 and 8.5. 
o. 
Dual energy X-ray absorptiometry must be performed before dosing at Week 52; however, it can be performed on the same day or in the days before dosing, but within the 
visit window. 
p. 
A minimum of 8 hours fasting is required prior to blood collection, samples have to be collected in the morning between a window of 7:30 and 10:00 a.m.  Participants should 
refrain from extensive physical exercise for 24 hours before blood collection. 

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2 Introduction 
RGB-14-P is an investigational medicinal product (IMP) under development intended to be a 
biosimilar to Prolia®.  The Sponsor is also developing RGB-14-X, as a proposed biosimilar to 
Xgeva®. 
Prolia® and Xgeva® are authorised in the European Union (EU) and are licensed in the United 
States (US).  Prolia® and Xgeva® share almost identical formulations and the mechanism of 
action of denosumab is the same in all approved indications.  Therefore, the two products may be 
regarded as two different strengths of the same product.  Consequently, the Sponsor is 
undertaking a common global development programme for RGB-14-X and RGB-14-P.  
Subsequently to demonstrating high level of similarity between the proposed biosimilars 
(RGB-14-X and RGB-14-P) and their respective reference products (Prolia® and Xgeva®) at the 
quality and in vitro non-clinical levels, the Sponsor intends to demonstrate clinical comparability 
by performing a comparative pharmacokinetic (PK) and pharmacodynamic (PD) study of 
RGB-14-X and Xgeva® and a comparative efficacy/safety study between RGB-14-P and Prolia®.  
Although the comparative PK/PD study will commence earlier, essentially the two studies will 
run in parallel. 
For further details regarding the programme please refer to the current version of the 
Investigator’s Brochure (IB) [1]. 
Since in the comparative efficacy and safety study RGB-14-P will be compared to Prolia® in 
women with postmenopausal osteoporosis, the subsequent sections will focus on these 
compounds only. 
The active pharmaceutical ingredient in RGB-14-P is denosumab, a fully human 
immunoglobulin G (IgG)2 monoclonal antibody hetero-tetramer consisting of 2 heavy chains of 
gamma 1 subclass (488 amino acids per chain) and 2 light chains of the kappa subclass 
(215 amino acids per chain).  It is produced in the mammalian cell line (Chinese hamster ovary 
cells) by recombinant deoxyribonucleic acid (DNA) technology. 
Denosumab belongs to the class of drugs affecting bone structure and mineralisation.  The 
proposed indications for RGB-14-P are the same as those of the reference product, Prolia®. 

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Therapeutic indications of Prolia according to the Summary of Products Characteristics (SmPC, 
EU) [2]: 
• Treatment of osteoporosis in postmenopausal women and men at increased risk of fractures. 
• Treatment of bone loss associated with hormone ablation in men with prostate cancer at 
increased risk of fractures. 
• Treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult 
patients at increased risk of fracture. 
Therapeutic indications of Prolia according to the Prescribing Information (US) [3]: 
• Treatment of postmenopausal women with osteoporosis at high risk for fracture. 
• Treatment to increase bone mass in men with osteoporosis at high risk for fracture. 
• Treatment of glucocorticoid-induced osteoporosis in men at high risk for fracture. 
• Treatment to increase bone mass in men at high risk for fracture receiving androgen 
deprivation therapy for non-metastatic prostate cancer. 
• Treatment to increase bone mass in women at high risk for fracture receiving adjuvant 
aromatase inhibitor therapy for breast cancer. 
The term “IMP” throughout the protocol, refers to the study drug (RGB-14-P, test product) 
and/or active comparator (Prolia®, reference product), supplied as a single-dose pre-filled syringe 
(see Section 6.1).  In addition, the terms participant and subject are used interchangeably. 
2.1 Background 
Osteoporosis is defined as a systemic skeletal disease characterised by low mineral bone mass 
and microarchitectural deterioration of bone tissue, and increased bone fragility and 
susceptibility to fracture [4].  Common sites for osteoporotic fracture are the spine, hip, distal 
forearm and proximal humerus.  Fractures resulting from osteoporosis become increasingly 
common in women after age 55 years and men after age 65 years; resulting in substantial 
bone-associated morbidities, and increased mortality and health-care costs [5].  As women age 
the rate of bone turnover increases, resulting in accelerated bone loss because of lack of 
oestrogen after menopause.  Due to its prevalence worldwide, osteoporosis is considered a 
serious public health concern.  Osteoporosis is preventable and treatable, but only a small 
proportion of those at increased risk for fracture are evaluated and treated. 

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Receptor activator of nuclear factor kappa-B ligand (RANKL) is a transmembrane or soluble 
protein, a member of the tumour necrosis factor (TNF) ligand superfamily.  It binds to receptor 
activator of nuclear factor kappa-B (RANK), a member of the TNF receptor superfamily.  
Receptor activator of nuclear factor kappa-B ligand is also known as TNF related activation 
induced cytokine (TRANCE), osteoprotegerin ligand (OPGL) and osteoclast differentiation 
factor (ODF) because of its role in the regulation of bone metabolism.  Receptor activator of 
nuclear factor kappa-B ligand plays and essential role in osteoclast (OC) formation, activity and 
survival [6].  Osteoclasts are bone-resorbing tissue resident immune cells that are derived from 
pluripotent haematopoietic stem cells.  Osteoclastogenesis requires stimulation by 
macrophage-colony stimulating factor (M-CSF) and the binding of RANKL, expressed on 
osteoblasts, to RANK receptor on the OC precursors [7].  Binding of RANKL to the RANK 
receptor on the cell surface of osteoclasts initiates a complex signalling cascade, which is 
mediated by TNF receptor associated factor (TRAF)6, TRAF3 and c-Fos transcription factor 
proteins, which leads to activation of mitogen activated protein kinases (MAPKs), nuclear factor 
(NK)-κB and activator protein (AP)-1.  These signalling pathways result in the translocation of 
transcriptional activators and subsequently to the expression of numerous effector genes 
involved in bone resorption [8, 9]. 
As a “decoy” receptor, denosumab binds with high affinity and specificity to RANKL, 
preventing activation of RANK on the surface of OC precursors and OCs.  Binding of 
denosumab with RANKL prevents the RANKL/RANK interaction, resulting in impaired OC 
formation, function and survival, thereby decreasing bone resorption in cortical and trabecular 
bone and cancer-induced bone destruction.  Bone strength is mainly determined by the cortical 
components.  Thus, loss of cortical bone contributes to a higher frequency of bone fractures.  
Denosumab affects not only the thickness of the cortex bus also bone strength, porosity and bone 
mineral density (BMD) [10]. 
2.1.1 
Summary of Non-clinical Studies 
2.1.1.1 
In vitro Studies 
In order to demonstrate analytical similarity between RGB-14-P and Prolia®, extensive 
physiochemical/structural and in vitro biological/functional characterisation has been carried out 
using a panel of comprehensive state-of-the-art analytical methods.  This analytical panel was 
endorsed by regulatory authorities. 
The results of the comprehensive non-clinical in vitro PD studies available to date demonstrated 
comparability between RGB-14-P and its reference medicinal product Prolia®. 

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For further details please refer to the current version of the IB [1]. 
2.1.1.2 
In vivo Studies 
Following the current regulatory guidance principles and scientific advices, no comparative 
in vivo toxicological or PD studies have been performed between RGB-14-P and Prolia®.  
Relevant information on the reference product, Prolia®, is presented based on the public 
assessment reports, SmPC and US package insert (USPI) of Prolia® [2, 3]. 
Non-clinical PK studies were conducted in mice, rats and cynomolgus monkeys.  While 
denosumab does not bind to RANKL in mice and rat it recognises and neutralises RANKL in 
non-human primates. 
In rodents the intravenous PK of denosumab were linear over the dose range 0.1 to 10 mg/kg, 
volume of distribution was similar to plasma volume and clearance was low with long terminal 
half-lives of 19 days in mice and 11 days in rats.  In contrast, clearance was 6- to 15-fold higher 
in knock-in mice that express a chimeric form of RANKL and in knock-out mice that lack 
expression of the Fc neonatal receptor. 
In the cynomolgus monkey PK were linear over both intravenous and subcutaneous dose range 
of 1 to 3 mg/kg but were non-liner at doses below 1 mg/kg.  The non-linearity in monkeys may 
reflect that binding of denosumab to RANKL leads to accelerated, but saturable, elimination and 
that elimination also involves the neonatal Fc receptor (FcRn) and the reticuloendothelial system.  
After repeated subcutaneous doses of 0.1 to 50 mg/kg in monkey approximately linear PK were 
reported.  Metabolism may be mediated through internalisation followed by intracellular 
degradation to small peptides and amino acids.  Antibodies may be protected from lysosomal 
degradation through binding to the Fc region of the neonatal receptor FcRn, at acidic pH in the 
endosome prior to releasing the antibody at the cell surface.  The role of FcRn was studied using 
FcRn knock-out mice.  Compared with wild-type mice a much shorter elimination half-live, that 
was similar to the half-life reported for a murine antibody, was recorded in FcRn knock-out mice 
and data indicated that FcRn protects denosumab from elimination and so influences tissue 
distribution. 
2.1.1.3 
Toxicology 
The non-clinical toxicology profile of denosumab is known from registration studies for Prolia®.  
Denosumab has been shown to be highly specific to RANKL.  In single and repeated dose 
toxicity studies, denosumab doses resulting in 100 to 150 times greater systemic exposure than 
the recommended human dose had no impact on cardiovascular physiology, male or female 

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fertility or produced specific target organ toxicity [2].  Moreover, in non-clinical toxicology 
studies no major differences were revealed regarding the possible immunomodulatory effect of 
denosumab. 
Standard tests to investigate the genotoxicity potential of denosumab have not been evaluated, 
since such tests are not relevant for this large molecule.  Due to its characteristics it is unlikely 
that denosumab has any potential for genotoxicity. 
2.1.2 
Summary of Clinical Studies 
No clinical studies have been performed to date with RGB-14-P.  This is the first clinical study 
with the test IMP.  The Sponsor is also developing RGB-14-X as a biosimilar to Xgeva® and is 
undertaking a comparative PK/PD study of RGB-14-X and Xgeva®.  Both RGB-14-P and 
RGB-14-X contain the same active ingredient (denosumab).  Although the comparative PK/PD 
study will commence earlier, essentially the two studies will run in parallel. 
The PK profile of denosumab in humans is known from relevant information on the reference 
products, Prolia® and Xgeva®.  In healthy participants and postmenopausal women, the PK of 
denosumab following subcutaneous administration is characterised by first-order absorption, 
linear distribution to the peripheral compartment and parallel linear and RANKL mediated 
non-linear elimination. 
2.2 Benefit/Risk Assessment 
There are potential benefits and risks with the administration of any new investigational 
medicine as the effects are not fully known.  Based on the potential benefit of RGB-14-P, it is 
being developed for the aforementioned indications (Section 2).  Since no clinical studies have 
been performed to date with RGB-14-P the information in this section is provided based on the 
SmPC [2] and USPI [3] of Prolia®. 
Postmenopausal osteoporotic women participating in the study are expected to directly benefit 
from the treatment with the IMPs.  In addition, the availability of biosimilars on the market will 
improve patient access to a highly effective treatment benefiting a wider community. 
2.2.1 
Risk Assessment 
Based on current available data, it is anticipated that the adverse event (AE) profile of RGB-14-P 
will be similar to that of Prolia®, therefore the same contraindications, precautions and warnings 
for Prolia® will also apply to RGB-14-P. 

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The adverse reactions associated with Prolia® are as follows [2]: 
• Very common (≥ 1/10): pain in limbs, musculoskeletal pain. 
• Common (≥ 1/100 to < 1/10): urinary tract infection, upper respiratory tract infection, 
sciatica, constipation, abdominal discomfort, rash, eczema, alopecia. 
• Uncommon (≥ 1/1000 to < 1/100): diverticulitis, cellulitis, ear infections, lichenoid drug 
eruptions. 
• Rare (≥ 1/10000 to < 1/1000): drug hypersensitivity, anaphylactic reaction, hypocalcaemia, 
osteonecrosis of the jaw (ONJ), atypical femoral fractures. 
• Very rare (< 1/10000): hypersensitivity vasculitis. 
• Not known: osteonecrosis of the external auditory canal. 
In postmenopausal women with osteoporosis the most common adverse reactions (> 5% and 
more common than placebo) included back pain, pain in extremities, hypercholesterolemia, 
musculoskeletal pain, cystitis and vertigo.  Pancreatitis has also been reported in clinical trials 
[3]. 
Adverse reactions reported in ≥ 2% of patients with osteoporosis and more frequently than in 
placebo-treated patients with Prolia® include; anaemia, angina pectoris, atrial fibrillation, upper 
abdominal pain, flatulence, gastroesophageal reflux disease, peripheral oedema, asthenia, 
vertigo, upper respiratory tract infection, pneumonia, pharyngitis, herpes zoster, bone pain, 
myalgia, spinal osteoarthritis, sciatica, insomnia, rash, pruritus [3]. 
Other adverse reactions reported in < 2% of patients with osteoporosis and more frequently than 
in placebo-treated patients with Prolia® include: hypocalcaemia, serious infections in the 
abdomen, serious urinary tract infections, serious ear infections, endocarditis, erysipelas, 
cellulitis, ONJ, atypical subtrochanteric and diaphyseal femoral fractures [3]. 
Vasculitis and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome has 
also been reported in postmarketing experience. 
A detailed description of adverse reactions is provided in the SmPC [2] and USPI [3] of Prolia®. 
The protocol has been designed to minimise the risk to the study participants.  Special warnings 
and precautions for the use of denosumab are reflected in strict inclusion and exclusion criteria 
for this study.  From Day 1 through the End-of-Study/Early Termination Visit, supplementation 

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of at least 1000 mg calcium and at least 800 IU vitamin D3 daily will be administered to all 
participants in this study. 
Participants will be monitored to detect AEs during the study and followed appropriately to 
ensure the resolution of AEs.  Safety assessments will consist of the regular monitoring of 
haematology, clinical chemistry, urinalysis, regular measurements of vital signs, physical 
examinations, injection site reactions and fracture assessments, electrocardiogram (ECG) as well 
as monitoring and recording of AEs and serious adverse events (SAEs). 
Participants might also experience procedural complications (e.g., blood draws, slight skin 
irritation from the adhesive on the ECG electrodes, device incident or device deficiency AEs). 
No serious adverse events are considered expected by the Sponsor for the purpose of expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs) and identification of 
SUSARs in the “Cumulative summary tabulation of serious adverse reactions” in the 
development safety update report for the IMP. 
Risk Assessment for Coronavirus Disease 2019 Pandemic 
The IMP is a human monoclonal IgG2 antibody targeting and binding RANKL and is believed 
not to cause immune suppression. 
The risk of exposure to infected people cannot be completely excluded as the participants may 
need to expose themselves to public areas (e.g., commute to the site) and have additional human 
contact (e.g., with site staff and other participants of the clinical study). 
Measures to mitigate the additional risks caused by coronavirus disease 2019 (COVID-19) are: 
• This study is going to start enrolling only when the Sponsor and contract research 
organisation (CRO) in collaboration deem it is safe to start the study.  In addition, the study 
will not start until the local confinement measures or other safety restrictions linked to the 
COVID-19 pandemic preventing safe study start are lifted by the local authorities. 
• Current national laws and local recommendations for prevention of pandemic will be strictly 
adhered to. 
• Participants will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnoea, sore throat, fatigue and loss of sense of taste or smell throughout 
the study.  Once clinical signs of infection are reported by participants, the Investigator needs 
to determine whether samples can be collected, and safety data can be recorded on site.  If 

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not, AEs and concomitant medications will be obtained via phone calls.  Body temperature 
measurements during visits will be implemented. 
• In case of suspected COVID-19 infection the Investigator will follow the local regulations.  
Dosing with the IMP is permitted only if COVID-19 could be ruled out.  Once diagnosis of 
COVID-19 was established, the Investigator should contact the Medical Monitor to discuss if 
the participant can continue in the study.  The next dose administration should be considered 
after recovery and after fulfilling local requirements. 
• Confirmation of COVID-19 infection by optional laboratory assessment will be conducted 
based on availability (test capacity and turnaround time) of approved tests and on 
Investigator’s discretion.  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
analysis can be performed at Screening and at any time point as deemed required by local 
regulation or by the Investigator.  It is the Investigator’s responsibility to adhere to local 
regulations and requirements for COVID-19 testing of asymptomatic as well as symptomatic 
participants. 
• The probability of virus transmission will be controlled as much as possible by: 
o Advice for participant to adhere to local requirements for reduction of the public 
exposure while ambulatory. 
o All participants are contacted by phone one day prior to every visit for assessing 
COVID-19 symptoms and signs and are informed on the possibility of attending the site 
as per local requirements.  In addition, participants are asked for any contact with a 
person who has tested positive for SARS-CoV-2.  If applicable, participants will be 
referred to the local health care system for further follow-up and treatment. 
o Physical distancing and person-to-person contact restrictions will be applied during site 
visits and in-house confinement (if applicable). 
o Where physical distancing is not possible personal protective equipment will be used by 
study participant (surgical face mask, gloves) and staff (for example but not limited to 
masks, gloves, protectors, medical suits) if deemed appropriate by the Investigators and 
site staff and guided by local requirements. 
2.2.2 
Benefit Assessment 
Denosumab is marketed in the EU and US under the trade names Prolia® and Xgeva®.  Prolia® 
was approved in 2010 for osteoporosis in postmenopausal women and in men at increased risk of 
fractures, for the treatment of bone loss associated with hormone ablation in men with prostate 

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cancer at increased risk of fractures and for the treatment of bone loss associated with long-term 
systemic glucocorticoid therapy in adult patients with increased risk of fracture. 
The efficacy and safety of denosumab have been demonstrated in many double-blind and 
open-label trials for postmenopausal women [11, 12, 13, 14].  In osteoporosis, it is proven to 
increase BMD and protect bones from fracture.  Since the authorisation extensive experience has 
been gained about Prolia® further substantiating its safe and efficacious use which has been 
associated with a positive benefit/risk ratio in the target population. 
Postmenopausal osteoporotic women participating in this study are expected to directly benefit 
from the denosumab effect of decreasing fracture risk.  In addition, they might also derive some 
health benefits from participating in the study through the rigorous medical assessments 
performed at the time of Screening and throughout the study.  Since biosimilar products improve 
patient access to highly effective treatments, their development and subsequent availability on 
the market come with significant socioeconomic benefits as well. 
2.2.3 
Overall Benefit: Risk Conclusion 
Since its marketing authorisation, extensive experience has been gained with Prolia® further 
substantiating its safety and efficacious use which has been associated with a positive/risk ratio 
in the target population. 
RGB-14-P has a potential to reduce osteoporosis and improve quality of life in study 
participants.  This study in women with postmenopausal osteoporosis will continue to evaluate 
the safety profile of RGB-14-P. 
RGB-14-P is expected to have a similar clinical outcome to Prolia® based on the physiochemical 
and biological similarity. 
Taking into account the measures taken to minimise risk to participants participating in this 
study, the potential risks identified in association with RGB-14-P are justified by the anticipated 
benefits that may be afforded to participants with osteoporosis. 
More detailed information about the known and expected benefits, risks and AE profile can be 
found in the current version of the IB [1]. 
 

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3 Objectives and Endpoints 
The study objectives and endpoints are summarised in Table 3-1. 
Table 3-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Efficacy 
To demonstrate similar efficacy and effect of 
RGB-14-P with US-licensed Prolia® on BMD at the 
lumbar spine at Week 52 in female participants with 
postmenopausal osteoporosis 
 
 
Efficacy 
%CfB in lumbar spine BMD at Week 52 
Pharmacodynamics 
To demonstrate similar pharmacodynamics (AUEC of 
%CfB in sCTX) of RGB-14-P with US-licensed 
Prolia® in female participants with postmenopausal 
osteoporosis (only required for EMA) 
Pharmacodynamics 
AUEC of %CfB sCTX0-m6 until Week 26 
(secondary for US FDA submission) 
Secondary 
Efficacy 
To provide additional comparative efficacy data of 
RGB-14-P with US-licensed Prolia® in female 
participants with postmenopausal osteoporosis 
 
 
Efficacy 
• 
%CfB in total hip BMD at Weeks 26, 52 and 78 
• 
%CfB in lumbar spine BMD at Weeks 26 and 78 
• 
%CfB in femoral neck BMD at Weeks 26, 52 
and 78 
• 
Vertebral fragility fracture incidence at Weeks 52 
and 78 
• 
Non-vertebral fragility fracture incidence at 
Weeks 52 and 78 
 
Pharmacodynamics 
To provide additional comparative pharmacodynamic 
data of RGB-14-P with US-licensed Prolia® in female 
participants with postmenopausal osteoporosis 
 
Pharmacodynamics 
• 
%CfB in serum P1NP at Weeks 4, 26, 52 and 78 
• 
%CfB in sCTX at Weeks 4, 26, 52 and 78 
Safety 
To compare the safety and tolerability of RGB-14-P 
with US-licensed Prolia® in female participants with 
postmenopausal osteoporosis 
Safety 
• 
AE, SAE, clinical laboratory safety assessments 
(haematology, clinical chemistry and urinalysis), 
vital signs, physical examination, ECG, injection 
site reaction and fracture assessment up to 
Week 78 
 
Immunogenicity 
To compare the immunogenicity of RGB-14-P with 
US-licensed Prolia® in female participants with 
postmenopausal osteoporosis 
Immunogenicity 
• 
Incidence of binding ADAs and NAbs at Weeks 0, 
2, 4, 26, 28, 30, 52, 54, 56 and 78 
• 
Titre determination of binding ADAs at Weeks 0, 
2, 4, 26, 28, 30, 52, 54, 56 and 78 
ADA = anti-drug antibody; AE = adverse event; AUEC = area under the effective curve; 
AUEC sCTX0-m6 = AUEC after the first dose until Day 183 of %CfB in serum type I collagen C-telopeptide; 
BMD = bone mineral density; %CfB = percent change from baseline; ECG = electrocardiogram; 
EMA = European Medicines Agency; FDA = Food and Drug Administration; NAbs = neutralising antibodies; 
P1NP = serum procollagen type 1 N-terminal propeptide; SAE = serious adverse event; sCTX0-m6 =  serum type I 
collagen C-telopeptide up to month 6; US = United States 

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4 Study Design 
4.1 Overall Design 
This is a randomised, double-blind, multicentre, multiple fixed-dose, 2-arm parallel-group study 
(Main Period) with a Transition Period to assess the efficacy, PD, safety, tolerability and 
immunogenicity of RGB-14-P compared to US-licensed Prolia® in participants with 
postmenopausal osteoporosis, in a comparative manner. 
Participants will attend a Screening Period within 35 days prior to first dosing.  Participants 
meeting eligibility criteria will enter into the Main Period of the study.  The Main Period 
(52 weeks) consists of Treatment Period 1 (26 weeks) and Treatment Period 2 (26 weeks).  The 
primary endpoint of the study is assessed at the end of the Main Period.  The Transition Period 
consists of Treatment Period 3 (26 weeks), the Transition Period will be applicable to a subset of 
participants (see Figure 1–2).  Day 1 of Treatment Periods 2 and 3 are the same as Day 183 of 
the preceding Treatment Period.  Timepoints of ambulatory site visits for Treatment Periods 2 
and 3 are calculated from the Day 1 of the respective Treatment Period. 
All participants will receive the IMP on 2 occasions (Weeks 0 and 26), on Day 1 of Treatment 
Periods 1 and 2.  Participants continuing to the Transition Period will receive the IMP on a third 
occasion (Week 52), Day 1 of Treatment Period 3.  One Treatment Period will take 6 months 
(26 weeks, 183 days). 
Participants will attend ambulatory site visits on the following timepoints for efficacy, PD, 
immunogenicity and safety assessment as indicated in the Schedule of Activities (SoA) 
(Table 1-1 and Table 1-2). 
Main Period: 
On Day 1 of Treatment Period 1, prior to dosing, participants will be randomised in a 1:1 ratio to 
receive either RGB-14-P or Prolia®.  Administration of IMP will take place on two occasions in 
a double-blinded manner (Main Period), on Day 1 of both Treatment Periods 1 and 2 (Weeks 0 
and 26). 
Visits during the Main Period: 
• Days 1, 8, 15, 30, 60, 90, 120 and 150 postdose during Treatment Period 1. 
• Days 1, 8, 15, 30 and 90 postdose during Treatment Period 2. 

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An End-of-Study Visit is planned on Day 183 (Week 52) during Treatment Period 2 for 
participants not continuing participation in the Transition Period.  Please see Section 6.7 for 
additional information on the transition treatment for participants not continuing in Transition 
Period of study. 
Transition Period: 
On Day 1 of Treatment Period 3 (Week 52) a total of approximately 198 participants will enter 
the Transition Period.  A subset of approximately 132 participants continuing in the Transition 
Period who received Prolia® during the Main Period will be re-randomised 1:1 to receive either a 
dose of RGB-14-P or Prolia® in a double-blinded manner.  A subset of approximately 
66 participants continuing in the Transition Period who received RGB-14-P during the Main 
Period will continue to receive a dose of RGB-14-P but will also follow the randomisation 
procedure to maintain blinding (see Section 9.2). 
Visits during the Transition Period: 
• Days 1, 8, 15, 30 and 90 postdose during Treatment Period 3. 
An End-of-Study Visit is planned on Day 183 (Week 78) postdose during Treatment Period 3.  
Please see Section 6.7 for additional information on the transition treatment for participants at 
the end of the study. 
The estimated duration of the clinical phase for participants in the Main Period from the 
Screening to the End-of-Study Visit is approximately 13 months and for participants continuing 
in the Transition period from the Screening Period until the End-of-Study Visit is approximately 
19 months. 
The primary outcome of this study is determined based on the results of the efficacy analysis at 
Week 52.  To evaluate the efficacy and safety of transitioning from Prolia® to RGB-14-P 
anticipated in a real-world setting, the study will continue up to Week 78. 
Details of the blinding strategy will be described in the Blinding Maintenance Plan. 
The Main Clinical Study Report will be completed based on the data obtained after all 
participants have completed the Week 52 study visit.  The data obtained in the Transition Period 
will be added as a Final Clinical Study Report. 

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4.2 Scientific Rationale for Study Design 
The clinical development programme for RGB-14-P follows the scientific and ethical principles 
as stated in the European Medicines Agency (EMA) regulations for biosimilar products: 
CHMP/437/04 Rev. 1., EMEA/CHMP/BMWP/42832/2005 Rev. 1, 
EMEA/CHMP/BMWP/14327/2006 Rev. 1, EMA/CHMP/BMWP/86289/2010, 
EMA/CHMP/BMWP/403543/201 and follows the Food and Drug Administration (FDA) 
regulations (Scientific Considerations in Demonstrating Biosimilarity to a Reference Product) 
and is designed based on Scientific Advices received from Paul-Ehrlich-Institut, the EMA and 
the FDA. 
This study forms part of the clinical development programme and is aimed to assess the efficacy 
and safety of RGB-14-P compared to Prolia® in women with postmenopausal osteoporosis as a 
randomised, double-blind, multicentre phase III study.  Of all therapeutic indications of Prolia® 
postmenopausal osteoporosis is considered to be the most sensitive one as postmenopausal 
osteoporotic females are exempt from underlying disease conditions and concomitant 
medications that might influence the efficacy and the safety of the IMPs consequently, they 
represent the most homogenous study population. 
In light of the outcome of a follow-up Scientific Advice at EMA, demonstration of analytical 
comparability between the US- and the EU-sourced reference materials serves as an adequate 
bridge, allowing Gedeon Richter Plc. to utilise only US-sourced reference material throughout 
the clinical development. 
The safety assessments for the study are accepted measures for ensuring safety of participants 
during a clinical study.  The sample size is considered adequate and sufficient to allow for a 
meaningful comparison between RGB-14-P and Prolia®.  The rationale for dose selection is 
discussed in Section 4.3.  The study design is deemed appropriate for conduct during the 
COVID-19 pandemic. 
4.3 Justification for Dose 
The approved dose for Prolia® is 60 mg administered every 6 months as a subcutaneous injection 
in the upper arm, upper thigh or abdomen [3].  The dose, frequency and route of administration 
of RGB-14-P have been selected to be consistent with that of Prolia® for the therapy of women 
with postmenopausal osteoporosis, as described in the Prolia® SmPC and USPI [2, 3]. 

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4.4 End of Study Definition 
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
(Table 1-2) for the last participant in the study. 

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5 Study Population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The study population will consist of approximately 434 female participants with postmenopausal 
osteoporosis.  Postmenopausal osteoporotic females are exempt from underlying disease 
conditions and concomitant medications that might influence the efficacy and the safety of the 
IMPs consequently they represent the most homogeneous and as such the most sensitive study 
population. 
Participants must be able to provide written consent and meet all the inclusion criteria and none 
of the exclusion criteria. 
5.1 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant is ≥ 60 to ≤ 90 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participant is an ambulatory postmenopausal woman, diagnosed with osteoporosis, able to 
walk and not bedridden.  A woman is considered postmenopausal if she meets any of the 
following criteria: 
a. Has 12 months of spontaneous amenorrhea without an alternative medical cause with 
serum follicle-stimulating hormone (FSH) levels falling in the normal postmenopausal 
range at the central laboratory at the time of the Screening Period. 
b. Female participant underwent bilateral oophorectomy (with or without hysterectomy) at 
least 6 weeks prior to the Screening Period. 
3. Participant has an absolute BMD consistent with T-score ≤ -2.5 and ≥ -4.0 at the lumbar 
spine as measured by dual energy X-ray absorptiometry (DXA) during the Screening Period 
and at least 2 lumbar vertebrae (from L1 to L4) must be evaluable by DXA. 
Weight 
4. Participant has body weight ≥ 50 and ≤ 90 kg at the Screening Period. 

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Informed Consent 
5. Participant is willing and able to give signed informed consent as described in Appendix 1 
(Section 10.1.3) which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
6. Participant has provided informed consent prior to any study-specific activities/procedures. 
Participant must meet the following criteria to be enrolled in the Transition Period: 
7. Have been enrolled, received both doses of IMP, adequately complied with the protocol and 
completed the scheduled Main Period (up to Week 52) of the RGB-14-101 study. 
5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Participant has a history and/or presence of a severe or more than two moderate vertebral 
fractures as determined by central reading of lateral spine X-ray during the Screening Period. 
2. Participant has a history and/or presence of hip fracture. 
3. Participant has a history and/or presence of atypical femur fracture. 
4. Participant presents with an active healing fracture according to the assessment of the 
Investigator. 
5. Participant has a bilateral hip replacement (unilateral is allowed if the other hip is evaluable 
with DXA). 
6. Participant has a vitamin D deficiency (defined as a serum 25 hydroxyvitamin D level 
< 50 nmol/L [20 ng/mL]), the assessment may be repeated once after vitamin D 
supplementation (including calcitriol).  Appropriate vitamin D dosing in addition to 
vitamin D supplementation is permitted at the discretion of the Investigator during the 
Screening Period. 
7. Participant has hypocalcaemia or hypercalcaemia (defined as albumin-adjusted serum 
calcium for hypocalcaemia < 2.1 mmol/L [8.4 mg/dL] or for hypercalcaemia > 2.62 mmol/L 
[10.6 mg/dL]) at the Screening Period, the assessment may be repeated once in the case of 
hypercalcaemia. 

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8. Participant has a history and/or presence of bone metastases, renal osteodystrophy, 
osteomyelitis, any metabolic, endocrine or traumatic bone disease (except postmenopausal 
osteoporosis) that may interfere with the interpretation of the results, e.g., Paget’s disease, 
rheumatoid arthritis, ankylosing spondylitis, osteomalacia, osteogenesis imperfecta, 
acromegaly, achondroplasia, osteopetrosis, Cushing’s disease, hyperprolactinemia or 
malabsorption syndrome.  Participants with history of childhood rickets may be eligible 
provided that the condition had been cured before the age of 25 years. 
9. Participant has a current uncontrolled status of hypothyroidism or hyperthyroidism.  
Uncontrolled means if any of the following are present: a) clinical signs and symptoms of 
active hyper/hypothyroidism, b) thyroid-stimulating hormone (TSH) is below the reference 
range of the central laboratory, c) TSH is above the reference range of the central laboratory 
which necessitates the initiation of treatment or if the treatment is already given it is deemed 
insufficient by the Investigator considering the age of the participant. 
10. Participant has a history (within 5 years prior to Screening) and/or current 
hypoparathyroidism or hyperparathyroidism other than clinically not significant secondary 
hyperparathyroidism. 
11. Participant has had major surgery within 8 weeks prior to the Screening Period or planned, 
anticipated major surgery during the study. 
12. Participant has malignancy within 5 years before Screening (except completely cured in situ 
cervical carcinoma or non-metastatic squamous or basal cell carcinoma of the skin). 
13. Participant has a history and/or presence of significant cardiac disease or ECG abnormalities 
indicating significant risk for participating in the study as judged by the Investigator. 
14. Participant has a known intolerance or malabsorption of calcium or vitamin D supplements. 
15. Participant has a known hypersensitivity (including severe allergic reaction) to monoclonal 
antibodies or a history of systemic hypersensitivity to any components of the IMPs. 
16. Participant shows contraindications to denosumab therapy (e.g., hypocalcaemia), or calcium 
or vitamin D supplementation before starting IMP administration. 
17. Participant has a latex allergy. 

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18. Participant has a history and/or presence of ONJ or risk factors for ONJ such as heavy 
smoking, invasive dental procedures without complete healing or planned during the study 
(e.g., tooth extraction, dental implants, oral surgery), planned radiotherapy to head and neck, 
poor oral hygiene, poor fitting dentures, periodontal, and/or pre-existing dental disease 
checked as required by local guidelines and if deemed to be at unacceptable risk for 
denosumab use by the Investigator. 
19. Participant has history and/or presence of osteonecrosis of the external auditory canal. 
Prior/Concomitant Therapy 
20. Participant requiring ongoing use of any osteoporosis treatment (other than calcium and 
vitamin D supplements). 
21. Participant has previously received denosumab or biosimilar denosumab. 
22. Participant has previously received the following medicines: 
a. Romosozumab (dose received at any time). 
b. Cathepsin K inhibitors (dose received at any time). 
c. Strontium or fluoride (for osteoporosis) (dose received at any time). 
d. Any investigational medicinal product not specified in the protocol for treatment of 
osteoporosis (dose received at any time). 
e. Intravenous bisphosphonates (dose received within 5 years prior to the Screening Period). 
f. Oral bisphosphonates (more than 3 years of cumulative use prior to the Screening Period 
or any dose received within 1 year prior to the Screening Period). 
g. Teriparatide, abaloparatide or any parathyroid hormone (PTH) analogues (dose received 
within 1 year prior to the Screening Period). 
h. Tibolone, oral or topical (e.g., transdermal, intravaginal) oestrogen, antioestrogens, 
selective oestrogen receptor modulators (SERMs) and aromatase-inhibitors (dose 
received within 1 year prior to the Screening Period). 
i. Calcitonin or its derivates and calcimimetics (such as cinacalcet or etelcacetide) (dose 
received within 6 months prior to the Screening Period). 
j. Systemic glucocorticosteroids (≥ 5 mg prednisone or equivalent per day for ≥ 10 days or 
a total cumulative dose of ≥ 50 mg) within the past 3 months prior to the Screening 
Period.  Topical and inhaled glucocorticosteroids are allowed. 

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k. Other bone active drugs including heparin (also low molecular weight heparins), 
vitamin K (supplementation or therapeutic dose), vitamin K antagonists (e.g., warfarin, 
acenocumarol), emtricitabine, tenofovir, adefovir, anti-convulsants (with the exception of 
benzodiazepines, gabapentin and pregabalin), systemic ketoconazole, adrenocorticotropic 
hormone (ACTH), lithium, protease inhibitors, gonadotropin-releasing hormone (GnRH) 
agonists or anabolic steroids within the past 3 months prior to the Screening Period. 
Prior/Concurrent Clinical Study Experience 
23. Participant is receiving or has received any investigational drug (or is currently using an 
investigational device) within 3 months before receiving IMP, or at least 10 times the 
respective elimination half-life (whichever period is longer). 
Diagnostic Assessments 
24. Participant has weight or girth measurements which may preclude accurate DXA 
measurements in Investigator’s opinion. 
25. Participant has inadequate renal and hepatic function at the Screening Period defined as 
patient on dialysis or estimated glomerular filtration rate (eGFR) < 30 mL/min (calculated 
using the modification of diet in renal disease [MDRD] formula) and alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 ×upper limit of normal 
(ULN) or total bilirubin ≥ 1.5 ×ULN (except in Gilbert’s syndrome, where the total bilirubin 
is accepted if ≤ 2.5 × ULN). 
26. Participant presents with clinically significant leukopenia, neutropenia or anaemia as judged 
by the Investigator; the assessment may be repeated once if the condition is deemed to be 
temporary by the Investigator. 
27. Participant has an active infection, including, but not limited to SARS-CoV-2, 
hepatitis B/hepatitis B surface antigen (HBsAg) positivity and/or participant who has 
anti-hepatitis B core antigen (HBcAg) positivity with anti-HBsAg negativity, hepatitis C and 
human immunodeficiency virus infections during the Screening Period. 
Other Exclusions 
28. Current or past alcohol or drug abuse. 
29. Any other clinically significant disorder/condition/disease or laboratory abnormality that in 
the opinion of the Investigator would pose a risk to participant safety or interfere with the 
study evaluation, procedures or completion. 

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30. Participant is pregnant at Screening or does not agree to not breastfeed starting at Screening 
and throughout the study period and for 5 months after final study treatment administration. 
Participant meeting the following criteria must not be enrolled in the Transition Period: 
31. Treatment continuation in the study is against the best interest of the participant as deemed 
by the Investigator. 
5.3 Lifestyle Considerations and Restrictions 
1. Participant must have blood samples taken for each PD analysis (bone turnover markers 
[serum type I collagen C-telopeptide (sCTX) and procollagen type 1 N-terminal propeptide 
(P1NP)]) after a minimum of 8 hours fasting.  During the pre-visit phone call participants 
will be reminded of fasting conditions for blood analysis (as applicable). 
2. Blood for PD sampling must be collected in the morning between 07:30 and 10:00 am. 
3.  Participants should refrain from extensive physical exercise for 24 hours before each blood 
collection for PD analysis. 
4. On the day of Baseline PD assessment (Treatment Period 1, Day 1 [Week 0]), calcium should 
not be given before the PD blood sampling. 
5. Participants are encouraged to maintain good oral hygiene and receive routine dental 
check-ups.  During the study treatment phase invasive dental procedures should be 
performed only after careful consideration (if required for AE/SAE management). 
6. Participants should seek prompt medical attention if they develop signs or symptoms of OJN, 
hypocalcaemia, infections, dermatological reaction or hypersensitivity. 
7. Participants are encouraged to adhere to country level and/or local COVID-19 regulations for 
prevention and monitoring of pandemic.  The guidance from Competent Authorities may 
continue to evolve, Investigators are encouraged to check for updates regularly and provide 
participants with appropriate instructions.  Please see Section 2.2.1 and Appendix 4 
(Section 10.4) for additional information. 
5.4 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomised.  Eligible but surplus participants will not be screen failures.  A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities.  Minimal information 

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includes demography, reason for screen failure (e.g., eligibility requirements failed), and any 
SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
considered for rescreening, only once, unless participants screen fail due to safety reasons which 
are significant and not likely to resolve, or if participation in the study would unacceptably 
jeopardise the safety of the participant as deemed by the Investigator.  In all cases without 
exception the rescreening is conditional upon approval of the Medical Monitor i.e., prior to 
rescreening, the Investigator must contact the Medical Monitor to discuss the rescreening on a 
case-by-case basis.  All screening procedures will be repeated during rescreening with the 
following exceptions: DXA, if it is within 5 weeks of the initial scan and lateral spine X-ray, if it 
is within 3 months of the initial scan.  In the event of rescreening the data gathered during 
rescreening should prevail. 
In the case of failure to meet criteria for vitamin D or calcium (Section 5.2, exclusion criteria 6 
and 7, respectively), vitamin D and calcium testing may be repeated (i.e., the participant is 
retested for those parameters) once during the screening period without rescreening the 
participant provided that the other criteria are met.  These retest cases will not be considered as 
rescreening. 
5.4.1 
Screening and Enrolment Log 
All screened participants will be assigned a unique enrolment number which is study specific.  
Enrolled participants who drop out of the clinical study before randomisation will retain their 
enrolment number.  The participant’s enrolment will be recorded in the Screening and Enrolment 
Log.  After enrolment, prior to dosing, participants will be randomised and receive a 
randomisation number.  Prior to dosing in Treatment Period 3, participants will be re-randomised 
and receive a second randomisation number.  Participant numbers must not be re-used for 
different participants. 

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6 Study Treatments 
Study treatment (IMP) is defined as the test product (RGB-14-P) and the reference product 
(US-sourced Prolia®), which are collectively referred to as IMP throughout the protocol.  The 
IMP is to be administered to the study participants according to the study protocol during this 
study. 
In light of the outcome of a follow-up scientific advice at the EMA, demonstration of analytical 
comparability between the US- and EU-sourced reference products serves as an adequate bridge 
allowing the Sponsor to utilise only the US-sourced reference product throughout the clinical 
development. 
6.1 Study Treatments Administered 
The study treatments that will be administered in this study are outlined in Table 6-1. 
Table 6-1 
Study Treatments Administered 
Arm Name: 
RGB-14-P 
Prolia® 
Intervention Name: 
RGB-14-P (test product) 
US-licensed Prolia® (reference product) 
Type: 
Drug 
Drug 
Dosage Formulation: 
Pre-filled syringe 
Pre-filled syringe 
Unit Dose Strength(s): 
60 mg 
60 mg 
Dosage Level(s): 
60 mg 
60 mg 
Route of 
Administration: 
Subcutaneous injection 
Subcutaneous injection 
Use: 
Experimental 
Active comparator 
IMP: 
IMP 
IMP 
Sourcing: 
Provided centrally by the Sponsor. 
Provided centrally by Parexel. 
Dosing Instructions: 
Main Period: 
On Day 1 of Treatment Period 1, prior to dosing, participants will be randomised in 
a 1:1 ratio to receive either RGB-14-P or Prolia®.  Participants will receive 
subcutaneous injection of RGB-14-P or Prolia®, into the thigh, abdomen or upper 
arm, administered on Day 1 of Treatment Periods 1 and 2 (Weeks 0 and 26). 
 
Transition Period: 
On Day 1 of Treatment Period 3 (Week 52) a subset of approximately 
66 participants in the RGB-14-P dose group will follow the randomisation procedure 
and receive one subcutaneous injection of RGB-14-P, into the thigh, abdomen or 
upper arm.  A subset of approximately 132 participants in the Prolia® dose group 
will be re-randomised to receive either one subcutaneous injection of RGB-14-P or 
Prolia® into the thigh, abdomen or upper arm. 
 
IMP will be administered in the morning. 
Device Description: 
IMP will be provided as a single-dose 
(1 mL solution) pre-filled syringe made 
from type I glass with 27 gauge needle, 
plunger stopper, staked-in needle and 
needle shield. 
IMP will be provided as a single-dose 
(1 mL solution) pre-filled syringe made 
from type I glass with 27 gauge needle, 
plunger stopper and needle shield. 

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Arm Name: 
RGB-14-P 
Prolia® 
Storage: 
IMP will be stored in a secure area at 2 to 
8°C (35.6 to 46.4°F) and in accordance 
with applicable regulatory requirements. 
IMP will be stored in a secure area at 
2 to 8°C (35.6 to 46.4°F) and in 
accordance with applicable regulatory 
requirements. 
IMP = investigational medicinal product; US = United States 
Please see Section 6.5.2 for information on calcium and vitamin D administration. 
6.1.1 
Study Treatment Devices 
6.1.1.1 
RGB-14-P 
RGB-14-P is supplied in a single-use disposable, handheld 1 mL long pre-filled syringe with a 
staked-in needle (27 gauge × ½ inch).  In order to prevent accidental needlesticks, the syringe is 
assembled with a needle guard.  Further information on packaging, labelling, storage, handling 
and administration of RGB-14-P can be found in the Investigator Manual.  Further description on 
the device will be provided in the Addendum to Investigator Manual. 
6.1.1.2 
Prolia® 
US-licensed Prolia® is supplied in a single-use disposable, handheld 1 mL long pre-filled syringe 
with a staked-in needle (27 gauge × ½ inch).  In order to prevent accidental needlesticks, the 
syringe is assembled with a needle guard.  Further information on packaging, labelling, storage, 
handling and administration of Prolia® can be found in the Investigator Manual.  Further 
description on the device will be provided in the Addendum to Investigator Manual. 
6.1.2 
Medical Device Events 
Medical device events related to Prolia® will qualify as device incidents (any malfunction or 
deterioration in the characteristics or performance of a device made available on the market, 
including use error due to ergonomic features, as well as any inadequacy in the information 
supplied by the manufacturer and any undesirable side-effects).  Medical device events related to 
RGB-14-P will qualify as device deficiencies (any inadequacy in the identity, quality, durability, 
reliability, safety or performance of an investigational device, including malfunction, use errors 
or inadequacy in information supplied by the manufacturer). 
Information on a device incident or device deficiency (e.g., needle broken, dose not administered 
properly, syringe condition problem) will be reported in the Product Complaint Form by 
unblinded site staff.  The Addendum to Investigator Manual and Product Complaint Form should 
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device events are described in the Addendum to Investigator Manual and the Product Complaint 
Procedure. 
Device incident or device deficiency that cause site staff related injury will be reported in the 
Product Complaint Form by unblinded site staff as it is described in the Addendum to 
Investigator Manual and the Product Complaint Procedure. 
Adverse events and SAEs caused by device incident or deficiency should be collected and 
reported in the electronic case report form (eCRF) according to Safety Procedures (see 
Sections 8.5 and 10.3), in addition, a Product Complaint Form should be completed and reported 
by unblinded site staff as it is described in the Addendum to Investigator Manual and the Product 
Complaint Procedure. 
6.2 Preparation, Handling, Storage, and Accountability 
The Investigator or designee must maintain a log to confirm appropriate temperature conditions 
have been maintained during transit for all IMP received and any discrepancies are reported and 
resolved before use of the IMP. 
Only participants enrolled in the study may receive IMP and only authorised site staff may 
supply or administer IMP.  All IMP must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labelled storage conditions with 
access limited to the Investigator and authorised site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (e.g., receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused IMP are provided in the 
IMP handling instructions. 
6.3 Measures to Minimise Bias: Randomisation and Blinding 
6.3.1 
Randomisation 
At randomisation (Treatment Period 1, Day 1) all eligible participants will be randomised via 
Interactive Response Technology (IRT) to one of the treatment groups.  The Investigator or 
his/her delegate will contact the IRT after confirming that the participant fulfils all the 
inclusion/exclusion criteria and Parexel Medical Monitor has no objection against inclusion of 
the participant.  The IRT will assign a randomisation number and will specify a unique 
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The randomisation numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and Investigator staff.  A 
participant randomisation list will be produced by the IRT provider using a validated system that 
automates the random assignment of enrolment (participant) numbers to randomisation numbers.  
In effect there will be a separate randomisation list for each stratum (combination of 
geographical region and prior bisphosphonate use).  These randomisation numbers are lined to 
the different treatment groups, which in turn are linked to medication numbers. 
6.3.2 
Re-randomisation and Participant Subset in Transition Period 
A subset of approximately 198 participants who complete the Main Period (Treatment Periods 1 
and 2) and continue participation in Treatment Period 3, will be allocated treatment for 
Treatment Period 3 at the beginning of Treatment Period 3 via IRT in a blinded fashion.  
Enrolment during the Transition Period will be consecutive (the next eligible participant will be 
enrolled).  A subset of approximately 132 participants in the Treatment Periods 1 and 2 Prolia® 
dose group will be re-randomised in a 1:1 ratio to either transition to receive RGB-14-P in 
Treatment Period 3 or continue on Prolia®.  A subset of approximately 66 participants originally 
randomised to RGB-14-P in Treatment Periods 1 and 2 will automatically continue on 
RGB-14-P in Treatment Period 3 but this will also be performed via the IRT system to maintain 
the blind of treatment assignment (i.e., all participants in the RGB-14-P dose group will be 
re-randomised to continue on RGB-14-P during Treatment Period 3). 
Investigational medicinal product will be administered at the study visits summarised in 
Section 6.1. 
6.3.3 
Blinding and Breaking the Blind 
A double-blind design will be used during the Main and Transition Periods to avoid any bias that 
may result from the Sponsor or staff being aware of the treatment sequence assignment for an 
individual participant, e.g., assigning relationship of AEs to IMP, bioanalysis of samples, 
exclusion of bioanalytical data from the evaluation and determination of analysis populations. 
During the Main Period, all participants and site personnel (except for delegated unblinded 
pharmacy staff, unblinded healthcare professional responsible for IMP administration), Parexel 
personnel (except for the logistics team, randomisation biostatistician and unblinded monitor) as 
well as subcontracted laboratory personnel will be blinded to the study treatment.  The Sponsor, 
including the bioanalytical laboratory, will be blinded to the assignment of study treatment 
during the 12-month double-blinded phase (Main Period).  However, the Sponsor’s Clinical 
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colleagues of Total Quality Management Directorate and Regulatory Science Division Medical 
Device Experts will serve as unblinded personnel throughout the whole study for safety reporting 
purposes.  Part of Parexel’s personnel will be unblinded after database lock for the 12-month 
Main Period and as such will not be in direct contact with the sites or involved in any treatment 
decisions during the Transition Period. 
During the 6-month Transition Period, participants, investigators and blinded site staff, as well as 
Parexel personnel in direct contact with the sites will remain blinded to the treatment assignment.  
Additionally, the Sponsor operational team, including the bioanalytical laboratory, will remain 
blinded to the assignment of study treatment until database lock for the 6-month Transition 
Period. 
Since the IMP pre-filled syringes will not be blinded, the pharmacy staff and monitor responsible 
for checking IMP accountability will be unblinded.  Unblinded site staff must not perform any 
clinical assessment. 
If a device incident or device deficiency cause an AE or SAE during the study the unblinded 
study team member needs to inform the Principal Investigator without providing information 
which may disclose the treatment arm.  The unblinded team member will complete the Product 
Complaint Form and share with the unblinded clinical team at Parexel.  In any circumstances, the 
unblinded study team members should not disclose any information that may lead to unblinding 
to treatment allocation. 
If an SAE occurs during the study that meets the criteria for expedited reporting (i.e., is a 
SUSAR) as assessed by the Sponsor, the blind should be broken by Parexel Pharmacovigilance 
team on behalf of the Sponsor (after Sponsor’s approval) for that specific participant only (peek 
blind).  The blind will be maintained for persons responsible for the ongoing conduct of the 
study (such as the study management, monitors and Investigators), and those responsible for data 
analysis and interpretation of results at the conclusion of the study such as biometric personnel.  
Unblinded information will only be accessible to those who need to be involved in the safety 
reporting to regulatory authorities and Independent Ethics Committees (IECs).  Treatment codes 
will not be broken for the planned analyses of data until all decisions on the evaluability of the 
data from each individual participant have been made and documented. 
The IRT will be programmed with blind-breaking instructions.  The assignment of study 
treatment may be unblinded in emergency situation when the knowledge of the study treatment 
assignment is considered absolutely necessary for the medical management of the participant or 
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impact a treatment decision, unblinding might not be required in many cases due to the 
biosimilarity and treatment options not being different between RGB-14-P and Prolia®).  The 
Investigator has the sole responsibility for determining if unblinding of a participant’s study 
treatment assignment is warranted.  Participant safety must always be the first consideration in 
making such a decision.  The Investigator should make an effort to contact the Parexel Medical 
Monitor, if possible, prior to unblinding.  The applicable Parexel standard operating procedure 
(SOP) will be followed for blind-breaking procedures.  In case of unblinding for safety reporting 
reasons, Parexel Pharmacovigilance reporting team has an IRT system access to obtain the 
treatment for a specific participant.  In case of a medical emergency healthcare professionals 
should contact the Investigator.  If the Investigator is not available, non-study healthcare 
professional may contact the emergency call centre for urgent information about the study drug 
and may break the blind if necessary (see Section 8.1.2).  The treatment code may only be 
broken in case of emergency when knowledge of the treatment received is necessary for the 
proper medical management of the participant. 
When a participant’s study treatment assignment is unblinded, a comprehensive source note must 
be completed by unblinding the Investigator that includes the date and time, the name of the 
study personnel responsible and the reason(s) the participant’s treatment code was unblinded.  
The source note must also include a record of the discussion with the Medical Monitor.  All 
unblinding information is captured by the unblinded safety team in the safety database.  The 
safety processing team who manages SAEs as well as the SAE Reporting Form remains blinded. 
In all unblinding cases, Parexel should contact the Sponsor as soon as possible.  In addition, the 
Clinical Research Associate, Clinical Operational Lead and the Project Lead should be informed.  
Following emergency unblinding, the participant’s further participation such as safety follow-up 
examinations in the study should be discussed with the Sponsor by Parexel. 
In the event of a quality assurance audit, the auditor(s) will be allowed access to unblinded study 
intervention records at the site(s) to verify that randomisation/administration has been done 
accurately. 
Further details regarding blinding, unblinding and communication routes can be found in the 
Blinding Management Plan. 
6.4 Investigational Medicinal Product Compliance 
At the investigational sites, in order to strictly maintain the blinded design of the study, nobody, 
except the delegated unblinded pharmacy staff, unblinded healthcare professional responsible for 
IMP administration or unblinded monitor should be in contact with the IMP, that keeps the 

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blinded design of the study intact.  When participants are dosed at the site, they will receive 
study intervention under supervision from the Investigator or designee, under medical 
supervision.  The date and time of each dose administered at the chosen site of administration 
(e.g., abdomen, thigh, upper arm, etc.) will be recorded in the source documents and recorded in 
the eCRF.  The dose of IMP and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the IMP. 
At the investigational site, all activities related to the handling of IMP until administration to a 
participant should be performed by the pharmacy staff/authorised designee.  Unblinded site staff 
must not perform any clinical assessment.  This person should be assigned by the Investigator 
and be responsible for: 
• Receipt of IMP. 
• Preparation of IMP for administration. 
• Storage of IMP. 
• Dispensing of IMP. 
• Accountability and reconciliation of IMP. 
• Preparation of IMP for destruction (used, expired, not fit to use, unused after last participant 
last visit). 
For medical device events procedures see Section 6.1.2. 
6.5 Prior and Concomitant Therapy 
Medications are classified as prior if the administration stop date was before the first dose of 
IMP and as concomitant if ongoing or if started after IMP dosing. 
The use of medications listed in exclusion criteria 20, 21 and 22 (Section 5.2) should be sought 
without time frame restrictions. 
All restrictions on medications as listed in Section 6.5.1 are applicable for the entire duration of 
the study.  Other concomitant medications that the participant receives on a regular basis may 
continue, if in the opinion of the Investigator, it does not put the participant at undue risk or does 
not interfere with the study evaluations.  Concomitant medication use may be warranted for the 
treatment of AEs.  All concomitant medications necessary for the health and well-being of a 
participant will be permitted.  Any medication or vaccine (including over-the-counter or 

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prescription medicines, vitamins, and/or herbal supplements) that the participant is receiving at 
the time of enrolment or receives during the study must be recorded along with: 
• Brand name and generic/international non-proprietary names (INN) name. 
• Route of administration. 
• Reason for medication (e.g., AE, medical history, prophylaxis). 
• Indication. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
Any changes in the dosage or regimen of a concomitant medication will be recorded. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1 
Prohibited Therapy 
The medications and interventions which are listed below will be prohibited during the study 
period unless required for AE/SAE management.  If any of these prohibited therapies are applied 
the Medical Monitor should be contacted to discuss whether the participant may continue the 
study. 
Participants must abstain from the use of the following concomitant treatment: 
• Any osteoporosis treatment (other than calcium and vitamin D supplements). 
• Products containing denosumab (e.g., Xgeva®) or biosimilar denosumab. 
• Romosozumab. 
• Cathepsin K inhibitors. 
• Strontium or fluoride (except topical use in toothpaste). 
• Intravenous or oral bisphosphonates. 
• Teriparatide, abaloparatide or any PTH analogues. 
• Tibolone, oral or topical (e.g., transdermal, intravaginal) oestrogen, antioestrogens, SERMs 
and aromatase-inhibitors. 
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• Systemic glucocorticosteroids (≥ 5 mg prednisone or equivalent per day for ≥ 10 days or a 
total cumulative dose of ≥ 50 mg).  Topical and inhaled glucocorticosteroids are allowed. 
• Other bone active drugs including heparin (also low molecular weight heparins), vitamin K 
(supplementation or therapeutic dose), vitamin K antagonists (e.g., warfarin, acenocumarol), 
emtricitabine, tenofovir, adefovir, anti-convulsants (with the exception of benzodiazepines, 
gabapentin and pregabalin), systemic ketoconazole, ACTH, lithium, protease inhibitors, 
GnRH agonists, anabolic steroids. 
• Invasive dental procedures (e.g., dental implants or oral surgery) and major surgeries or bone 
surgeries (unless required for AE/SAE management after careful consideration) will be 
prohibited during the study period. 
See Section 5.2 for specific restrictions on prohibited medications. 
6.5.2 
Additional Study Treatments 
According to the Prolia® USPI [3] and as indicated in the IB [1], as precautionary measure for 
denosumab use, all participants should have an adequate intake of calcium and vitamin D.  
Therefore, at latest from the first day of IMP dosing until the End-of-Study/Early Termination 
Visit all participants must take at least 1000 mg of calcium and at least 800 IU of vitamin D or 
calcitriol daily.  Once weekly or monthly administration of higher vitamin D dose is allowed if 
this is the local practice and preference, but the average daily 800 IU should be achieved.  Higher 
starting and maintenance doses of vitamin D and calcium supplementation are also permitted, 
especially for participants with serum vitamin D level in the lower range.  Elemental calcium 
should be taken into consideration for calculation of the calcium dosage.  Calcium and vitamin D 
will be provided locally by the study site. 
Compliance with daily calcium and vitamin D intake will be monitored and assessed throughout 
the study. 
If hypercalcaemia or hypocalcaemia occurs, the Investigator can modify the dietary intake of 
calcium and adjust the calcium and/or vitamin D dosage if needed, according to local practice.  
The change should be reported in the eCRF and hypercalcaemia or hypocalcaemia should be 
reported as an AE if clinically significant. 
Intolerance to non-IMP may occur, especially for calcium.  Calcium intolerance can manifest as 
bloating or constipation.  The formulation and/or dose frequency (e.g., dose divided twice daily) 
can be changed to reduce intolerance and increase compliance at the Investigator’s discretion.  If 
intolerance continues after lowering the dose, temporary discontinuation may be considered.  

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Permanent discontinuation of calcium and/or vitamin D should be discussed with the Medical 
Monitor in the CRO and should be documented in the source data. 
6.6 Dose Modification 
Not applicable. 
6.7 Intervention After the End of the Study 
Discontinuation of treatment with denosumab has been associated with a rebound increase in 
bone turnover accompanied by rapid bone loss and subsequent increase in the risk of fractures, 
including multiple vertebral fractures, therefore administration of denosumab should not be 
delayed or stopped without transitioning the participant to another antiresorptive agent 
(e.g., bisphosphonates, hormone replacement therapy or SERMs) or in some cases other therapy 
may also be considered [15].  Consequently, the Investigator must ensure that in line with the 
local guidelines appropriate follow-up osteoporosis treatment is prescribed to all participants 
upon conclusion of the therapy with the study drug either due to early termination or upon 
completion of the study at 12 or 18 months.  The subsequent treatment options will be discussed 
with the participant either at the Early Termination Visit or at the End-of-Study Visit and should 
be clearly documented in the source data. 

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7 Discontinuation of Investigational Medicinal Product and Participant 
Discontinuation/Withdrawal from the Study 
7.1 Discontinuation of Investigational Medicinal Product, Participant 
Discontinuation/Withdrawal from the Study 
It may be necessary for a participant to discontinue IMP.  If IMP is discontinued, the participant 
may remain in the study to be evaluated, unless the participant withdraws consent, or it is against 
the participant’s best medical interest or does not serve the well-being of the participant as 
deemed by the Investigator or Sponsor. 
Participants will discontinue IMP if any of the following events occurs: 
• Adverse drug reactions of grade 3 or 4 severity including but not limited to: 
o 
Drug-related hypersensitivity, anaphylactic reaction 
o 
Osteonecrosis of the jaw, osteonecrosis of the external auditory canal 
o 
Atypical femoral fracture 
• Any relevant AE or SAE, if the Sponsor or Investigator deems it as medical reason to warrant 
IMP discontinuation.  The Investigator must notify the Medical Monitor immediately if a 
participant discontinued the IMP because of an AE/SAE. 
• Participant is pregnant or breastfeeds, see Section 8.5.5. 
• Unsatisfactory therapeutic effect of the IMPs or disease progression (e.g., decrease of BMD 
or new osteoporotic fracture) that requires change of osteoporosis treatment, agreed by the 
Investigator. 
If a participant experiences BMD reduction of ≥ 5% from baseline at the total hip, femoral 
neck and/or the lumbar spine at any time during the study, the Investigator is required to 
explore if factors other than postmenopausal osteoporosis, such as non-compliance with 
vitamin D/calcium supplementation or secondary causes of osteoporosis could contribute to 
the BMD decrease, discuss implications for individual fracture risk, alternative treatment 
options and options for continuing in the study with the participant, and to document that 
discussion.  If a decision is made to begin alternative treatment, the IMP must be 
discontinued.  Please refer to Section 6.7 for details on the transition to another osteoporosis 
treatment at the conclusion of IMP therapy. 
• Prohibited concomitant medication, unless a written confirmation is provided by the Sponsor 
that the participant may continue taking the IMP. 

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• Following emergency unblinding. 
• At the discretion of the Investigator or Sponsor any circumstances that could prevent the 
participant to comply with the protocol requirements and study objectives. 
• Withdrawal of consent.  A participant may withdraw from the study at any time at her own 
request without giving any reasons. 
If discontinuation of IMP or withdrawal of consent occurs, the Investigator should make effort to 
understand the primary reason for the participant’s premature discontinuation or withdrawal of 
consent and record this information. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  If a participant 
withdraws from the study, she may request destruction of any samples taken and not tested, and 
the Investigator must document this in the study site records. 
Every case of early discontinuation from study treatment should be discussed with the Medical 
Monitor and all reasonable effort should be made to retain the participant until all remaining 
study procedures are completed, except IMP administration until Week 52.  If the participant 
opts not to continue with the completion of all remaining study procedures until Week 52, all 
reasonable effort should be made to complete the End-of-Study/Early Termination procedures as 
shown in the SoA (Table 1-1 and Table 1-2).  Refer to the SoA (Table 1-1 and Table 1-2) for 
assessments to be done at the time of study discontinuation or early withdrawal. 
7.2 Loss of Participants to Follow-Up 
A participant 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 participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined) and counsel the participant on 
the importance of maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
• In cases in which the participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 telephone 
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local equivalent methods).  These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, she will be considered to have withdrawn 
from the study. 

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8 Study Assessments and Procedures 
Study procedures and their timing are summarised in the SoA (Table 1-1 and Table 1-2).  
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue IMP. 
Adherence to the study design requirements, including those specified in the SoA (Table 1-1 and 
Table 1-2), is essential and required for study conduct.  The criteria for the assessment and 
reporting of protocol deviations will be stipulated in a separate study-specific protocol deviations 
specifications document. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria.  The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
A summary blood log including volume as well as instruction for all sample collection, 
processing, storage and shipment information will be available in the Laboratory Manual. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.  In the case of repeated measurements, the new results and the reason for repeat must be 
documented in the eCRF.  Investigators and site staff should make reasonable effort to 
understand the reason for missing data and document it in the source data and eCRF.  This 
requirement will be part of the Investigators’ training and site staff will be re-trained in case of 
noncompliance. 
8.1 Administrative Procedures 
8.1.1 
Informed Consent 
Informed consent must be documented according to Appendix 1 (Section 10.1.3). 
8.1.2 
Participant Identification and Visit Reminder Card 
All participants will be given a participant identification card identifying them as participants in 
a research study.  The card will contain study site contact information (including direct telephone 
numbers) to be used in the event of an emergency.  The Investigator or qualified designee will 
provide the participant with a participant identification card immediately after the participant 
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personnel will add the intervention/randomisation number to the participant identification card.  
At each visit participants will be provided with a participant identification and visit reminder 
card.  The Investigator must update the visit reminder card at each visit with the details for the 
next visit. 
The participant identification card also contains contact information for the emergency 
unblinding call centre so that a healthcare provider can obtain information about IMP in 
emergency situations where the Investigator is not available. 
8.2 Screening and Eligibility Assessments 
8.2.1 
Eligibility Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or designee to ensure 
that the participant qualifies for the study. 
The Investigator or designee must enter all screening data in the electronic data capture (EDC) 
system in a timely manner to allow the Parexel Medical Monitor to review eligibility data before 
participant is randomised.  Only after Medical Monitor approval (i.e., there is no objection 
against inclusion of the participant), the Investigator or his/her delegate may contact the IRT. 
8.2.2 
Demography 
Demographic data will be collected including age, gender, race and ethnicity as allowed by the 
local regulations. 
8.2.3 
Medical and Surgical History 
Medical history and surgical history will be obtained by the Investigator or qualified designee.  
The medical history will collect all active conditions and any prior condition.  The medical 
history will also include fracture history and active healing fracture assessment by Investigators.  
The medical history will be documented in the source documents and eCRF. 
8.2.4 
Prior and Concomitant Medications Review 
The Investigator or qualified designee will review prior medication use in order to verify that the 
eligibility criteria are met and record those medications, including bone-specific medications, 
taken by the participant prior to the Screening Period. 

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Medications are classified as prior if the administration stop date was before the first dose of 
IMP and as concomitant if ongoing or if started after IMP dosing.  The use of medications listed 
in exclusion criteria 20, 21 and 22 (Section 5.2) should be sought without time frame restrictions. 
The Investigator or qualified designee will record concomitant medication, if any, taken by the 
participant during the study until the End-of-Study/Early Termination Visit (or longer if related 
to an SAE). 
8.2.5 
Screening Assessment 
Participants who have signed the informed consent will undergo the following procedures and 
assessments: 
• Height, without shoes (cm). 
• Body weight, without shoes (kg). 
• Body mass index (kg/m2) to be calculated. 
• History and current use of alcohol and/or drugs and tobacco products. 
• Medical and surgical history. 
• Physical examination (including oral cavity and dental health). 
• Examine for any signs and/or symptoms of any acute or chronic infections including 
COVID-19. 
• Vital signs. 
• 12-lead ECG. 
• Clinical laboratory tests including haematology, clinical chemistry, urinalysis and viral 
serology. 
• Prior medication. 
• Medical occurrence (AEs), if any, since the time of signing the ICF. 
• Review of inclusion and exclusion criteria. 
• Review of lifestyle restrictions. 
• Dual energy X-ray absorptiometry assessment (see Section 8.3.1). 
• Lateral spine X-ray (see Section 8.3.2). 

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The Screening visit may be conducted over the Screening period (i.e., more than 1 day can be 
utilised for Screening during the Screening period), if necessary, for logistical reasons. 
8.2.6 
Recommended Order of Assessments 
The following recommended order will be in effect when more than one assessment is required 
at time point, please also see to the SoA (Table 1-1 and Table 1-2): 
• 12-lead ECG. 
• Vital signs: 
o Blood pressure. 
o Body temperature. 
• Blood sampling for sCTX/P1NP. 
• Blood sampling for immunogenicity and serum drug concentration assessment. 
• Blood sampling for safety assessment. 
• Urinalysis. 
• Physical examination and other assessment. 
8.3 Efficacy Assessments 
8.3.1 
Dual Energy X-ray Absorptiometry Measurement 
Dual energy X-ray absorptiometry measurements will be used to confirm participant eligibility 
and to determine the change in BMD as indicated in the SoA (Table 1-1 and Table 1-2).  If the 
participant withdraws from the study early a measurement during the Early Termination Visit 
will not be required if the previous measurement was taken within 5 weeks prior. 
For all participants bone density will be measured at the lumbar spine, total hip and femoral 
neck.  The lumbar spine scan must include L1 through L4 vertebrae.  To be eligible for 
participation in the study, a participant must have a BMD consistent with a T-score ≤ -2.5 and 
≥ -4.0 at the lumbar spine and at least 2 evaluable lumbar vertebrae during the Screening Period 
as confirmed by central independent review.  For total hip and proximal femur, the left side 
should be used for all DXA scans at all study visits.  If the right side must be used (e.g., due to 
implants) or is inadvertently used at Baseline, then it must be consistently used throughout the 
study. 

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The same DXA scanner should be used for all study procedures for a particular participant at 
each site.  All DXA scans must be submitted to and analysed centrally by Parexel. 
Detailed instructions on DXA scan acquisition can be found in the separate Image Acquisition 
Guideline. 
8.3.2 
Lateral Spine X-ray 
Lateral spine X-ray assessment will be used to confirm participant eligibility and to determine 
the change in bone imaging/occurrence of fractures from Baseline as indicated in the SoA 
(Table 1-1 and Table 1-2).  Semi-quantitative assessment using Genant scoring method of 0 – 3 
for presence and severity of vertebral fractures (0 = normal, 1 = mild, 2 = moderate, 3 = severe) 
will be used [16].  The responsibility of other (e.g., incidental findings) analyses of the lateral 
spine X-ray, which are out of the scope of the central assessment (i.e., vertebral fracture 
assessment with Genant scoring method), remains with the Investigator.  If the participant 
withdraws from the study early an image during the Early Termination Visit will not be required 
if the previous image was taken within 5 weeks prior.  All X-rays must be submitted to and 
analysed centrally by Parexel. 
Detailed instructions on lateral spine X-ray can be found in the Image Acquisition Guideline. 
8.3.3 
Fracture Assessment 
Fracture rates (the incidence of vertebral and non-vertebral fragility fractures) will be monitored 
and assessed as a secondary efficacy endpoint throughout the study.  In addition, any fracture 
(symptomatic and asymptomatic) that occurs during the study will be recorded as an AE (see 
Section 8.4).  Fragility fractures are fractures that occur as a result of “low energy trauma”, often 
from a fall from standing height or less, that would not normally result in a fracture. 
8.3.3.1 
Vertebral Fracture 
Information on vertebral fractures will be centrally evaluated through the lateral thoraco-lumbar 
spine X-ray (see Section 8.3.2) scheduled as indicated in the SoA (Table 1-1 and Table 1-2).  For 
central assessment of vertebral fractures by lateral spine X-ray, a visual semiquantitative grading 
scale will be used [16] and further defined in the Independent Review Charter.  Details on the 
X-rays acquisition requirements are provided in the Image Acquisition Guideline. 
8.3.3.2 
Non-vertebral Fracture 
The diagnosis of non-vertebral fractures will not require central X-ray reading and will be based 
on local radiological reports. 

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8.4 Safety Assessments 
Safety assessment will consist of the regular monitoring of haematology, clinical chemistry, 
urinalysis, ECG, regular measurements of vital signs, physical examinations, injection site 
reactions and fracture assessment (see Section 8.3.3) as well as monitoring and recording of all 
AEs and SAEs.  Any fracture (symptomatic and asymptomatic) that occurs during the study will 
be recorded as an AE.  Consequently, any new or worsening fracture reported after central 
reading of lateral spine X-ray should be documented as an AE by the Investigator.  Severity of 
vertebral fractures will be defined and reported using the Genant score (i.e., 1 = mild, 
2 = moderate, 3 = severe).  Planned time points for all safety assessments are provided in the 
SoA (Table 1-1 and Table 1-2). 
8.4.1 
Physical Examinations 
A comprehensive physical examination will be performed as outlined in the SoA (Table 1-1 and 
Table 1-2) and will include assessments of general appearance and review of systems (head, 
eyes, ears, nose, mouth/oral cavity/throat/neck, thyroid, lymph nodes, dermatologic, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurological systems). 
At all other visits physical examination might be performed as per the Investigator’s discretion. 
Height and weight will also be measured and recorded and body mass index (BMI) will be 
calculated.  Height will be measured without shoes at the Screening Period and at all timepoints 
when BMI is measured.  Weight will be measured as outlined in the SoA (Table 1-1 and 
Table 1-2) in light clothes and without shoes. 
8.4.2 
Vital Signs 
Body (axillary, forehead or tympanic) temperature will be measured, pulse and blood pressure 
will be assessed as outlined in the SoA (Table 1-1 and Table 1-2).  Respiratory rate to be 
assessed at the discretion of the Investigator. 
Systolic and diastolic blood pressure and pulse measurements will be assessed after the 
participant has been sitting for at least 5 minutes with back supported and both feet on the floor, 
using a validated device.  All blood pressure measurements should be performed on the same 
arm, as much as possible. 
When timepoint for procedures overlap, it is recommended that vital signs are to be collected 
before blood sample collection. 

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8.4.3 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (Table 1-1 and Table 1-2) after 
10 minutes rest in supine position using an ECG machine. 
According to the Prolia® label, rarely, patients receiving Prolia® may develop hypocalcaemia, 
which may also lead to QT prolongation. 
Safety ECGs will be reviewed and interpreted on-site by the Investigator.  Abnormalities in an 
ECG will be assessed as “clinically significant” or “not clinically significant”. 
8.4.4 
Clinical Safety Laboratory Assessments 
Refer to Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to 
the SoA (Table 1-1 and Table 1-2) for the timing and frequency. 
A central laboratory will be used to measure laboratory parameters that are to be listed in the 
clinical study report.  All blood samples will be obtained by venepuncture. 
Full instruction for collection, aliquoting, labelling, processing, storage and shipment of samples 
will be provided in the Laboratory Manual.  The actual date and time (24-hour clock time) of 
blood sampling will be recorded.  Any deviation in the storage conditions and sample processing 
defined in the Laboratory Manual should be reported to the central laboratory analysing the 
samples and to the Clinical Research Associate. 
Sites will perform a urine dipstick (all dipstick results should be reported in the eCRF).  In case 
of abnormal results, a urine sample may be sent to the central lab for full analysis if deemed 
necessary by the Investigator.  See Appendix 2 (Section 10.2). 
The Investigator will evaluate the clinical relevance of each laboratory value outside of the 
reference range.  This evaluation will be based upon the nature and degree of the observed 
abnormality.  Any abnormal clinical laboratory test result (haematology, clinical chemistry or 
urinalysis) that worsen from baseline and is considered to be clinically significant in the medical 
and scientific judgement of the Investigator are to be recorded as AEs or SAEs.  Additionally, 
abnormal laboratory values that induce clinical signs or symptoms or that require therapy must 
also be recorded as AEs in the eCRF. 
In case of an abnormal result, the Investigator may consider repeating the test once in order to 
rule out laboratory error.  Unscheduled laboratory assessments may be obtained at any time 
during the study upon Investigator’s discretion. 

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Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or AEs as appropriate. 
8.4.4.1 
Hypocalcaemia 
Clinical monitoring of calcium level and vitamin D will be performed as indicated in the SoA 
(Table 1-1 and Table 1-2).  Hypocalcaemia (albumin-adjusted serum calcium < 2.1 mmol/L 
[< 8.4 mg/dL]) must be corrected by adequate supplementation of calcium and vitamin D before 
initiating treatment and administration of IMP. 
According to local guideline or practice and upon the discretion of the Investigator, (preferably 
albumin-adjusted) serum calcium level may be measured prior to the administration of IMP or at 
any timepoint at local laboratory.  The results, as well as the lower and upper limit of normal 
value of (albumin-adjusted) serum calcium at the local laboratory should be documented in the 
eCRF.  Clinically significant abnormal values should be reported as an AE.  However, for clinical 
study report purposes the values from the central laboratory will be considered. 
In the case of hypocalcaemia, the following procedures should be followed: 
• Temporarily withhold IMP dosing. 
• Upon Investigator’s discretion, perform a physical examination or additional assessments, 
e.g., ECG. 
• Administer additional calcium as per Investigator’s discretion (see Section 6.5.2) as deemed 
acceptable as per local guidelines or practice. 
• Repeat albumin-adjusted serum calcium test as many times as deemed appropriate, until 
hypocalcaemia resolves. 
• Continue with study treatment only if hypocalcaemia is resolved and is not contraindicated 
any more. 
• Contact the Medical Monitor if additional information is required. 
8.4.5 
Local Tolerance (Skin Examination) 
A local tolerance (skin examination) assessment will be done by the Investigator as indicated in 
the SoA (Table 1-1 and Table 1-2).  On dosing days, injections site reaction assessment should 
be done predose (i.e., for exclusion of a pre-existing, not IMP injection induced condition) and 
approximately 1 hour postdose, during this 1 hour period (i.e., from dosing to the injection site 
assessment) the participant will stay in the clinic for general safety observation.  Any further 
assessment of the injection site or prolonged observation of the participant may be done at the 

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discretion of the Investigator.  The grading of severity of each injection site reaction will be 
based on the Common Terminology Criteria for Adverse Events (CTCAE) v 5 criteria included 
in Table 8-1.  Injection site reactions with a grading of ≥ 1 will be recorded as an AE. 
Table 8-1 
Common Terminology Criteria for Adverse Events Injection Site 
Reaction Grading 
Grade 
Reaction 
Grade 1 
Tenderness with or without associated symptoms (e.g. warmth, erythema, itching) 
Grade 2 
Pain, lipodystrophy, edema, phlebitis 
Grade 3 
Ulceration or necrosis, severe tissue damage, operative intervention indicated 
Grade 4 
Life-threatening consequences, urgent intervention indicated 
Source: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf 
8.5 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3).  The definitions of 
AEs and SAEs caused by device incident (Prolia®) or device deficiency (RGB-14-P) can be 
found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorised representative).  Information on device 
incident/deficiency will be reported in the Product Complaint Form by unblinded site staff (see 
Section 6.1.2).  Device incident or device deficiency that cause site staff related injury will be 
reported in the Product Complaint Form by unblinded site staff as it is described in the 
Addendum to Investigator Manual and the Product Complaint Procedure. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up AE, considered related to the IMP or the study, or that caused the participant to discontinue 
the IMP (see Section 7).  In order to fulfil regulatory obligations, the Investigator is responsible 
for the documentation of any AEs or SAEs (whether or not caused by a device 
incident/deficiency) that occur during the study. 
8.5.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
All AEs and SAEs will be collected from the signing of ICF until the End-of-Study or Early 
Termination Visit at the time points specified in the SoA (Table 1-1 and Table 1-2) or anytime 
during the study. 

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All SAEs including, but not limited to SAEs caused by device incidents/deficiencies, will be 
recorded and reported to Parexel within 24 hours of it being available, as indicated in Appendix 
3 (Section 10.3).  The Investigator will submit any updated SAE data to Parexel within 24 hours 
of it being available. 
In addition, all AEs caused by device incidents/deficiencies are to be reported as AEs following 
the same reporting periods and procedures as all study AEs.  Further details regarding device 
incident or device deficiency AEs can be found in Appendix 3 (Section 10.3). 
Any adverse effect on health or safety, any life-threatening problem or death caused by, or 
associated with the devices needs to be recorded in the eCRF and reported as it is defined in the 
SAE processing procedure, the Addendum to Investigator Manual and the Product Complaint 
Procedure. 
Investigators are not obliged to actively seek AEs or SAEs after the conclusion of study 
participation.  However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the IMP or study participation, the Investigator must promptly notify the 
Sponsor. 
8.5.2 
Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.5.3 
Follow-up of Adverse Events and Serious Adverse Events 
All participants with AE/SAEs that occur during the study will be treated according to daily 
clinical practice.  After the initial AE/SAE report, the Investigator is required to proactively 
follow each participant at subsequent visits/contacts.  All AE/SAEs (caused by device 
incidents/deficiencies or not) will be followed until resolution (i.e., recovery or evident trend 
towards recovery, recovery with sequalae), stabilisation or until the condition determined to be 
chronic or permanent, or the participant is lost to follow-up (as defined in Section 7.2).  Further 
information on follow-up procedures is given in Appendix 3 (Section 10.3). 

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8.5.4 
Regulatory Reporting Requirements for Serious Adverse Event 
Prompt notification (within 24 hours, see Appendix 3 [Section 10.3]) by the Investigator to 
Parexel of an SAE is essential so that legal obligations and ethical responsibilities towards the 
safety of participants and the safety of the IMP under clinical investigation are met. 
The Sponsor (Parexel on behalf of the Sponsor) has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety of an IMP under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, Institutional Review Board (IRB)/IEC, and 
Investigators. 
The Sponsor (Parexel on behalf of the Sponsor) has a legal responsibility to report, without delay 
to all Member States in which the clinical study is being conducted, including: 
1. any SAE that has a causal relationship with the investigational device, the comparator or the 
investigation procedure or where such causal relationship is reasonably possible, 
2. any device event that might have led to an SAE, if appropriate action had not been taken, if 
intervention had not occurred, or circumstances had been less fortunate, 
3. any new findings in relation to any event referred to in points 1 and 2 above. 
For all studies including those which use combination products such as RGB-14-P and Prolia®, 
Investigator safety reports must be prepared for SUSAR according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
On behalf of the Sponsor, after Sponsor’s approval, the Parexel Pharmacovigilance team shall 
report any SUSARs to the regulatory agencies and IECs, if applicable.  The Parexel 
Pharmacovigilance team shall provide the Sponsor with local regulatory reporting requirements 
related to pharmacovigilance activities.  The Parexel Pharmacovigilance team shall inform the 
Investigator in the clinical study about the occurrence of SUSARs. 
In addition, on behalf of the Sponsor, after Sponsor’s approval, the Parexel Pharmacovigilance 
team shall report any medical device incident or deficiency that qualifies for a reportable medical 
device event according to the above-mentioned criteria.  The Parexel Pharmacovigilance team 
shall provide the Sponsor with local regulatory reporting requirement related to medical devices. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from Parexel will file it along with the IB 
and will notify the IRB/IEC, if appropriate according to local requirements. 

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8.5.5 
Pregnancy 
For postmenopausal participants, pregnancy is not expected.  In the rare occurrence of 
pregnancy: 
• Details of all pregnancies in female participants will be collected after signing of the ICF. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and IMP must be discontinued. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered to be SAEs. 
As a general rule, the study medication must be discontinued, though the participant may stay in 
the study and follow the assessments, if she wishes to do so.  Each pregnancy occurring after 
signing of the informed consent must be reported to Parexel within 24 hours of learning of its 
occurrence.  Pregnancy should be recorded and reported by the Investigator to Parexel or its 
designated representative.  The pregnancy should be followed up to determine the outcome, 
including spontaneous or voluntary termination, details of the birth and the presence or absence 
of any birth defects, congenital abnormalities or maternal and/or newborn complications.  
Generally, follow-up will not be required for longer than 8 weeks beyond the actual delivery 
date.  Any termination of the pregnancy will be reported, regardless of foetal state (presence or 
absence of anomalies) or indication for the procedure. 
Pregnancy should be recorded and reported by the Investigator to Parexel or its designated 
representative.  Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study medication and any pregnancy outcomes.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  A spontaneous abortion is 
always considered to be an SAE and will be reported as such.  Any post-study pregnancy-related 
SAE considered reasonably related to IMP by the Investigator will be reported to the Sponsor or 
its designated representative.  While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 

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8.6 Treatment of Overdose 
The Sponsor does not recommend specific treatment for an overdose.  There is no experience 
with overdose in clinical studies with RGB-14-P.  Denosumab has been administered in clinical 
studies using doses up to 180 mg every 4 weeks, with no additional adverse reactions observed. 
[1]  As RGB-14-P and Prolia® are supplied in pre-filled syringes and participants will not 
self-administer the IMP, incidences of overdose are not expected. 
Accidental or intentional overdose of the intended dose of study drug requires reporting to the 
Parexel Medical Monitor within 24 hours of learning. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose in the eCRF. 
8.7 Immunogenicity Assessments 
Antibodies to denosumab (anti-RGB-14-P antibodies and anti-Prolia® antibodies) will be 
evaluated in serum samples collected from all participants according to the SoA (Table 1-1 and 
Table 1-2).  Blood samples will be collected for determination of binding anti-drug antibodies 
(ADAs) and neutralising antibodies (NAbs).  Additionally, serum samples should also be 
collected at the final visit from participants who discontinued IMP or were withdrawn from the 
study.  These samples will be tested by the Sponsor. 
Full instruction for collection, aliquoting, labelling, processing, storage and shipment of samples 
will be provided in the Laboratory Manual.  The actual date and time (24-hour clock time) of 
blood sampling will be recorded.  Any deviation in the storage conditions and sample processing 
defined in the Laboratory Manual should be reported to the central laboratory and Sponsor’s 
laboratory analysing the samples. 
Serum immunogenicity samples will be assessed for ADAs according to the following stepwise 
analytical approach: 
1. Screening analysis (assay). 
2. For those who had a positive screening result, confirmatory analysis will be done. 
3. Confirmed positive samples will be titrated. 

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4. Confirmed ADA positive samples will be analysed with neutralising assay to detect the 
neutralising potency of ADAs. 
Serum samples will be screened for ADAs and the titre of confirmed positive samples will be 
reported.  Confirmed ADA positive samples will also be analysed with neutralising assay to 
detect the neutralising potency of ADAs.  Other analyses may be performed to verify the stability 
of ADAs. 
The detection and characterisation of ADAs will be performed using validated assay methods by 
the Sponsor.  In parallel, blood samples will be collected together with the immunogenicity 
samples for determination of denosumab serum concentration to enable interpretation of the 
antibody data (Section 8.8). 
Samples may be stored for a maximum of 15 years following the last participant’s last visit for 
the study at a facility selected by the Sponsor to enable further analysis of immune responses to 
denosumab.  Samples may also be used for validation of the analytical methods and generation 
of human positive control. 
Participant confidentiality will be maintained. 
8.8 Serum Drug Concentration 
Blood samples will be collected at the time of immunogenicity sample collection for 
measurement of serum concentrations of denosumab (RGB-14-P and Prolia®) as specified in the 
SoA (Table 1-1 and Table 1-2), to support the interpretation of immunogenicity data.  These 
samples will be tested by the Sponsor. 
Full instruction for collection, aliquoting, labelling, processing, storage and shipment of samples 
will be provided in the Laboratory Manual.  The actual date and time (24-hour clock time) of 
each sample will be recorded.  Any deviation in the storage conditions and sample processing 
defined in the Laboratory Manual should be reported to the central laboratory and Sponsor’s 
laboratory analysing the samples. 
Samples collected for analyses of denosumab serum concentration may also be used to evaluate 
safety, efficacy or immunogenicity aspects that address concerns arising during or after the 
study.  Serum denosumab concentration will be determined using a validated assay method by 
the Sponsor. 

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Samples may be stored for a maximum of 15 years following the last participant’s last visit for 
the study at a facility selected by the Sponsor to enable further analysis.  Samples may also be 
used for validation of the analytical methods and generation of human positive control. 
Participant confidentiality will be maintained. 
8.9 Pharmacodynamics 
In this study PD markers such as serum P1NP and CTX will be measured and compared as 
specified at the endpoints (Section 3). 
Area under the effective curve (AUEC) after first dose until Day 183 percent change from 
Baseline (%CfB) in sCTX will be estimated as key PD parameter. 
Blood samples will be collected for measurement of serum concentrations of sCTX and P1NP as 
specified in the SoA (Table 1-1 and Table 1-2). 
Instructions for the collection and handling of biological samples will be provided by the 
bioanalytical laboratory.  Full instructions for collection, aliquoting, labelling, processing, 
storage and shipment of samples will be provided in the Laboratory Manual.  The actual date and 
time (24-hour clock time) of blood sampling will be recorded.  Any deviation in the storage 
conditions and sample processing defined in the Laboratory Manual should be reported to the 
bioanalytical laboratory analysing the samples and to the Clinical Research Associate. 
Samples collected for analyses of sCTX and P1NP serum concentration may also be used to 
evaluate safety or efficacy aspects that address concerns arising during or after the study. 
Analysis will be performed in a blinded manner.  Participant confidentiality will be maintained. 
8.10 Genetics 
Genetics are not evaluated in this study. 
8.11 Biomarkers 
Biomarkers are not evaluated in this study. 
8.12 Medical Resource Utilisation and Health Economics 
Medical Resource Utilisation and Health Economics parameters are not evaluated in this study. 

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9 Statistical Considerations 
9.1 Statistical Hypotheses 
The null hypothesis being tested is the RGB-14-P and Prolia® are not equivalent in favour of the 
alternative hypothesis that the two treatments are equivalent. 
• Efficacy estimand for EMA submission 
 
 
Where: 
μRGB: BMD mean %CfB in RGB-14-P study arm 
μProlia: BMD mean %CfB in Prolia® study arm 
δ = μRGB-14-P – μProlia 
Significance level = 0.05 (two-sided), i.e., 95% (two-sided) confidence interval (CI) to be 
contained within acceptance region. 
• Efficacy estimand for FDA submission 
Two separate hypothesis tests to be applied: 
o Non-superiority of RGB-14-P compared to Prolia® 
 
 
Significance level = 0.05 (one-sided) 
o Non-inferiority of RGB-14-P compared to Prolia® 
 
 
Significance level = 0.05 (one-sided) 
CCI
CCI
CCI
CCI
CCI
CCI

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• PD endpoint 
Null Hypothesis H0: Geometric Mean Ratio (GMR, RGB-14-P / Prolia®) not contained within 
[80.00%, 125.00%] 
Alternative Hypothesis H1: GMR (RGB-14-P / Prolia®) contained within [80.00%, 125.00%] 
Significance level = 0.05 (two-sided), i.e., 95% (two-sided) CI to be used. 
9.2 Sample Size Determination 
Approximately 434 women with postmenopausal osteoporosis are planned to be enrolled 1:1 
(217 participants per arm, including 17% drop-out) in the study to have 362 evaluable 
participants to evaluate the primary efficacy endpoint at 90% power during the Main Period.  
Participants will be stratified by previous use of bisphosphonates and geographical region. 
It is planned that 198 participants will continue to participate during the Transition Period, which 
should ensure to have 180 evaluable participants; approximately 66 participants will continue on 
the RGB-14-P arm, whereas approximately 132 participants initially assigned to the Prolia® arm 
will be re-randomised 1:1 whereby approximately 66 participants will continue to receive Prolia® 
and approximately 66 participants will be switched to RGB-14-P. 
Based on a meta-analysis of 3 different studies conducted with denosumab [11, 12, 17], sample 
size was calculated from the following parameters: 
• The primary parameter is the %CfB in lumbar spine BMD. 
• 
 
 
• The expected (true) value of the primary parameter in the reference arm is equal to 5.35. 
• The expected (true) difference between the study arms equal -0.2675 (i.e., 5% of the 
expected reference arm value); such a difference between study arms is supposed to be 
common across study strata. 
• The expected (true) common standard deviation is 3.44. 
 
 
With regards to the PD co-primary endpoint, healthy volunteer data [18] was used for the sample 
size calculations due to the lack of information on AUEC sCTX0-m6 derived from the participants 
CCI
CCI
CCI
CCI

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population.  The expected variability to the proposed PD endpoint is considered to be 
significantly lower than that of the proposed efficacy endpoint (in study NCT2053753 the 
interCV of AUEC sCTX0-m6 was approximately 28%).  Therefore, no formal sample size 
calculation was performed for AUEC sCTX0-m6. 
Calculating with a dropout rate of 1/6, 217 participants per arm are planned to be recruited in the 
planned comparative efficacy study.  Although theoretically dropout should not be applied for 
the Treatment Policy Estimand, its use in the study is supported by the uncertainty of the 
variance of the primary parameter among different estimands, and by the fact that even if all the 
2 × 217 = 434 participants are evaluable, the power will stay below 95%. 
A subset of approximately 66 participants from the RGB-14-P arm and approximately 
132 participants from the Prolia® arm (approximately 198 participants in total) will participate in 
the Transition Period, which should ensure to have 60 evaluable participants per arm: 
• Approximately 66 participants who received RGB-14-P in the Main Period will continue 
with RGB-14-P in the Transition Period; 
• Approximately 66 participants who received Prolia® in the Main Period will switch to 
RGB-14-P in the Transition Period; 
• Approximately 66 participants who received Prolia® in the Main Period will continue with 
Prolia® in the Transition Period. 
Sample size selection for the Transition Period is not driven by statistical assumptions for formal 
hypothesis testing but was based on the safety objective for this study period.  The table below 
(Table 9-1) provides the probability for a sample size (N) of 60 and 66 evaluable participants to 
observe at least 1 participant per AE, considering different frequencies of AE. 
Table 9-1 
Probability to Observe at Least One Participant with a Given Adverse 
Event 
Frequency of AE 
Probability to observe at least one participant with a given AE 
N = 60 
N = 66 
5% 
95.39% 
96.61% 
10% 
99.82% 
99.90% 
15% 
99.99% 
100.00% 
20% 
100.00% 
100.00% 
25% 
100.00% 
100.00% 
AE = adverse event 

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With 60 participants, events which occur at a frequency of 10% or more will be detected with at 
least 99% probability, while events which occur at a frequency of 5% or more will be detected 
with at least 95% probability.  It is understood that slightly increasing the number of evaluable 
participants in a range from 60 to 66, the probability of detecting events will slightly increase 
accordingly. 
9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 
Table 9-2 
Populations for Analysis 
Population  
(Analysis Set) 
Description 
ENR 
All participants who signed the informed consent form (including screening failures). 
FAS 
The FAS comprises all participants to whom the IMP has been randomised. 
PPS 
The PPS comprises a subset of the FAS. 
A participant will be completely excluded from the PPS in case of protocol deviations which 
can affect interpretability of the primary endpoint analysis. 
SAF 
The SAF consists of all participants who received at least one full or partial dose of IMP.  
Participants will be analysed according to the IMP they actually received.  A precise definition 
of “as actually received” will be added in the SAP. 
PDS 
The PDS consists of all participants in the safety population with at least one evaluable 
pharmacodynamic parameter (%CfB and AUEC) and do not have any protocol deviations that 
have a relevant impact on sCTX or serum P1NP measurements. 
IAS 
The IAS consists of all participants in the safety population who have at least one available 
immunogenicity assessment and do not have any protocol deviations that have a relevant 
impact on immunogenicity evaluations. 
AUEC = area under the effective curve; %CfB = percentage change from baseline; ENR = Enrolled Analysis Set; 
FAS = Full Analysis Set; IAS = Immunogenicity Analysis Set; IMP = investigational medicinal product; 
P1NP = procollagen type 1N-terminal propeptide; PDS = Pharmacodynamic Analysis Set; PPS = Per Protocol 
Analysis Set; SAF = Safety Analysis Set; SAP = Statistical Analysis Plan; sCTX = serum type I collagen 
C-telopeptide 
 
The roles of the Full Analysis Set (FAS) and Per Protocol Set (PPS) will be detailed in 
Section 9.4. 
9.4 Statistical Analyses 
The Statistical Analysis Plan (SAP) will be developed and finalised prior to Database Lock and 
unblinding.  Below is a description of planned statistical analyses.  Further details are presented 
in the SAP. 

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9.4.1 
General Considerations 
Continuous data will be summarised by treatment group using descriptive statistics (number, 
mean, median, standard deviation [SD], minimum and maximum).  Categorical data will be 
summarised by treatment group using frequency tables (frequency and percent). 
Unless otherwise specified, baseline will be taken as the last available assessment prior to 
randomisation.  Repeated and unscheduled assessments will be included in listing.  Except 
considered as baseline, the repeated and unscheduled assessments will not be included in the 
summaries (if the repeat was necessitated by a technical issue/e.g., incorrect sampling 
processing/i.e., there is not a result or the result is not valid because of the technical issue, the 
repeat value will be considered and included in the summaries). 
Similarity between RGB-14-P and Prolia® will be assessed based on the simultaneous success of 
hypothesis tests for all primary endpoints.  Alpha adjustment is not planned. 
Statistical tests will be two-sided and will be performed at the 5% level of significance, thus 95% 
CIs will be computed, unless otherwise stated. 
9.4.2 
Estimands 
The primary endpoint will be analysed following the framework of the estimand concept as 
detailed in the latest International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E9 (R1) addendum on estimands and sensitivity analysis 
in clinical trials to the guideline on statistical principles for clinical trials guidance.  From this 
end, efficacy analysis will be defined with terms used for the estimand concept. 
Table 9-3 
Summary of the primary and secondary estimands 
Estimands 
Primary: “Treatment Policy” 
estimand (TP) 
Secondary: “Principal Stratum” 
estimand (PS) 
Clinical Question of 
Interest 
Do RGB-14-P and US licensed Prolia® 
have a similar efficacy and a similar 
effect on BMD at the lumbar spine at 
Week 52 in females with 
postmenopausal osteoporosis regardless 
of the ICEs occurring during the Double-
Blind phase? 
Do RGB-14-P and US licensed Prolia® 
have a similar efficacy and a similar effect 
on BMD at the lumbar spine at Week 52 in 
females with postmenopausal osteoporosis 
in the Principal Stratum of participants 
who would not experience any ICEs on 
either treatment arms? 
Variable 
Percent increase in BMD from Baseline to Week 52, i.e., %CfB, is the primary study 
endpoint and is defined as: 
%CfB = (Post Baseline – Baseline) / Baseline * 100 
ICE 
ICE1: The first and/or the second dose of randomised IMP is not administered 
ICE2: The participants received other medication alongside the IMP, which affects the 
primary variable (please refer to Section 6.5.1 [Prohibited Therapy]) 
ICE Strategy 
ICE1: Treatment policy strategy will be 
applied; All follow-up is relevant to the 
Principal stratum casual estimand strategy 
will be used: Only participants who would 

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Estimands 
Primary: “Treatment Policy” 
estimand (TP) 
Secondary: “Principal Stratum” 
estimand (PS) 
clinical question, in line with the ITT-
principle. 
 
ICE2: Composite variable strategy will 
be applied; Intercurrent event is 
considered to be informative about the 
outcome, so that the responses obtained 
after ICE occurrence will be imputed 
under the null hypothesis. 
not experience either ICE if exposed to 
either treatment are relevant to the clinical 
question. 
To control the validity of the estimand 
dropout and ICE rates and reasons will be 
monitored. 
Treatments 
Test product: RGB-14-P subcutaneous injection 60 mg 
Reference product: Prolia® subcutaneous injection 60 mg 
Study Population as 
defined in Section 5 
Females with postmenopausal 
osteoporosis 
The principal stratum of females with 
postmenopausal osteoporosis who would 
not experience any ICEs on either 
treatment 
Population-level 
Summary 
Difference of means between the test and reference arms in change from baseline 
BMD: 
δ = μRGB-14-P -μProlia 
μRGB: BMD mean %CfB in RGB-14-P study arm 
μProlia: BMD mean %CfB in Prolia® study arm 
Analysed data points 
All captured data points in the FAS are 
included to the analysis. 
All captured data points in the PPS are 
included to the analysis. 
Main Estimator 
For EMA submission: 
δ will be estimated by using ANCOVA 
model (SAS PROC GLM) with the 
following factors: 
• 
Randomised treatment 
• 
Baseline BMD value 
• 
Previous use of bisphosphonates 
• 
Geographical region 
• 
Machine type 
• 
Machine type * Baseline BMD 
value interaction 
 
Missing data will be assumed to be 
MCAR and will not be imputed (see 
Section 9.4.5) 
δ will be estimated by using ANCOVA 
model (SAS PROC GLM) with the 
following factors: 
• 
Treatment 
• 
Baseline BMD value 
• 
Previous use of bisphosphonates 
• 
Geographical region 
• 
Machine type 
• 
Machine type * Baseline BMD value 
interaction 
 
In the event of missing primary endpoint, 
to help alleviate the concern on the 
uncertainty introduced by missing data 
with potential impact on the integrity of 
randomisation, the strategy analysis with 
MI will be followed (as described 
Section 9.4.5) 
For US FDA submission: 
δ will be estimated by using ANCOVA 
model (SAS PROC GLM) with the 
following factors: 
• 
Treatment 
• 
Baseline BMD value 
• 
Previous use of bisphosphonates 
• 
Geographical region 
• 
Machine type 
• 
Machine type * Baseline BMD 
value interaction 
 
In the event of missing primary 
endpoint, to help alleviate the concern on 
the uncertainty introduced by missing 

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Estimands 
Primary: “Treatment Policy” 
estimand (TP) 
Secondary: “Principal Stratum” 
estimand (PS) 
data with potential impact on the 
integrity of randomisation, the strategy 
analysis with MI will be followed (as 
described in Section 9.4.5) 
Sensitivity Estimator 
For EMA submission: 
As a sensitivity estimation for the 
primary analysis of the primary 
endpoint, missing data may be imputed 
using MI rules.  Criteria will be specified 
in the SAP, techniques proposed by 
Jakobsen et al, 2017 will be considered 
[19]. 
In case MCAR assumption appears to be 
questionable due to high amount or 
imbalanced distribution of missing data, 
relevance of the Sensitivity Estimator 
may increase. 
 
For FDA submission: 
Robustness of the main estimator will be 
assessed by using two-dimensional 
tipping point analyses allowing 
assumptions about missing outcomes in 
the two treatment arms to vary 
independently, including scenarios 
where the difference between imputed 
test and reference values is assumed to 
be beyond the predefined equivalence 
margin. Details will be provided in the 
SAP. 
Due to the parallel design, robustness of 
the estimator will be assessed by tipping 
point analysis [20]. 
ANCOVA = analysis of covariance; BMD = bone mineral density; %CfB = percentage change from baseline; 
EMA = European Medicines Agency; FAS = Full Analysis Set; FDA = Food and Drug Administration; 
ICE = intercurrent event; MCAR = missing completely at random; MI = multiple imputation; MNAR = missing 
non at random; PPS = Per Protocol Analysis Set; SAP = Statistical Analysis Plan; US = United States 
 
Descriptive analysis of the number, proportion, reasons and timing of intercurrent events 
(ICEs) will be presented. 
9.4.2.1 
Supplementary (tertiary) estimand 
The supplementary estimand of BMD %CfB at Week 52 will utilize a hypothetical ICE handling 
strategy as if the ICE did not occur, as a further, sensitive, investigation into whether differences 
in outcomes would emerge if the whole study population were fully compliant with treatment.  
Data points captured after the ICE will be left out from the FAS analysis set.  The same ICEs 
will be applied as for the primary and secondary estimands. 
Primary endpoint will be analysed by using mixed model for repeated measures (MMRM) with 
the following factors: 

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• Randomised treatment 
• Baseline BMD value 
• Previous use of bisphosphonates 
• Geographical region 
• Machine type 
• Machine type * Baseline BMD value interaction 
• Study Week 
• Study Week * Treatment interaction 
Missing data will be assumed to be missing completely at random (MCAR) and will not be 
imputed. 
9.4.3 
Primary pharmacodynamic analysis 
The individual serum concentration of sCTX and P1NP will be listed and summarised by 
treatment group at each planned sampling time using descriptive statistics.  Percent change from 
baseline (%CfB) will be derived from sCTX concentrations (100 * (postdose sCTX – baseline 
sCTX) / baseline sCTX), listed and summarised in tabular and graphical format.  Percent change 
from baseline (%CfB) of P1NP will be calculated in a similar manner. 
To evaluate the AUEC sCTX0-m6 (required as primary endpoint for EMA and secondary for 
FDA), the treatment comparison will be made using the analysis of variance (ANOVA) on 
log-transformed data.  Pharmacodynamic equivalence will be assessed if the 95% CI of the 
treatment ratio is contained within the acceptance limits of 80% to 125%. 
9.4.4 
Additional analyses 
9.4.4.1 
Efficacy 
Below secondary endpoints will be analysed descriptively: 
• Percent change from Baseline in total hip BMD at Weeks 26, 52 and 78. 
• Percent change from Baseline in lumbar spine BMD at Weeks 26 and 78. 
• Percent change from Baseline in femoral neck BMD at Weeks 26, 52 and 78. 
• Vertebral fragility fracture incidence at Weeks 52 and 78. 
• Non-vertebral fragility fracture incidence at Weeks 52 and 78. 

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9.4.4.2 
Pharmacodynamics 
Below secondary endpoints will be analysed descriptively: 
• Percent change from Baseline in serum P1NP at Weeks 4, 26, 52 and 78. 
• Percent change from Baseline in sCTX at Weeks 4, 26, 52 and 78. 
9.4.4.3 
Safety 
All safety analyses will be performed on the Safety Analysis Set. 
Safety information will be summarised with descriptive statistics when appropriate.  Tabulations 
will be provided for categorical data. 
Safety analyses will be conducted “as treated”. 
9.4.4.3.1 
Adverse Events 
Assessment of safety will be done by determining the number of participants with any AE, 
including SAE. 
Reported AE terms will be mapped to current version of Medical Dictionary for Regulatory 
Activities (MedDRA)-preferred terminology.  All reported events will appear in AE listings; 
however, only treatment-emergent adverse events (TEAEs) will be summarised.  A TEAE is an 
AE that starts or increases in severity on or after the first administration of study treatment up to 
the End-of-Study/Early Termination Visit following the last administration of study treatment. 
Safety population data sets will be used for safety analysis: 
• Adverse events will be coded according to MedDRA. 
• The occurrence of AEs or adverse reactions, SAEs or serious adverse reactions and AEs or 
adverse reactions resulting in withdrawal will be summarised and analysed in the form of a 
frequency table (number of cases, number of participants with cases and incidence). 
• The occurrence of varying severity orders of AEs or adverse reactions, SAEs or serious 
adverse reactions and AEs or adverse reactions resulting in withdrawal will be subject to 
descriptive statistical analysis in the form of a frequency table (number of cases, case and 
incidence) according to system organ class and preferred term. 
• A detailed list of various AEs or adverse reactions, SAEs or serious adverse reactions and 
AEs or adverse reactions resulting in withdrawal will be created. 

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• Listing for any device incident or device deficiency AE or SAE will be created, including but 
not limited to seriousness, outcome and action taken. 
9.4.4.3.2 
Other Safety Data 
Other safety parameters (e.g., laboratory test values, ECGs, vital signs and injection site 
assessment) will be summarised using descriptive statistics such as mean, standard deviation, 
minimum and maximum values. 
Safety Analysis Set will be used for safety analysis: 
• Changes in the clinical significance determination of laboratory indicators, ECG, physical 
examinations and local tolerance at each visit after administration and baseline test results 
will be described in the form of shift tables. 
• The laboratory indices and vital signs examinations will be subject to descriptive statistical 
analysis according to treatment arm and visit as well as changes from baseline. 
• A detailed list of laboratory indices, ECG, vital signs, clinically significant physical 
abnormalities and local tolerance will be created. 
• Number and intensity of injection site reaction. 
• Fracture assessment (details on analysis will be further described in the SAP). 
9.4.4.4 
Immunogenicity 
All immunogenicity results (ADA confirmed positive or negative, ADA titres and neutralising 
activity) will be listed and summarised by treatment group, assay type and sampling point.  The 
incidence of participants who develop binding ADAs and NAbs will be compared by visit and 
overall descriptively.  More details will be provided in the SAP. 
9.4.5 
Handling of Missing Data 
In general, if not stated otherwise, missing data will not be imputed. 
Missing BMD baseline values would lead to impossibility to include the participant in the 
statistical analysis of the primary and secondary estimand, but due to eligibility review 
performed by the Medical Monitor, the probability of this phenomenon is negligeable. 
Missing data in case of the analysis of the efficacy estimands (see Section 9.4.2) will be handled 
as follow: 
• For EMA submission, missing data will be assumed to be MCAR and will not be imputed. 

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• For FDA submission, two separate one-sided tests, i.e., a test of non-inferiority and a test of 
non-superiority, will be conducted with each alpha = 0.05 and with missing data imputed 
under the corresponding null using a multiple imputation (MI) method.  Specifically, for the 
first test, i.e., test of non-inferiority, missing values for the RGB-14-P group will be imputed 
under the corresponding 
ng 
; for the second test, 
i.e., test of non-superiority, missing values for the RGB-14-P group will be imputed under the 
corresponding 
.  Overall, RGB-14-P will be claimed 
to be equivalent to Prolia® in the event that both H0(non-inf test) and H0(non-sup test) are rejected; 
considering the use of MI, all randomized subjects will be included in the analysis. In 
addition, a sensitivity tipping point analysis will be conducted to assess the robustness of the 
results, at both week 52 and week 78. Details will be provided in the SAP. 
In the primary PD analysis participants with missing sCTX sampling at Baseline will not be 
included in the analysis of the AUEC sCTX0-m6, additionally to be included in the analysis of the 
AUEC sCTX0-m6, participants will need to have at least 6 postbaseline available results of which: 
• Results within Week 1, Week 2 and Week 4. 
• At least one available result within Week 8 and Week 12. 
• At least one available result within Week 17 and Week 21 
• Results within Week 26. 
Participants with missing results from two consecutive timepoints will not be eligible for 
analysis. 
Serum CTX concentration below the limit of quantification (BLQ) will be considered as BLQ in 
summary tables and graphically representation, including derivation of AUEC. 
9.4.6 
Other Analyses 
9.4.6.1 
Disposition of Participants 
Participants entering and completing the study will be listed and summarised using number and 
percentage. 
Participants excluded from each analysis sets will be listed including the reason for exclusion.  
Participants disposition will be summarised and will include the following information: number 
of participants randomised and dosed, number and percentage of participants completing the 
study and the number and percentage of participants who were withdrawn (including reasons for 
withdrawal).  Participants disposition will be summarised. 
CCI
CCI

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Participants discontinuations will be listed including the date of study exit, duration of treatment 
(i.e., number of IMP doses received) and reason for discontinuation.  A listing of informed 
consent response will also be presented. 
A randomisation listing will be presented which includes but is not limited to the following: each 
participant’s randomisation number, the participant’s full enrolment number, the treatment to 
which the participant has been randomised and the location of the clinical unit. 
9.4.6.2 
Protocol Deviations 
Protocol deviations will be listed by participant, reasons and timing of the deviation.  Major 
protocol deviations which are considered to impact efficacy analyses will be identified prior to 
unblinding and may lead to exclusion of participants from the PPS analysis set. 
9.4.6.3 
Demographics and Baseline Characteristics 
Demographic and anthropometric variables (age, sex, ethnicity, race, height, weight, and BMI) 
will be listed by participant.  Demographic characteristics (age, sex, ethnicity, and race) and 
anthropometric characteristics (height, weight, and BMI) will be summarised descriptively by 
calculating means, medians, quartiles minimum and maximum for continuous variable, and 
frequencies and percentages for categorical variables.  The denominator for percentages will be 
the number of participants in the safety population for each treatment arm or for all participant as 
applicable. 
Medical history data will be listed by participant including visit, description of the 
disease/procedure, MedDRA system organ class, MedDRA preferred term, start date and stop 
date (or ongoing if applicable). 
9.4.6.4 
Prior and Concomitant Medication 
Prior medications are those that started and stopped prior to the first dose of IMP.  Concomitant 
medications are those taken after dosing (including medications that started prior to dosing and 
continued after). 
Prior and concomitant medications will be listed by participant and will include the following 
information: brand name and generic/INN name, preferred term, the route of administration, 
dose, frequency, start date/time, stop date/time and indication. 
Prior and concomitant medications will be coded according to the World Health Organization 
Drug Dictionary latest version. 

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9.4.6.5 
Investigational Medicinal Product Administration 
A listing of IMP administration will be created and will include the date, time and site of 
administration. 
9.5 Interim Analyses 
No interim analysis will take place. 
9.6 Data Monitoring Committee 
Not applicable. 

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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
o Applicable ICH Good Clinical Practice (GCP) Guidelines. 
o Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC. 
o Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures. 
o Overall conduct of the study at the site and adherence to requirements of 21 Code of 
Federal Regulation (CFR), ICH GCP guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 
10.1.2 Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities.  
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 

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10.1.3 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant or 
her legally authorised representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary.  Participants or their legally 
authorised representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study centre. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date and time the written consent was obtained.  
The authorised person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most recent version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorised 
representative. 
Participants who are rescreened are required to sign a new ICF. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol.  If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB 
and signed by all participants subsequently enrolled in the study as well as those currently 
enrolled in the study. 
10.1.4 Data Protection 
Parexel and the Sponsor will take appropriate measures to ensure the processing of personal data 
and the free movement of such data are handled according to the EU General Data Protection 
Regulation 2016/679. 
All clinical study findings and documents will be regarded as confidential.  Study documents 
(protocols, IBs and other material) will be stored appropriately to ensure their confidentiality.  
The Investigator and members of his/her research team (including the IEC) must not disclose 
such information without prior written approval from the Sponsor, except to the extent necessary 
to obtain informed consent from participants who wish to participate in the study or to comply 
with regulatory requirements. 

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Participants will be assigned unique identifiers (enrolment and randomisation number) by 
Parexel.  Any participant records or datasets that are transferred to the Sponsor will contain the 
identifier only; participant names or any information which would make the participant 
identifiable will not be transferred. 
The participant must be informed that her personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that her medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 Dissemination of Clinical Study Data 
All clinical study findings and documents will be regarded as confidential.  Study documents 
(protocols, IBs and other material) will be stored appropriately to ensure their confidentiality.  
The Investigator and members of his/her research team (including the IEC) must not disclose 
such information without prior written approval from the Sponsor, except to the extent necessary 
to obtain informed consent from participants who wish to participate in the study or to comply 
with regulatory requirements. 
The anonymity of participants must be maintained.  Participants will be specified on study 
documents by their enrolment/randomisation number, initial or birth year, not by name.  
Documents that identify the participant (e.g., the signed ICF) must be maintained in confidence 
by the Investigator. 
The clinical study may be considered for publication in the scientific literature irrespective of 
whether the results of the clinical study are positive or negative (Appendix 1 [Section 10.1.9]).  
In addition, the results of clinical studies will be provided on the publicly funded websites such 
as www.ClinicalTrials.gov, www.clinicaltrialsregister.eu, in line with the applicable regulations. 
10.1.6 Data Quality Assurance 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 

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• 
All participant data relating to the study will be recorded on eCRF unless transmitted to the 
Sponsor or designee electronically (e.g., laboratory data).  The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategies (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
• 
Parexel is responsible for the data management of this study including quality checking of 
the data. 
• 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations 
or institutional policies require a longer retention period.  No records may be destroyed 
during the retention period without the written approval of the Sponsor.  No records may be 
transferred to another location or party without written notification to the Sponsor. 
• All data generated by the site personnel will be captured electronically at each study centre 
using eCRFs.  Data from external sources (such as laboratory data) will be imported into the 
database.  Once the eCRF clinical data have been submitted to the central server at the 
independent data centre, corrections to the data fields will be captured in an audit trail.  The 
reason for change, the name of the person who performed the change, together with the time 
and date will be logged to provide an audit trail. 

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• If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the EDC application.  The appropriate staff at the study site will answer queries sent 
to the Investigator.  The name of the staff member responding to the query, and time and date 
stamp will be captured to provide an audit trail.  Once all source data verification is complete 
and all queries are closed, the Clinical Research Associate will freeze the eCRF page. 
• The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual.  In addition, site personnel 
will receive training on the EDC system/eCRF. 
• After database lock, the Investigator will receive copies of their participant data for archiving 
at the investigational site.  The data will also be extracted and provided to the Sponsor. 
• Monitoring visits at site might be limited to a minimum required as deemed appropriate 
during the COVID-19 pandemic. 
10.1.7 Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents (including X-ray and DXA films/images) are 
filed at the Investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained.  The Investigator may need to request 
previous medical records or transfer records, depending on the study.  Also, current medical 
records must be available. 
10.1.8 Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The study may be halted for evaluation of possible risk to participants, prior to decision as to 
whether to terminate the study if any of the following criteria are met: 
• The occurrence of an SAE, if considered to be at least possibly related to the IMP. 
• The occurrence of 2 severe or clinically significant AEs, both considered at least possibly 
related to the IMP. 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
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study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. 
The Investigator may initiate study termination or study site closure at any time after discussion 
with the Sponsor, provided there is reasonable cause and sufficient notice is given in advance of 
the intended termination.  However, dosing of a given participant may be suspended immediately 
on safety grounds pending discussion between the Investigator and Sponsor. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Significant violation of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
Reasons for early termination of the study by the Sponsor or Investigator may include: 
• Occurrence of serious or severe adverse event(s) considered to be related to the IMP. 
• New information regarding the safety of the IMP that indicates a change in the risk/benefit 
profile for the compound, such that the risk/benefit is no longer acceptable for participants 
participating in the study. 
• Discontinuation of further IMP development. 
• New data become available regarding COVID-19, which raises concern for the safe study 
conduct so that continuation would pose potential risks to the participants or study site staff. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements.  
The Investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
10.1.9 Publication Policy 
The data generated by this study are considered confidential information and the property of 
Gedeon Richter Plc.  This confidential information may be published only in collaboration with 
participating personnel from Gedeon Richter Plc. and in every case upon written consent from 
Gedeon Richter Plc. to publish the article.  The publication of the results or presentation of the 
results at scientific meetings in whole or in part are within the sole and absolute discretion of the 
Sponsor.  If this is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission.  This allows the Sponsor to protect proprietary information and to 

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provide comments.  The Sponsor reserves the right to reject any article utilising any data 
generated by Parexel during the study before such article is presented or submitted for 
publication.  The Sponsor will also not use Parexel’s name in connection with any publication or 
promotion without the prior consent of Parexel.  The Sponsor will comply with the requirements 
for publication of study results. 
• The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission.  This allows the Sponsor to protect proprietary information and to provide 
comments. 
• In accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. 
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.10 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements.  The 
Sponsor must ensure that all ethical and legal requirements have been met before the first 
participant is enrolled in the study. 
This protocol is to be followed exactly.  To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). 
Administrative changes (not affecting the participant benefit/risk ratio) may be made without the 
need for a formal amendment.  All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.11 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
legal requirements.  The civil liability of the Investigator, the persons instructed by him or her 
and the hospital, practice or institute in which they are employed and the liability of the Sponsor 
with respect to financial loss due to personal injury and other damage that may arise as a result of 
the carrying out of this study are governed by the applicable law. 

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The Sponsor will arrange for participants participating in this study to be insured against 
financial loss due to personal injury caused by the pharmaceutical products being tested or by 
medical steps taken in the course of the study. 
10.1.11.1 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
EDC/eCRF entries and individual participant’s medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements.  
Electronic data capture/eCRF entries will be verified with source documentation.  The review of 
medical records will be performed in a manner to ensure that participant confidentiality is 
maintained. 
Checking of the EDC/eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study.  Moreover, regulatory 
authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audits/inspections.  Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality.  The Investigator assures 
Parexel and the Sponsor of the necessary support at all times. 

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10.2 Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 10-1 will be performed by the central laboratory with the 
exceptions specified at the end of the table. 
According to local guideline or practice and upon the discretion of the Investigator, (preferably 
albumin-adjusted) serum calcium level may be measured prior to the administration of IMP or at 
any timepoint at local laboratory.  The results, as well as the lower and upper limit of normal 
value of (albumin-adjusted) serum calcium at the local laboratory should be documented in the 
eCRF.  Clinically significant abnormal values should be reported as an AE.  However, for clinical 
study report purposes the values from the central laboratory will be considered. 
Local laboratory tests can be done in the event that the central laboratory results are not available 
in time for IMP administration and the Investigator considers it as necessary for the safe 
administration of the IMP or for any other safety reason.  If a local sample is required, it is 
important that the sample for central analysis is obtained at the same time.  Additionally, if the 
local laboratory results are used to make either an IMP decision or response evaluation, the 
results as well as the normal values must be entered into the eCRF. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1and 5.2 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
Table 10-1 
Protocol-Required Laboratory Assessments 
Laboratory Assessments 
Parameters 
Haematology 
Platelet Count 
RBC Count with MCV, MCH and 
MCHC 
Haemoglobin 
Haematocrit 
WBC count, Total with Differential (in 
absolutes and percentages): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Large Unstained cells (if applicable) 
Clinical Chemistry 
BUN 
Creatinine 
Uric acid 
Creatine kinase 
eGFR using MDRD formula 
Glucose 
Potassium 
Sodium 
Calcium (Total) 
Albumin adjusted calcium 
AST 
ALT 
Alkaline phosphatase 
GGT 
Total and direct bilirubin 
Total Protein 
Albumin 
Total cholesterol 
Triglyceride 
LDH 

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Laboratory Assessments 
Parameters 
Magnesium 
Phosphorus 
CRP (high-sensitivity) 
Lipase 
Routine Urinalysis 
Specific gravity 
pH, Glucose, Protein, Blood, Ketones, Bilirubin, Urobilinogen, Nitrite, Leukocyte 
esterase 
Microscopic analysis will be performed if Blood, Protein, Leukocyte esterase or 
Nitrite is positive or if deemed necessary by the Investigator. 
Microscopic urine sediment examination (if required) 
Hormonal Tests 
FSH (Screening only) 
TSH (Screening only) 
Vitamin D (25-hydroxyvitamin D) (Screening and day of IMP administration) 
PTH (Screening only) 
Serology Tests 
Serology (HIV-1 and HIV-2 antibodies, anti-HBcAg total, HBsAg, anti-HBsAg 
and anti-HCV IgG and IgM) 
Bone Turnover Markers 
(PD marker) 
sCTX 
Serum P1NP 
Immunogenicity Tests 
Binding ADAs and NAbs 
Serum Drug 
Concentration 
Denosumab concentration 
Note: 
All study-required laboratory assessments will be performed by a central 
laboratory, with the exception of: 
• 
Dipstick urinalysis at all visits. 
• 
Immunogenicity and serum drug concentration samples (assessed by 
Sponsor). 
ADAs = anti-drug antibodies; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CRP = c-reactive protein; eGFR = estimate glomerular filtration rate; FSH = follicle-stimulating 
hormone; GGT = gamma-glutamyl transferase; HBcAg = hepatitis B core antigen; HBsAg = hepatitis B surface 
antigen; HCV = hepatitis C virus; IgG = immunoglobulin G; IgM = immunoglobulin M; IMP = investigational 
medicinal product; LDH = lactate dehydrogenase MCH = mean corpuscular haemoglobin; MCHC = mean 
corpuscular haemoglobin concentration; MCV = mean corpuscular volume; MDRD = modification of diet in 
renal disease; NAbs = neutralising antibodies; P1NP = procollagen type 1 N-terminal propeptide; 
PD = pharmacodynamic(s); PTH = parathyroid hormone; RBC = red blood cell count; sCTX = serum type I 
collagen C-telopeptide; TSH = thyroid-stimulating hormone; WBC = white blood cell count 
 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigational 
sites or other blinded personnel until the study has been unblinded. 

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10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
The definitions and procedures detailed in this document related to medical device events are in 
accordance with ISO 14155 [25]. 
10.3.1 Definition of Adverse Event 
Adverse Event (or Adverse Experience) Definition 
• An AE or adverse experience is any untoward medical occurrence in a patient or 
clinical investigation participant administered a pharmaceutical product and which 
does not necessarily have to have a causal relationship with this treatment. 
• NOTE: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
 
Events Meeting the Adverse Event Definition 
• Any abnormal laboratory test results, see Section 8.4.4 (haematology, clinical 
chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, 
vital signs measurements, local tolerance, fracture assessment), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgement of the Investigator (e.g., not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after IMP administration even though it may 
have been present before the start of the study. 
• Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms or the clinical sequelae of a suspected overdose of either IMP or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it 
is an intentional overdose taken with possible suicidal/self-harming intent.  Such 
overdoses should be reported regardless of sequelae. 

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• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy 
assessments.  However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE or 
SAE. 
 
Events NOT Meeting the Adverse Event Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.  However, fragility fractures will be considered as AEs. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
 Definition: Adverse Event Caused by Device Incident/Deficiency 
• An AE caused by device incident/deficiency is any AE related to the use of a 
combination product [23, 24] or medical device.  Adverse events caused by device 
incident/deficiency include AEs resulting from insufficient or inadequate instructions 
for use, AEs resulting from any malfunction of the device, or AEs resulting from use 
error or from intentional misuse of the device.  Therefore, an AE caused by device 
incident/deficiency could be any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including an abnormal laboratory finding) in 
participants, whether or not related to the investigational medical device. 
 

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10.3.2 Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met. 
A Serious Adverse Event is defined as any untoward medical occurrence that, at any 
dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• In general, hospitalisation signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalisation are AE.  If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalisation” occurred or was necessary, the 
AE should be considered serious. 
• Hospitalisation for elective intervention of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 

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f. Other situations 
• Medical or scientific judgement should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalisation but may 
jeopardise the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These events should usually 
be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive intervention 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation, or development of drug dependency 
or drug abuse. 
• Emergency room visits that do not result in admission to the hospital should be 
evaluated for one of the other outcomes in the definition of serious 
(e.g., life-threatening experience, important medical event). 
• Symptomatic overdose if it results in any of the serious outcomes listed above. 
• Suicide attempt – with or without any sign or symptom – when considered to be 
threat of life. 
• Neoplasia (benign or malignant) if judged to be medically serious. 
• NOTE: In lethal cases, the cause of death shall be considered as an SAE and the death 
itself shall be considered as SAE outcome.  Death may be indicated as an SAE if the 
cause has not been established.  The Investigator should assess the event scientifically 
and medically and decide whether the event should be immediately reported to 
Parexel. 
Definition: Serious Adverse Events Caused by Device Incident/Deficiency 
• A serious adverse event caused by device incident/deficiency is defined as an adverse 
event that led to any of the following: 
o Death. 
o Serious deterioration in the health of the subject that resulted in any of the 
following: 
▪ life-threatening illness or injury, 
▪ permanent impairment of a body structure or a body function, 

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▪ hospitalisation or prolongation of patient hospitalisation, 
▪ medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
▪ chronic disease. 
o Foetal distress, foetal death or a congenital physical or mental impairment or birth 
defect. 
Definition: Unanticipated Serious Adverse Event Caused by Device 
Incident/Deficiency 
• An unanticipated serious adverse event caused by device incident/deficiency is a 
serious adverse event caused by device incident/deficiency which by its nature, 
incidence, severity or outcome has not been identified in the current version of the 
risk analysis report. 
 
10.3.3 Definition of Medical Device Events 
Definition: Medical Device Events 
A medical device event could be a device incident (in the case of Prolia®) or a device 
deficiency (in the case of RGB-14-P). 
• A device incident is any malfunction or deterioration in the characteristics or 
performance of a device made available on the market, including use error due to 
ergonomic features, as well as any inadequacy in the information supplied by the 
manufacturer and any undesirable side-effects. 
• A device deficiency is any inadequacy in the identity, quality, durability, reliability, 
safety or performance of an investigational device, including malfunction, use errors 
or inadequacy in information supplied by the manufacturer. 
 
10.3.4 Recording and Follow-up of Adverse Event and Serious Adverse Event 
Adverse Event and Serious Adverse Event Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 

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• The Investigator will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to Parexel in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by Sponsor.  In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  If a diagnosis is 
unknown, then the Investigator should report in detail signs and symptoms. 
• For AEs caused by device incidents/deficiency, it is very important that the 
Investigator describes any corrective or remedial actions taken to prevent recurrence 
of the incident. 
 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE/SAE reported during 
the study and assign it to one of the following categories: 
• Grade 1/Mild: The AE was an annoyance to the participant but did not further hinder 
baseline functioning; the AE may have been intermittent or continuous. 
• Grade 2/Moderate: The AE caused the participant to experience some discomfort or 
some interference with normal activities but was not hazardous to health; prescription 
drug therapy may have been employed to treat the AE. 
• Grade 3/Severe: The AE caused the participant to experience severe discomfort or 
severely limited or prevented normal activities and represented a definite hazard to 
health; prescription drug therapy and/or hospitalisation may have been employed to 
treat the AE. 
• Grade 4/Life-threatening: The participant was at immediate risk of death form the 
event as it occurred. 
• Grade 5/Death: The participant died due to the event. 

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An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.  If AE severity or 
seriousness changed during its development, it should be recorded as a separate event. 
Please see Table 8-1 for the assessment of intensity of injection site reactions. 
 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between IMP and each 
occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• The Investigator will use clinical judgement to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to IMP administration will be 
considered and investigated. 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has 
minimal information to include in the initial report to Parexel.  However, it is very 
important that the Investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to Parexel. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Causal relationship should be assessed by answering the following question: “Is there a 
reasonable possibility the IMP caused the event?”. 

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• Yes: There is a possible or probable relationship (i.e., there is a reasonable or strong 
temporal relationship, and the events are likely to be attributable to other drugs, 
underlying disease or other factors). 
• No: The relationship is unlikely or non-existent (i.e., there is no strong temporal 
relationship and/or the use of other drugs, underlying diseases, or other factors 
provide plausible explanations for the event), or the participant did not take the 
investigational product. 
 
Follow-up of Adverse Event and Serious Adverse Event (Caused by Device 
Incident/Deficiency or Not) 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE/SAE (caused by device 
incidence/deficiency or not) as fully as possible.  This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
• If a participant dies during participation in the study or during a recognised follow-up 
period, the Investigator will provide Parexel with a copy of any post-mortem findings 
including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE data on Follow-up SAE Report Form 
to Parexel immediately (but no later than 24 hours) of receipt of the information. 
All AEs shall be followed up by the Investigator until resolution or the follow-up 
assessment, whichever comes first.  Independently form the time of the next visit in case 
of AE the participant can revisit the Investigator.  If, during follow-up, any non-serious 
AE worsen and eventually meets the criteria for an SAE, that AE should be recorded as a 
new SAE.  Data privacy rules should be adhered to. 
To fully understand the nature of any SAE, it is important to obtain follow-up 
information.  Follow-up reports must reported promptly within 24 hours or receipt.  
Whenever possible, relevant medical records such as discharge summaries, autopsy 
reports, medical consultations, and the like should be obtained.  These records should be 
reviewed in detail, and the Investigator should comment on any event, laboratory 

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abnormality, or any other finding, noting whether it should be considered a serious or 
non-serious AE, or whether it should be considered as part of the participant’s history. 
In addition, all events or other findings determined to be SAEs should be identified on the 
follow-up SAE Report Form and the Investigator should assess whether it is related or 
not related to IMP.  All SAEs are to be followed by the study staff until resolution or 
until the SAE is deemed stable. 
It is the responsibility of the Investigator to report all relevant new information using the 
same procedures and timelines as those for the initial report.  Serious adverse events 
occurring after the end of the study should be reported to the Sponsor/Parexel by the 
Investigator if the Investigator considers there a causal relationship with the IMP. 
For instruction on follow-up of medical device related events see Section 6.1.2. 
 
Action Taken to an Adverse Event 
The Investigator will describe the action taken in the participant’s source documentation 
and in the appropriate field of the eCRF.  Action take to the AE will be documented as 
follows: 
• None. 
• Medication. 
• Intervention. 
• Medication and intervention. 
 
Assessment of Outcome of Adverse Events 
Outcome of an AE will be defined as: 
• Recovered without sequelae. 
• Recovered with sequelae. 
• Not recovered (AE continuing). 
• Recovering. 

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• Death. 
• Unknown. 
 
10.3.5 Reporting of Serious Adverse Events 
Serious Adverse Event Reporting to Parexel via Electronic Data Collection Tool 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• The Investigator shall report any SAEs and pregnancy cases immediately (within 
24 hours of the Investigator’s awareness) to Parexel.  The Investigator is obliged to 
complete a separate SAE Report Form and Pregnancy Report Form in addition to the 
information in the eCRF. 
• In particular, if the SAE is fatal or life-threatening, Parexel must be notified 
immediately, irrespective of the extend of available AE information. 
• Parexel will then follow expedited reporting procedures according to local and 
international regulations as appropriate. 
• The Investigator is obligated to pursue and provide information to Parexel on all 
SAEs in accordance with the timeframes and reporting specified above. 
• In addition, the Investigator may be requested by Parexel to obtain specific additional 
follow-up information in an expedited fashion.  In the case of a participants’ death, a 
summary of available autopsy findings must be submitted as soon as possible to 
Parexel. 
• The immediate report shall be followed by detailed written reports.  The immediate 
and follow-up reports shall identify participants by unique code numbers assigned to 
the latter.  For reported deaths, the Investigator shall supply the Sponsor and the local 
IECs with an additional information requested. 
• For every AE, the Investigator should: 
o Provide a description (Investigator’s verbatim term describing the event). 
o Provide dates of onset and resolution. 
o Assess the severity. 
o Provide the relationship to IMP. 

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o Provide the outcome. 
o Provide action taken regarding IMP. 
o Advise if other action (treatment, non-drug therapy) is required. 
o Determination of “seriousness”. 
• Date and time of onset, outcome, date and time of off set and interventions, if 
applicable in case of each AE should be recorded. 
• When calling Parexel’s designated agent to report an SAE, state that you are reporting 
an SAE and give the Investigator’s name, your name, the telephone number where 
you can be reached, and the protocol number and title.  Parexel’s designated agent 
will then inform the Sponsor of the receipt of a new SAE. 
• The Investigator and Parexel (or Parexel’s designated agent) will review each SAE 
report and Parexel will evaluate the seriousness and the causal relationship of the 
event to IMP.  In addition, Parexel (or Parexel’s designated agent) will evaluate the 
expectedness according to the reference document (IB, SmPC or USPI).  Based on 
the Investigator and Parexel’s assessment of the event, a decision will be made 
concerning the need for further action. 
• The Sponsor (Parexel on behalf of the Sponsor) has the legal responsibility to report, 
without delay to all Member States in which the clinical study is being conducted, 
including: 
o any SAE that has a causal relationship with the investigational device, the 
comparator or the investigation procedure or where such causal relationship is 
reasonably possible, 
o any device event that might have led to a serious adverse event, if appropriate 
action had not been taken, intervention had not occurred, or circumstances had 
been less fortunate, 
o any new findings in relation to any event referred to in the above-mentioned bullet 
points. 
• On behalf of the Sponsor, after Sponsor’s approval, the Parexel Pharmacovigilance 
team shall report any medical device incident or deficiency that qualifies for a 
reportable medical device event according to the abovementioned criteria.  The 
Parexel Pharmacovigilance team shall provide the Sponsor with local regulatory 
reporting requirement related to medical devices. 

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• After the study is completed, the electronic data collection tool will be taken off-line 
to prevent the entry of new data or changes to existing data. 
• The contact details of Parexel International for reporting SAEs are 
 the contact details will also be specified on the SAE 
Report Form. 
• If the site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information to the Sponsor’s Clinical 
Safety Unit by telephone, fax or email.  The contact details of the Clinical Safety Unit 
are provided below: 
 
 
 
Phone: 
 
Fax: 
 
Email: : 
 
• Further details on SAE/SUSAR reporting, including notification of Sponsor by 
Parexel after SAE/SUSAR events can be found in the SAE processing procedure and 
Global Safety reporting plan. 
Serious Adverse Event Caused by Device Incident/Deficiency Reporting to Parexel 
• NOTE: There are additional reporting obligations for medical device 
incidents/deficiencies that are potentially related to SAEs that must fulfil the local 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical studies. 
• Any medical device incidents/deficiencies that is associated with an SAE must be 
reported to Parexel immediately (but no later than 24 hours) after the determination 
that the event meets the definition of a medical device incident/deficiency associated 
with an SAE as it is described in the Addendum to Investigator Manual and the 
Product Complaint Procedure. 
PPD
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• The Investigator and Parexel (or Parexel’s designated agent) shall review all device 
incidents/deficiencies and determine and document in writing whether they could 
have led to an SAE.  The Investigator will remain blinded.  These shall be reported to 
the regulatory authorities and IRBs/IECs as required by national regulations. 
• The Sponsor is responsible for the final investigation of all device 
incidents/deficiencies. 
• The contact details of Parexel International for reporting SAEs are 
, the contact details will also be specified on the SAE 
Report Form. 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Any AE that is serious, associated with the use of the IMP, and unexpected (SUSAR) has 
additional reporting requirements, as described below. 
• If the SUSAR is fatal or life-threatening, associated with IMP, and unexpected, 
regulatory authorities and IECs will be notified by Parexel within seven calendar days 
after Parexel learns of the event.  Additional follow-up (cause of death, autopsy report 
and hospital report) information should be reported within an additional 8 days 
(15 days total). 
• If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with 
IMP, and unexpected, regulatory authorities and IECs will be notified within 
15 calendar days after Parexel learns of the event. 
Parexel shall inform the Investigators in the clinical study about the occurrence of 
SUSARs.  All relevant follow-up information concerning SUSARs should be reported by 
Parexel to the regulatory authorities and IECs as soon as possible but within a maximum 
of 15 calendar days after Parexel learns of the event.  Parexel on behalf of the Sponsor 
after Sponsor’s approval will also provide annual safety updates to the regulatory 
authorities and IECs responsible for the study.  These updates will include information on 
SUSARs and other relevant safety findings. 
 
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The minimum information required for an initial report is: 
• An identifiable Reporter. 
• One single identifiable participant. 
• At least one suspect adverse reaction. 
• At least one suspect medicinal product. 
However, as far as possible all points on the SAE form should be covered in the initial report, or 
the completed SAE form itself must be faxed to the Parexel Safety Contact.  The original SAE 
form must then be sent by mail to the Parexel Safety Contact.  In addition, the event must be 
document in the eCRF. 
In case the Parexel Safety Contact cannot be contacted (e.g., out of normal working hours or at 
weekend), an automated reporting service is available.  The required information should be faxed 
and a message should be left on the voicemail service (for phone/fax numbers see the numbers in 
the Section 10.3.5). 
After receipt of the initial report, the safety centre will review the information and, if necessary, 
contact the Investigator, to obtain further information for assessment of the event.  Parexel will 
be responsible for all information processing and reporting according to local legal requirements. 
Details of the reporting procedures are determined in the Safety Management Plan. 
 
 

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10.4 Appendix 4: Coronavirus Disease 2019 (COVID-19) Related 
Considerations 
Background to Coronavirus Disease 2019 (COVID-19) 
There is currently an outbreak of COVID-19 caused by a novel SARS-CoV-2 that was first 
detected in Wuhan City, Hubei Province, China in 2019.  This new virus has rapidly spread 
across the globe causing the World Health Organization to declare a pandemic situation on 
March 11, 2020.  The countermeasures initiated by national and local governments worldwide 
and the recommendations issued by the health authorities have impacted current and new clinical 
studies.  As the threat of pandemic burden including new outbreaks, locally or globally, will 
impact the further conduct of clinical studies, appropriate risk assessments and mitigation 
measures will need to be taken into consideration in all clinical studies to protect participants, 
site staff and society as a whole. 
Both EMA [21] and FDA [22] as well as national health authorities in Europe have issued new 
guidelines that aim to provide recommendations for actions for conduct of clinical studies of 
medical products during COVID-19 pandemic.  Since the pandemic situation is evolving, 
guidelines, recommendations, national laws and local restrictions may change at high pace.  
Given the circumstances of potentially relapsing pandemic or epidemic situation with regard to 
the spread of COVID-19 in future, special attention will be paid to protect participants 
participating in the study and site staff involved in the investigations against infection with 
SARS-CoV-2 as requested by the newly issued EMA guideline. 
Appropriate medical measures have been implemented into this protocol to detect COVID-19 
disease to confirm eligibility of participants and to safely conduct the trial. 
Restriction 
Participants are advised to adhere to local requirements for reduction of the public SARS-CoV-2 
exposure while ambulatory.  All participants are called one day prior to every visit for assessing 
COVID-19 symptoms and signs and are asked not to attend the site in case of suspected 
infection.  In addition, participants are asked for any contact with a person who has confirmed 
infection.  If applicable, participants will be referred to the local health care system.  Physical 
distancing and person-to-person contact restrictions will be applied and explained to participants 
while staying at the study site.  Where physical distancing is not possible study participants will 
be asked to use surgical face masks and/or gloves if deemed appropriate by the Investigator and 
site staff and guided by local requirements. 

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10.5 Appendix 5: Abbreviations and Trademarks 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AP 
activator protein 
AST 
aspartate aminotransferase 
AUEC 
area under the effective curve 
AUEC sCTX0-m6 
area under the effective curve after the first dose until Day 183 of %CfB in 
serum type I collagen C-telopeptide 
BLQ 
below the limit of quantification 
BMD 
bone mineral density 
BMI 
body mass index 
%CfB 
percent change from baseline 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organisation 
DXA 
dual energy X-ray absorptiometry 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form(s) 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EU 
European Union 
FAS 
full analysis set 
FcRn 
neonatal Fc receptor 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMR 
Geometric Mean Ratio 
GnRH 
gonadotropin-releasing hormone 

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HBcAg 
hepatitis B core antigen 
HBsAg 
hepatitis B surface antigen  
IB 
Investigator’s Brochure 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IMP 
investigational medicinal product 
INN 
international non-proprietary names 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
MAPKs 
mitogen activated protein kinases 
MCAR 
missing completely at random 
M-CSF 
macrophage-colony stimulating factor 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed model for repeated measures 
MNAR 
missing non at random 
NAbs 
neutralising antibodies 
NK 
nuclear factor 
OC 
osteoclast 
ODF 
osteoclast differentiation factor 
ONJ 
osteonecrosis of the jaw 
OPGL 
osteoprotegerin ligand 
P1NP 
procollagen type 1 N-terminal propeptide 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PPS 
per protocol analysis set 
PTH 
parathyroid hormone 
RANK 
receptor activator of nuclear factor kappa-B 
RANKL 
receptor activator of nuclear factor kappa-B ligand 
SAE 
serious adverse event 
SAP 
statistical analysis plan 

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SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
sCTX 
serum type I collagen C-telopeptide 
SD 
standard deviation 
SERM 
selective oestrogen receptor modulator 
SmPC 
Summary of Products Characteristics 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse events 
TNF 
necrosis factor 
TRAF 
TNF receptor associated factor 
TRANCE 
TNF related activation induced cytokine 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
USPI 
US package insert 
 
 

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10.6 Appendix 6: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Non-substantial Amendment 1: 20 Jul 2021 
Overall Rationale for the Amendment 
The protocol is amended to incorporate and implement responses and suggestions made by the 
Czech Republic Regulatory Authority. 
Non-Substantial Amendment 1 Summary of Changes: 
Section # and Name 
Description of Change* 
Brief Rationale 
1.3 Schedule of Activities 
Reference ‘m’ of Table 1-1 and 
Reference ‘k’ of Table 1-2 amended as 
follows:  
“Injection site reaction assessment 
should be done predose and 
approximately 1 hour postdose,. 
during this 1 hour period. Any 
further assessment of the injection 
site or prolonged observation of the 
participant may be done at the 
discretion of the Investigator. At the 
discretion of the Investigator another 
assessment of the injection site may be 
done after the initial 1 hour.” 
Amended following 
suggestion from the Czech 
Republic Regulatory 
Authority. 
6.3.3 Blinding and breaking the blind 
Third paragraph of section amended as 
follows: 
The Investigator should make an 
effort to contact the Parexel Medical 
Monitor, if possible, prior to 
unblinding.   If the Investigator 
decides that unblinding is warranted, 
the Investigator should make every 
effort to contact Parexel Medical 
Monitor prior to unblinding a 
participant’s study treatment 
assignment unless this could delay 
emergency treatment of the participant.  
If this is not possible and the situation 
is an emergency the Investigator or 
his/her delegated deputy may break the 
blind and contact Parexel as soon as 
possible thereafter.    
Amended following 
suggestion from the Czech 
Republic Regulatory 
Authority. 

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Section # and Name 
Description of Change* 
Brief Rationale 
6.3.3 Blinding and breaking the blind 
Fifth paragraph of section amended as 
follows: 
In all unblinding cases, Parexel 
should contact the Sponsor as soon as 
possible.  In all unblinding cases, 
Parexel should contact the Sponsor 
prior to or as soon as possible (< 24 
hours) after unblinding.   
Amended following 
suggestion from the Czech 
Republic Regulatory 
Authority. 
8.4.5. Local Tolerance (Skin 
Examination) 
First paragraph of section amended as 
follows: 
On dosing days, injections site reaction 
assessment should be done predose 
(i.e., for exclusion of a pre-existing, not 
IMP injection induced condition) and 
approximately 1 hour postdose;.  At 
during this 1 hour period (i.e., from 
dosing to the injection site 
assessment) the participant will stay 
in the clinic for general safety 
observation.  Any further assessment 
of the injection site or prolonged 
observation of the participant may 
be done at the discretion of the 
Investigatoranother assessment of the 
injection site may be done after the 
initial 1 hour.   
Amended following 
suggestion from the Czech 
Republic Regulatory 
Authority. 
* Bolded text is added text, struck-through text is deleted text. 

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Substantial Amendment 1: 03 Aug 2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The protocol is mainly amended to incorporate and implement responses and suggestions made 
by the United States Food and Drug Administration. 
Substantial Amendment 1 Summary of Changes: 
Section # and Name 
Description of Change 
Brief Rationale 
Sponsor signatory page 
Sponsor signatories were amended. 
Sponsor request. 
1.1 Synopsis 
1.3 Schedule of Activities (SoA) 
2.2.1 Risk Assessment 
3 Objectives and Endpoints 
8.3.3 Fracture Assessment 
8.3.3.2 Non-vertebral Fracture 
8.4 Safety Assessments 
9.4.4.3.2 Other Safety Data 
10.1.7 Source Documents 
10.3.1 Definition of Adverse Event 
Text added and updated to include 
fracture assessment as adverse event 
evaluation. 
Amended following 
suggestion from the United 
States Food and Drug 
Administration (US FDA). 
1.3 Schedule of Activities (SoA) 
2 Introduction 
6.1 Study Treatments Administered 
6.1.1 Study Treatment Devices 
6.1.2 Device-related Complaints 
6.3.3 Blinding and Breaking the 
Blind 
8.5 Adverse Events and Serious 
Adverse Events 
8.5.3 Follow-up of Adverse Events 
and Serious Adverse Events 
10.3 Appendix 3: Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-up, 
and Reporting 
Text added to specify recording 
device-related events. 
Amended following 
suggestion from the US FDA. 
Section 6.1 Study Treatments 
Administered (Table 6-1) 
Packaging and Labelling updated to 
Device Description and additional 
information relating to devices added. 
Clarification of devices. 
1.3 Schedule of Activities (SoA) 
Period for submission of dual energy 
X-ray absorptiometry and X-ray 
imaging for central independent review 
increased to 10 days. 
Increased to allow for 
sufficient time for review. 
1.3 Schedule of Activities (SoA) 
8.4.4 Clinical Safety Laboratory 
Assessments 
Text amended to specify urine sample 
analysis in case of abnormal results 
may be sent to the central laboratory if 
deemed necessary by Investigator. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (SoA) 
8.4.5 Local Tolerance (Skin 
Examination) 
Text amended to better clarify 
observation period of injection site post 
investigational medicinal product 
administration. 
Amended for clarification. 
1.3 Schedule of Activities (SoA) 
9.4.1 General Considerations 
Baseline value for bone mineral density 
(BMD) clarified. 
Amended following 
suggestion from the US FDA. 
2.2.1 Risk Assessment 
Text added on serious adverse reaction 
and reporting of suspected unexpected 
serious adverse reactions. 
Text added at Sponsor 
request. 
2.2.1 Risk Assessment 
11 References 
Text added post-marketing experience 
with US Prolia. 
Amended for consistency 
with latest Prescribing 
Information. 
2.2.1 Risk Assessment 
Text added to indicate Investigator 
responsibility for coronavirus disease 
2019 testing in symptomatic and 
asymptomatic participants. 
Text added for clarification. 
5.2 Exclusion Criteria 
Text added on inclusion/exclusion of 
participants with a history of childhood 
rickets. 
Text added for clarification. 
5.2 Exclusion Criteria 
Text added to specify described 
uncontrolled hypo- and 
hyperthyroidism. 
Text added for clarification. 
5.2 Exclusion Criteria 
Text added to further clarify exclusion 
criteria with regards to osteonecrosis of 
the jaw. 
Text added for clarification. 
5.2 Exclusion Criteria 
6.5.1 Prohibited Therapy 
Update to excluded medication prior to 
and during the study. 
Text added for clarification. 
5.4 Screen Failures 
Text added to indicate participants 
retested for vitamin D and calcium 
testing will not be classified as screen 
failures. 
Text added for clarification. 
1.1 Synopsis 
4.1 Overall Design 
6.3.3 Blinding and Breaking the 
Blind 
Text removed for consistency of 
responsibilities of treatment and 
unblinding throughout the protocol. 
Amended for clarification. 
6.5.2 Additional Study Treatment 
Text added to specify procedures to 
following in the case of intolerance to 
non-investigational products. 
Text added for clarification. 
6.7 Intervention After the End of the 
Study 
Text amended to clarify risks 
associated with denosumab 
discontinuation and actions to be taken 
after study treatment discontinuation. 
Text amended to further 
clarify risks and actions to be 
taken. 
7.1 Discontinuation of 
Investigational Medicinal Product, 
Participant 
Discontinuation/Withdrawal from the 
Study 
Text added to address management of 
reduction in BMD below a pre-defined 
threshold that may occur during the 
study. 
Amended following 
suggestion from the US FDA. 
Text added to establish individual 
stopping criteria (e.g., life-threatening 
treatment-related 
hypersensitivity/allergic reaction). 
Text added for clarification. 
8.4.1 Physical Examinations 
Text updated to clarify timing of height 
assessment. 
Text added for clarification. 
8.7 Immunogenicity Assessment 
8.8 Serum Drug Concentration 
Text removed for clarification. 
Clarification of text. 

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Section # and Name 
Description of Change 
Brief Rationale 
9.3 Population for Analysis 
9.4.2 Estimands 
9.4.5 Handling of Missing Data 
Text updated to reduce the number of 
participants who discontinue the study 
early and the amount of missing data. 
Amended following 
suggestion from the US FDA. 
9.4.2 Estimands 
Text updated to include all 
randomisation stratification factors in 
analysis model. 
Amended following 
suggestion from the US FDA. 
10.2 Appendix 2: Clinical Laboratory 
Tests 
Removal of erythrocyte sedimentation 
rate. 
Removed from haematology 
panel as not performed by 
central laboratory. 
10.3 Appendix 3: Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-up, 
and Reporting 
11 References 
References added for device-related 
complaints definitions and procedures. 
Amended at Sponsor request. 
10.3.1 Definition of Adverse Event 
Definition updated to be in line with 
the International Council for 
Harmonisation Topic E2A (Clinical 
Safety Data Management: Definitions 
and Standards for Expedited 
Reporting). 
Amended at Sponsor request. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not 
been summarized. 

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Substantial Amendment 2: 10 Jan 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The protocol is mainly amended to incorporate and implement changes for statistical analysis, 
consistency with supporting study documents and suggestions made based on Investigator 
experiences. 
Substantial Amendment 2 Summary of Changes: 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; 
3 Objectives and Endpoints (Table 3-1) 
Added text to specify primary 
pharmacodynamic endpoint 
secondary for the United States 
Food and Drug Administration 
(US FDA) submission. 
Text added for clarification. 
1.1 Synopsis; 
4 Overall Design; 
6.3.3 Blinding and Breaking the Blind 
Added text to specify blinded and 
unblinded staff during the Main 
and Transition Periods for 
reporting purposes. 
Text added for clarification. 
1.3 Schedule of Activities (Table 1-1) 
Deleted pre-visit phone call for 
Screening visit. 
Participants will not be contacted 
before the Screening visit to 
assess coronavirus disease 2019 
symptoms and signs. 
1.3 Schedule of Activities (Table 1-1 
and Table 1-2) 
Added footnote to specify dual 
energy X-ray absorptiometry 
should be performed before 
dosing at Week 26 and Week 52. 
Text added for clarification. 
1.3 Schedule of Activities (Table 1-1 
and Table 1-2); 
2.2.1 Risk Assessment; 
6.1.2 Medical Device Events; 
6.3.3 Blinding and Breaking the Blind; 
6.4 Investigational Medicinal Product 
Compliance; 
8.5 Adverse Events and Serious 
Adverse Events; 
8.5.1 Time Period and Frequency for 
Collecting Adverse Events and Serious 
Adverse Event Information; 
8.5.3 Follow-up of Adverse Events and 
Serious Adverse Events; 
10.3 Adverse Events: Definitions and 
Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
Text and terminology amended to 
align with the Product Complaint 
Procedure document. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (Table 1-1); 
2.2.1 Risk Assessment; 
10.2 Clinical Laboratory Tests 
(Table 10-1) 
Text amended or deleted for 
severe acute respiratory syndrome 
coronavirus-2 testing to specify as 
required by local regulation. 
Text amended or deleted as 
infection may occur at any time 
during the study and should be 
assessed as required by local 
requirements. 
1.3 Schedule of Activities (Table 1-1); 
8.2.5 Screening Assessment 
Text added to specify the 
Screening visit may be conducted 
over more than 1 day during the 
Screening period, as required for 
logistical reasons. 
To extent Screening period to 
allow required time to perform 
all requirement assessments to 
determine participant eligibility 
for study participation. 
5.2 Exclusion Criteria 
Updated exclusion criterion for 
participants with inadequate renal 
and hepatic function (exclusion 
criterion 25) to specify exception 
for participants with Gilbert’s 
syndrome. 
Text added for clarification. 
5.2 Exclusion Criteria; 
6.5.1 Prohibited Therapy 
Added antioestrogens, 
aromatase-inhibitors, low 
molecular weight heparins, 
vitamin K, vitamin K antagonists 
(e.g., warfarin, acenocumarol), 
emtricitabine, tenofovir, adefovir 
and pregabalin as prohibited 
medication. 
Pregabalin, antioestrogens, 
aromatase-inhibitors, low 
molecular weight heparins, 
vitamin K antagosists (e.g., 
warfarin, acenocumarol), 
emtricitabine, tenofovir added to 
list of prohibited medication due 
to potential effect on bone. 
5.2 Exclusion Criteria; 
7.1 Discontinuation of Investigational 
Medicinal Product, Participant 
Discontinuation/Withdrawal from the 
Study 
Added pregnancy and 
breastfeeding as exclusion criteria 
and breastfeeding under 
discontinuation/withdrawal 
criteria. 
Added as per request from Italian 
Ethics Committee. 
5.2 Exclusion Criteria; 
10.2 Clinical Laboratory Tests 
Amended text to specify 
hepatitis B exclusion criteria. 
Text amended for clarification. 
8.2.4 Prior and Concomitant 
Medication Review 
Text updated to define prior and 
concomitant medication 
timeframe. 
Text updated for consistency 
with Section 6.5. 
8.5 Adverse Events and Serious 
Adverse Events 
Text added to specify medical 
device events that cause adverse 
events (AEs) and serious adverse 
events (SAEs) will be reported 
following the same periods and 
procedures as study AEs and 
SAEs. 
Text added for clarification. 
8.5.4 Regulatory Reporting 
Requirements for Serious Adverse 
Events; 
9.4.4 Additional Analyses; 
10.3.5 Reporting of Serious Adverse 
Events 
Added text on reporting device 
events to all Member States in 
which clinical study is being 
conducted. 
Text added for clarification. 

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Section # and Name 
Description of Change 
Brief Rationale 
9.1 Statistical Hypotheses; 
9.2 Sample Size Determination; 
9.4.1 General Consideration; 
9.4.2 Estimands; 
9.4.2.1 Supplementary (tertiary) 
estimands; 
9.4.4.3 Safety; 
9.4.5 Handling of Missing Data 
Text added and updated to clarify 
study hypotheses, study 
estimands and statistical analysis 
of safety and handling of missing 
data. 
Text amended for clarification. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not been 
summarized. 
 

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Substantial Amendment 3: 19 Jan 2023 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment:  
This protocol is mainly amended to incorporate and implement 10% increase in the number of 
participants to be enrolled for the Transition Period to meet the requirements of United States 
(US) Food and Drug Administration (FDA), considering the drop-out is higher than expected. 
Substantial Amendment 3 Summary of Changes 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.2 Schema (Figure 1-2) 
4.1 Overall Design 
6.1 Study Treatment Administered 
(Table 6-1) 
6.3.2 Re-randomisation and Participant 
Subset in Transition Period 
9.2 Sample Size Determination 
Amended text to implement 10% 
increase of the number of 
participants to be enrolled during 
the Transition Period than 
previously. 
Participants might withdraw the 
consent right after the Main 
Period that would trigger lack of 
data from follow-up visits. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not been 
summarized. 
 

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11 References 
1. Investigator’s Brochure, RGB-14, Gedeon Richter, Plc., current version. 
2. Prolia Summary of Product Characteristics. 
https://www.ema.europa.eu/en/medicines/human/EPAR/prolia 
3. Prolia (denosumab) Package Insert. US Approval: Amgen; current version, revised: 05/2021. 
https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-
com/prolia/prolia_pi.pdf. 
4. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. 
Am. J, Med. 1993; 94(6):646-50. 
5. Compston JE, McClun MR, Leslie WD. Osteoporosis. Lancet 2019; 393(10169):364-76. 
6. Takegami N, Akeda K, Yamada J et al. RANK/RANKL/OPG system in the intervertebral 
disc. Arthritis Res Ther. 2017; 19(1):121. 
7. Cheng ML, Fong L. Effects of RANKL-Targeted Therapy in Immunity and Cancer. Front 
Oncol. 2014; 3:329. 
8. Renema N, Navet B, Heymann et al. RANK-RANKL signalling in cancer. Biosci Rep. 2016; 
36(4):e00366. 
9. Park JH, Lee NK, Lee SY. Current understanding of RANK signalling in osteoclast 
differentiation and maturation. Mol Cells. 2017; 40(10):706-13. 
10. Chiu YG, Ritchlin CT. Denosumab: targeting the RANKL pathway to treat rheumatoid 
arthritis. Expert Opin Biol Ther. 2017; 17(1):119-29. 
11. Cummings SR, San Martin J, McClung MR et al. FREEDOM Trial. Denosumab for 
prevention of fractures in postmenopausal women with osteoporosis. N. Eng. J. Med. 2009; 
361(8):765-65. 
12. 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. 
13. Nakamura T, Matsumoto T, Sugimoto T et al. Clinical Trials Express: fracture risk reduction 
with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab 
fracture intervention randomized placebo controlled trial (DIRECT). J. Clin. Endocrinol. 
Metab. 2014; 99(7):2599-607. 

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14. Kendler DL, Roux C, Benhamou CL et al. Effects of Denosumab on Bone Mineral Density 
and Bone Turnover in Postmenopausal Women Transitioning from Alendronate Therapy. J. 
Bone. Miner. Res. 2010; 25(1):72-81. 
15. Dolores S, Rosen CJ, Black DM et al. Pharmacological Management of Osteoporosis in 
Postmenopausal Women: An Endocrine Society Guideline Update. J. Clin. Endocrinol. 
Metab. 2020; 105(3):587-94. 
16. Genant HK, Chun YW, van Kuijk C et al. Vertebral fracture assessment using a 
semiquantitive technique. J. Bone Miner. Res. 1993; 8(9):1137-48. 
17. McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with 
low bone mineral density. N. Eng. J. Med. 2006; 354(8):821-31. 
18. https://clinicaltrials.gov/ct2/show/results/NCT2053753?view=results 
19. Jakobsen JC, Gluud C, Wettersley J, et al. When and how should multiple imputation be used 
for handling missing data in randomised clinical trials – a practical guide with flowcharts. 
BMC Med. Res. Methodol. 2017; 17:162:1-10. 
20. Lou Y, Jones MP, Sun W. Estimation of causal effects in clinical endpoint bioequivalence 
studies in the presence of intercurrent events: noncompliance and missing data. J Biopharm 
Stat. 2019; 29(1):151-73. 
21. Guidelines on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
pandemic, EMA, Version 3 (28/04/2020). 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf 
22. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency, March 2020, Updated April 16, 2020. https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-
products-during-covid-19-public-health-emergency 
23. FDA Guidance on Current Good Manufacturing Practice Requirements for Combination 
Products, January 2017. https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/current-good-manufacturing-practice-requirements-combination-products 

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24. FDA Guidance on Postmarketing Safety Reporting for Combination Products, July 2019. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postmarketing-
safety-reporting-combination-products 
25. ISO 14115:2020. Clinical Investigation of Medical Devices for Human Subjects – Good 
Clinical Practice, Version 3. July 2020. https://www.iso.org/standard/71690.html 
 
 

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Investigator Agreement Page 
Declaration of the National Coordinating Investigator 
Title: A Randomised, Double-blind, Multicentre Phase III Study to Assess the Efficacy and 
Safety of RGB-14-P Compared to Prolia® in Women with Postmenopausal Osteoporosis 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
product as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, as amended in 2013 and the guidelines on GCP. 
National Coordinating Investigator 
 
_____________________________________ 
_____________________ 
Signature  
 
 
 
 
 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 

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Declaration of the Investigator 
Title: A Randomised, Double-blind, Multicentre Phase III Study to Assess the Efficacy and 
Safety of RGB-14-P Compared to Prolia® in Women with Postmenopausal Osteoporosis 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, EDC system/electronic CRF (eCRF), and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
IRB or IEC. No changes will be made to the study protocol without the prior written approval of 
the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the 
participants. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the Local Study Centre 
 
_____________________________________ 
_____________________ 
Signature  
 
 
 
 
 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number