Clinical trial NCT05087030
Conditions: Postmenopausal Osteoporosis
Keywords: Biosimilars Prolia®
Sponsor: Gedeon Richter Plc.
Start date: 2021-09-21; Completion date: 2023-11-15
Enrollment: 473 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted to assess the efficacy, pharmacodynamic (PD), safety, tolerability, and immunogenicity of RGB -14- P compared to US-licensed Prolia® in participants with postmenopausal osteoporosis, in a comparative manner.

Detailed description:
This is a randomized, double-blind, multicentre, multiple fixed-dose, 2-arm parallel-group study that includes 2 periods as:

1. Main period (52 weeks), consists of Treatment Period 1 (26 weeks) and Treatment Period 2 (26 weeks). On Day 1 of Treatment Period 1, prior to dosing, participants will be randomized in a 1:1 ratio to receive either RGB-14-P or Prolia®.
2. Transition Period: consists of Treatment Period 3 (26 weeks). On Day 1 of Treatment Period 3 (Week 52), a subset of participants who received Prolia® during the Main Period will be re-randomized 1:1 to receive either a dose RGB-14-P or Prolia® in a double-blinded manner. A subset of 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 randomization procedure to maintain blinding.

All participants will receive the study drugs 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 study drugs on a third-occasion (Week 52), Day 1 of Treatment Period 3. One Treatment Period will take 6 months (26 weeks, 183 days).

Arms: arm 1: Randomized participants will receive subcutaneous (SC) injection of RGB-14-P, on Day 1 of Treatment periods 1 and 2. arm 2: Randomized participants will receive SC injection of Prolia®, on Day 1 of Treatment periods 1 and 2. arm 3: Re-randomized participants will receive SC injection of RGB-14-P, on Day 1 of Treatment period 3. arm 4: Re-randomized participants will receive SC injection of Prolia®, on Day 1 of Treatment period 3. arm 5: Randomized participants will continue to receive SC injection of RGB-14-P from the main period till Day 1 of Treatment period 3.
Interventions: intervention 1: RGB-14-P intervention 2: Prolia®
Intervention descriptions: intervention 1: Participants will receive RGB-14-P into the thigh, abdomen, or upper arm as per the arm assigned. intervention 2: Participants will receive Prolia® into the thigh, abdomen, or upper arm as per the arm assigned.

Protocol documents:
Prot_000.pdf: 
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
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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 
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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 
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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 
only be accessible to unblinded staff.  Details pertaining to processing and reporting medical 


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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 
medication number for the first package of IMP to be dispensed to the participant. 


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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 
Safety Unit, Clinical Good Manufacturing Practice Quality Assurance and Qualified Person 


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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 
for clinical decision-making (i.e., when knowledge of the study treatment assignment would 


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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. 
• Calcitonin or its derivates and calcimimetics (such as cinacalcet or etelcacetide). 


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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 
provides written informed consent.  At the time of intervention allocation/randomisation, site 


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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 
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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 
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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. 
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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 
reason at the sole discretion of the Sponsor.  Study sites will be closed upon study completion.  A 


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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. 
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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 
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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. 
Text amended for clarification. 


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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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Clinical Study Protocol 
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CONFIDENTIAL 
 
Version 5.0 
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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 

SAP_001.pdf: 
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 Statistical analysis plan: 13-Dec-2023


Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan 
Project Document Version No.: Error! Reference source not found.; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 1 of 154 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Gedeon Richter Plc. 
RGB-14-101 
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 
Statistical Analysis Plan 
Version:  1.0 
Parexel Project Number: 252679 


Parexel International 
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RGB-14-101 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 2 of 154 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Sponsor Signature Page 
This document has been approved and signed electronically on the final page by the 
following:  
Approved by: 
_________________________ 
_______________ 
Date 
Gedeon Richter Plc. 
Approved by: 
_________________________ 
_______________ 
Date 
Gedeon Richter Plc. 
Approved by: 
_________________________ 
_______________ 
Date 
Gedeon Richter Plc. 
PPD
PPD
PPD
PPD
PPD
PPD


Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 3 of 154 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Parexel Signature Page 
Signature(s) below confirm that the Statistical Analysis Plan was developed in accordance with 
SOP-GDO-WW-019 and that it is approved for release. 
This document has been approved and signed electronically on the final page by the 
following:  
Signatory 
Author 
PPD
PPD


Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 4 of 154 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Table of Contents 
Sponsor Signature Page ................................................................................................................... 2
Parexel Signature Page .................................................................................................................... 3
Table of Contents ............................................................................................................................ 4
Table of Tables ................................................................................................................................ 8
Table of Figures ............................................................................................................................... 9
Version History ............................................................................................................................. 10
1
Introduction .................................................................................................................... 12
1.1
Objectives, Endpoints, and Estimands ........................................................................... 15
1.2
Study Design .................................................................................................................. 20
2
Statistical Hypotheses .................................................................................................... 25
2.1
Multiplicity Adjustment ................................................................................................. 26
3
Analysis Sets .................................................................................................................. 27
4
Statistical Analyses ........................................................................................................ 30
4.1
General Considerations .................................................................................................. 30
4.1.1
Analysis Conventions ..................................................................................................... 30
4.1.2
Study Days ..................................................................................................................... 31
4.1.3
Study Visits .................................................................................................................... 32
4.1.4
Definition of Baseline .................................................................................................... 35
4.1.5
Data Listings ................................................................................................................... 35
4.1.6
Tables ............................................................................................................................. 35
4.1.7
Figures ............................................................................................................................ 40
4.1.8
Software .......................................................................................................................... 41
4.2
Primary Endpoints Estimand Analysis ........................................................................... 41
4.2.1
Primary Efficacy Endpoint and Analysis ....................................................................... 41
4.2.1.1
Primary Efficacy Endpoint – Definition of Endpoint .................................................... 43
4.2.1.2
Primary Efficacy Endpoint – Main Analytical Approach .............................................. 46
4.2.1.3
Primary Efficacy Endpoint – Sensitivity Analyses ........................................................ 55
4.2.1.4
Primary Efficacy Endpoint – Supplementary Analyses ................................................. 66
4.2.2
Primary Pharmacodynamic Endpoint and Analysis ....................................................... 67
4.2.2.1
Primary Pharmacodynamic Endpoint – Definition of Endpoint .................................... 68
4.2.2.2
Primary Pharmacodynamic Endpoint – Main Analytical 
Approach ........................................................................................................................ 69
4.2.2.3
Primary Pharmacodynamic Endpoint – Sensitivity Analyses ........................................ 70


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RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 5 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.2.2.4 
Primary Pharmacodynamic Endpoint – Supplementary Analyses ................................. 70 
4.3 
Secondary Endpoints and Analysis ................................................................................ 70 
4.3.1 
Secondary Efficacy Endpoints ....................................................................................... 70 
4.3.1.1 
Secondary Efficacy – Definition of Endpoint(s) ............................................................ 71 
4.3.1.2 
Secondary Efficacy – Main Analytical Approach .......................................................... 73 
4.3.1.3 
Secondary Efficacy – Sensitivity Analyses .................................................................... 75 
4.3.1.4 
Secondary Efficacy – Supplementary Analyses ............................................................. 75 
4.3.2 
Secondary Pharmacodynamic Endpoints ....................................................................... 75 
4.3.2.1 
Secondary Pharmacodynamic – Definition of Endpoint(s) ............................................ 75 
4.3.2.2 
Secondary Pharmacodynamic – Main Analytical Approach ......................................... 76 
4.4 
Immunogenicity Analysis and Serum drug concentrations ............................................ 76 
4.4.1 
Immunogenicity .............................................................................................................. 76 
4.4.1.1 
Immunogenicity binding ADAs and NAbs – Definition of 
Endpoint(s) ..................................................................................................................... 77 
4.4.1.2 
Immunogenicity – Main Analytical Approach ............................................................... 77 
4.4.1.3 
Immunogenicity – Supplementary Analysis .................................................................. 79 
4.4.2 
Serum drug concentrations – Supporting immunogenicity ............................................ 81 
4.5 
Safety Analyses .............................................................................................................. 81 
4.5.1 
Extent of Exposure ......................................................................................................... 82 
4.5.2 
Adverse Events ............................................................................................................... 82 
4.5.2.1 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events ............................................................................................................................. 86 
4.5.3 
Additional Safety Assessments ...................................................................................... 89 
4.5.3.1 
Clinical Laboratory Evaluation ...................................................................................... 89 
4.5.3.2 
Vital Signs, Physical Findings and Other Observations Related to 
Safety .............................................................................................................................. 92 
4.6 
Other Analyses ............................................................................................................... 94 
4.6.1 
Other Variables and/or Parameters ................................................................................. 94 
4.6.1.1 
Health Economics .......................................................................................................... 94 
4.6.1.2 
Patient Reported Outcome (PRO) Measures .................................................................. 94 
4.6.2 
Subgroup Analyses ......................................................................................................... 94 
4.6.3 
Pharmacokinetics, Pharmacokinetic-Pharmacodynamic 
Relationships .................................................................................................................. 95 
4.7 
Interim Analysis ............................................................................................................. 95 
4.8 
Changes to Protocol-planned Analyses .......................................................................... 95 
5 
Sample Size Determination ............................................................................................ 96 


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Statistical Analysis Plan 
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Related to:  SOP-GDO-WW-019 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6
Supporting Documentation ............................................................................................ 99
6.1
Appendix 1: List of Abbreviations ................................................................................. 99
6.2
Appendix 2: Supporting Study Information ................................................................. 104
6.2.1
Disposition of Subjects ................................................................................................. 104
6.2.2
Demographics ............................................................................................................... 105
6.2.3
Baseline and Disease Characteristics ........................................................................... 105
6.2.4
Treatment Compliance ................................................................................................. 106
6.2.5
Protocol Deviations ...................................................................................................... 106
6.2.6
Medical and Surgical History and Concurrent Illnesses .............................................. 107
6.2.7
Prior/Concomitant Medications ................................................................................... 107
6.2.8
Prohibited therapies ...................................................................................................... 108
6.2.9
Concomitant Procedures ............................................................................................... 109
6.2.10
Schedule of Activities .................................................................................................. 111
6.3
Appendix 3: Data Handling Conventions .................................................................... 120
6.3.1
Missing Date Imputation .............................................................................................. 120
6.3.1.1
Missing/Incomplete AE Start Date .............................................................................. 120
6.3.1.2
Missing/Incomplete AE End Date ................................................................................ 120
6.4
Appendix 4: Sample SAS code .................................................................................... 121
6.4.1
Secondary Estimand – ANCOVA sample SAS code is provided 
as general example and will be adapted in phase of analysis ....................................... 121
6.4.2
ICE2 Multiple Imputation for EMA – sample SAS code (code is 
provided as general example and will be adapted in phase of 
analysis) ........................................................................................................................ 122
6.4.3
Multiple Imputation for FDA – sample SAS code (code is 
provided as general example and will be adapted in phase of 
analysis) ........................................................................................................................ 125
6.4.4
Multiple Imputation for EMA Sensitivity analysis – sample SAS 
code (code is provided as general example and will be adapted in 
phase of analysis) ......................................................................................................... 129
6.4.5
Tipping point for FDA Sensitivity analysis – Approach 1 (code is 
provided as general example and will be adapted in phase of 
analysis) ........................................................................................................................ 131
6.4.5.1
Macro sample SAS code .............................................................................................. 131
6.4.5.2
Use of macro and plots production (code is provided as general 
example and will be adapted in phase of analysis) ...................................................... 135
6.4.6
Tipping point for FDA Sensitivity analysis – Approach 2 (code is 
provided as general example and will be adapted in phase of 
analysis) ........................................................................................................................ 137
6.4.6.1
Macro sample SAS code .............................................................................................. 137


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Statistical Analysis Plan 
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Related to:  SOP-GDO-WW-019 
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6.4.6.2
Use of macro and plots production (code is provided as general 
example and will be adapted in phase of analysis) ...................................................... 142
6.4.7
Supplementary Estimand – sample SAS code (code is provided as 
general example and will be adapted in phase of analysis) .......................................... 146
6.4.8
Derivation of AUEC of %CfB in sCTX from baseline to Week 26 
– sample SAS code (code is provided as general example and will
be adapted in phase of analysis) ................................................................................... 147
6.4.9
Primary Pharmacodynamic Endpoint ANCOVA model and GMR 
derivation – sample SAS code (code is provided as general 
example and will be adapted in phase of analysis ) ..................................................... 151
6.4.10
ADA persistent versus transient response – Example cases ........................................ 152
7
References .................................................................................................................... 153


Parexel International 
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Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 8 of 154 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Table of Tables 
Table 1 – Objectives and Endpoints ............................................................................................... 15
Table 2 – Summary of the Primary and Secondary Estimands ...................................................... 17
Table 3 – Populations for Analysis ................................................................................................ 27
Table 4 – Assessments scheduled at Week 52 for subjects enrolled into the transition period ..... 34
Table 5 – Rules for assessments not usable in summary tables due to severe deviation from visit 
window ........................................................................................................................................... 35
Table 6 – Overall ADA status classification .................................................................................. 77
Table 7 – Overall NAb status classification ................................................................................... 79
Table 8 - Protocol-Required Safety Laboratory Assessments ........................................................ 90
Table 9 - Probability to Observe at Least One Participant with a Given Adverse Event .............. 97
Table 10 – Schedule of Activities (SoA) – Main Period .............................................................. 111
Table 11 – Schedule of Activities (SoA) – Transition Period ...................................................... 116
Table 12 – sCTX example data .................................................................................................... 147
Table 13 – ADA persistent versus transient response, in main and transition period – Example 
cases .............................................................................................................................................. 152


Parexel International 
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Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 9 of 154 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Table of Figures 
Figure 1 – Scheme of Study Design - Main Period only ................................................................ 23
Figure 2 – Scheme of Study Design - Main and Transition Period ............................................... 24
Figure 3 – Example of Tipping Point Plot ..................................................................................... 66
Figure 4 – sCTX example data from baseline up to Week 26 ..................................................... 148
Figure 5 – %CfB AUEC in sCTX example data from baseline up to Week 26 .......................... 149


Parexel International 
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Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 10 of 154 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Version History 
SAP 
Version 
Date 
Change 
Rationale 
Draft 0.1 
28 Jan 2022 
Document 
creation 
First draft 
Draft 0.2 
16 Nov 2022 
Major 
Use of newest PAREXEL template, based 
on TransCelerate common statistical 
analysis plan (version 2.0). 
Comments implementation. 
In deep details added for 
pharmacodynamic and immunogenicity 
analysis. 
Draft 0.3 
17 March 2023 
Major 
Updates to accommodate new eCRF 
version 5 and new Protocol Amendment 5 
Draft 0.4 
28 April 2023 
Major 
Updates in the primary analysis strategy 
due to protocol amendments in protocol 
version 5.0 from Protocol Amendment 5 
Draft 0.5 
20 July 2023 
Minor 
Fix of client comments & minor 
refinements 
Draft 0.6 
17 August 2023 
Minor 
Minor refinements and removal of 
SUSAR from safety section 
Draft 0.7 
05 October 2023 
Minor 
Adding new requested safety summaries, 
reverting the definition of significant 
ADA titre increase back to the fold 
increase instead of using the minimal 
significant ration (MSR) 
Draft 0.8 
27 October 2023 
Minor 
Minor refinements 
Draft 0.9 
07 November 2023 
Major 
Request to changes in the logics for 
handling out of schedule assessments, 
with major impact on mapping analysis 
visits. 


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RGB-14-101 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 11 of 154 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Request to add additional sensitivity 
analysis for secondary efficacy endpoint 
of vertebral fracture. 
Final 1.0 
Date of last signature Minor 
Fix of last comments and document 
finalization 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 12 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
1 Introduction 
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 in 
healthy volunteers as well as a comparative efficacy and safety study between RGB-14-P and 
Prolia® in women with postmenopausal osteoporosis. Although the comparative PK/PD study 
will commence earlier, essentially the two studies will run in parallel. 
The primary outcome of this study is determined based on the results of the efficacy analysis at 
Week 52 (please refer to section 4.2.1). 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 are described in the Blinding Maintenance Plan. 
The Main Clinical Study Report will be completed based on the data obtained after all 
participants have either completed the Week 52 study visit or discontinued the study. The data 
obtained in the Transition Period will be added as a Final/Supplemental Clinical Study Report. 
In this statistical analysis plan (SAP), analyses will be presented separately for the main and the 
transition period, and separate sets of Tables, Figures and Listings (TFLs) will be produced for 
the main and transition period.  
In particular: 
➔ EMA submission is required at 12 months; EMA will receive CSR based on 12 months 
data (main period) 
 
➔ FDA submission required at 18 months; FDA will receive CSR based on whole study data 
(main + transition period). 
 
The main CSR for EMA submission and the final/supplemental CSR for FDA submission will be 
supported by two different sets of SDTMs and ADAMs. Full regular SDTM and ADAM will 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 13 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
include all the study data and will be used when running analysis for FDA submission, while 
SDTM_Main (i.e., the ‘_main’ extension will be added to each domain) and ADAM_Main 
(again, the ‘_main’ extension will be added to each dataset) will include only the data belonging 
to the main period and will be used when running analysis for EMA submission.  
For main period CSR, TFLs will include an identifier for the main period data cut off and will 
include “for main period” on the analysis set (i.e. Full Analysis Set for Main Period).   
For final/ supplemental CSR, TFLs will be executed on the full regular datasets and will include 
data cut off and identification of main / transition period as relevant on the analysis set (i.e:. “Full 
Analysis Set for Main Period” or “Full Analysis Set for Transition Period”) as appropriate.   
Two different Blinded Data Review Meetings (BDRM) and database locks (DB Lock) will 
happen, one covering the main period and one covering the transition period. General unblinding 
will happen after the last DB Lock, i.e., the transition period one. A separate unblinded team may 
be assigned at Parexel to proceed with unblinding TFLs production in between the two DB 
Locks.    
The analyses described in this SAP are based upon the following study documents: 
− 
Study Protocol, Version 5.0 (March 28th, 2023) 
− 
electronic Case Report Form (eCRF), Version 5.0 (March 21th, 2023) 
− 
Blinding Maintenance Plan, Version 3.0 (Nov 15th, 2023) 
− 
Global Data Operation (GDO) Plan, Version 3.0 (12th December,2023) 
The structure and content are based upon International Conference on Harmonisation (ICH) 
requirements as detailed in  
− 
ICH E3 Structure and Content of Clinical Study Reports [1] 
− 
ICH E9 Statistical principles for Clinical Trials [2] 
− 
ICH E9(R1) Addendum on estimands and sensitivity analysis in clinical trials [3] 
The SAP details the statistical methodology to be used in analysing study data and outlines the 
statistical programming specifications for the TFLs. It describes the variables and populations, 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 14 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
anticipated data transformations and manipulations and other details of the analyses not provided 
in the Clinical Study Protocol (CSP). In case of discrepancies between CSP and SAP, these will 
be documented in section 4.8 of the SAP and the SAP supersedes the CSP. 
 
 
 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 15 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
1.1 
Objectives, Endpoints, and Estimands 
 
 
Table 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 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 16 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Objectives 
Endpoints 
• 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 
• Titer 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 
 
 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 17 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Primary and Secondary estimand(s) 
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 [3]. From this 
end, efficacy analysis will be defined with terms used for the estimand concept. 
 
Table 2 – Summary of the Primary and Secondary Estimands 
Estimands 
Primary: Treatment Policy Estimand 
(TPE) 
Secondary: Principal Stratum 
Estimand (PSE) 
Clinical questions of 
interest 
Do RGB-14-P and US-licenced 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-licenced 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 have not experienced 
any ICEs on either treatment arms? 
Variable 
Percent increase in BMD in lumbar spine from Baseline to Week 52, i.e., %CfB, is the 
primary study endpoint and is defined in Section 4.2.1.1 (%CfB = (Post Baseline – 
Baseline) / Baseline * 100). 
ICE 
ICE1: The first and/or the second dose of randomised IMP is not administered. 
ICE2: The participant received other medication alongside the IMP, which affects the 
primary variable (please refer to protocol section [Prohibited Therapy]). 
ICE strategy 
ICE1: Treatment policy strategy will be 
applied: All obtained data points will be 
included in the analysis, 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. In other words, responses 
obtained after ICE occurrence will be 
imputed with multiple imputation 
techniques so that outcomes observed 
after ICE2 occurrence will be modelled 
under the null hypothesis. 
Principal stratum causal estimand strategy 
will be used: Only patients who would 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. 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 18 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Estimands 
Primary: Treatment Policy Estimand 
(TPE) 
Secondary: Principal Stratum 
Estimand (PSE) 
Treatments 
Test product: RGB-14-P subcutaneous injection 60 mg. 
Reference product: Prolia® subcutaneous injection 60 mg. 
Study Population 
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, as far as ICE1 
and ICE2 are not met. 
Main estimator 
For EMA submission (details in sections 
4.2.1.2.1 and  4.2.1.2.1.1): 
δ will be estimated by using ANCOVA 
model (SAS PROC GLM) with the 
following factors: 
1. Randomised treatment 
2. Baseline BMD value 
3. Previous use of bisphosphonates 
4. Geographical region 
5. Machine type 
6. Machine type * Baseline BMD value 
interaction 
Missing data will be assumed to be 
MCAR and will not be imputed (details in 
section 4.2.1.2.1.1). 
δ will be estimated by using ANCOVA 
model (SAS PROC GLM) with the 
following factors: 
1. Treatment 
2. Baseline BMD value 
3. Previous use of bisphosphonates 
4. Geographical region 
5. Machine type 
6. 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 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 19 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Estimands 
Primary: Treatment Policy Estimand 
(TPE) 
Secondary: Principal Stratum 
Estimand (PSE) 
For US FDA submission (details in 
sections 4.2.1.2.1 and  4.2.1.2.2): 
δ will be estimated by using ANCOVA 
model (SAS PROC GLM) with the 
following factors: 
1. Treatment 
2. Baseline BMD value 
3. Previous use of bisphosphonates 
4. Geographical region 
5. Machine type 
6. 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 in 
section 4.2.1.2.1.2) 
randomisation, the strategy analysis with 
MI will be followed. 
 
Details in section 4.2.1.2.2. 
Sensitivity estimator 
For EMA submission (details in sections 
4.2.1.2.1.1 and 4.2.1.3.1): 
As a sensitivity estimation for the primary 
analysis of the primary endpoint, missing 
data may be imputed using MI rules, 
techniques proposed by Jakobsen et al, 
2017 will be considered [4]. 
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 
Due to the parallel design, robustness of 
the estimator will be assessed by tipping 
point analysis [5]. 
Details in section 4.2.1.3.3. 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 20 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Estimands 
Primary: Treatment Policy Estimand 
(TPE) 
Secondary: Principal Stratum 
Estimand (PSE) 
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 
section 4.2.1.3.2. 
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; IMP = investigational medicinal product; ITT = intent-to-treat; MCAR = missing 
completely at random; MI = multiple imputation; MNAR = missing non at random; PPS = per protocol analysis 
set; US = United States 
 
1.2 Study 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 efficacy 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 and Figure 2). Day 1 of Treatment Periods 2 and 3 is 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). 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 21 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Participants will attend ambulatory site visits for efficacy, PD, immunogenicity and safety 
assessment as indicated in the Schedule of Activities (Table 10 and Table 11). 
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 post dose during Treatment Period 1 
- 
Days 1, 8, 15, 30 and 90 post-dose during Treatment Period 2 
An End of Study Visit is planned on Day 183 (Week 52) post-dose during Treatment Period 2 for 
participants not continuing participation in Transition Period. Please see Protocol 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 180 participants will enter 
the Transition Period. A subset of approximately 120 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 
60 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. 
Visits during the Transition Period: 
- 
Days 1, 8, 15, 30 and 90 post-dose during Treatment Period 3 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 22 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
An End of Study Visit is planned on Day 183 (Week 78) post-dose during Treatment Period 3.  
Please see Protocol 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. 
 
 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 23 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Figure 1 – Scheme of 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 2 
RGB-14-Pa (n = 217) 
RGB-14-Pa (n = 217) 
Screening 
and Informed 
Consent 
procedures 
Screening 
and Informed 
Consent 
procedures 
Proliab = (n = 217) 
Proliab = (n = 217) 
Randomisation 
Screening 
Randomisation 
Screening 
EOS 
EOS 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 24 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Figure 2 – Scheme of 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 = 60) 
Proliab(n = 217) 
Proliab(n = 60) 
RGB-14-Pa(n = 60) 
Randomisation 
Screening 
Re-randomisation 
EOS 
Screening 
and Informed 
Consent 
procedures 
RGB-14-Pa(n = 217) 
RGB-14-Pa(n = 60) 
Proliab(n = 217) 
Proliab(n = 60) 
RGB-14-Pa(n = 60) 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 25 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
2 Statistical Hypotheses 
This study is designed to test for bio-equivalence of RGB-14-P and Prolia®. 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. 
 is considered for 
this study, as per sample size determination considerations at section 5 of this SAP. 
- 
Efficacy estimand for EMA submission 
 
 
where: 
δ = μRGB-14-P - μProlia 
μRGB: BMD mean %CfB in RGB-14-P study arm 
μProlia: BMD mean %CfB in Prolia® study arm 
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) 
where: 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 26 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
δ = μRGB-14-P - μProlia 
μRGB: BMD mean %CfB in RGB-14-P study arm 
μProlia: BMD mean %CfB in Prolia® study arm 
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. 
- 
PD endpoint 
According to bioequivalence criteria, the AUEC variability can range from −20% to 
+25% between the generic and the reference product [6] [7]. Bioequivalence criteria 
margin of 80.00–125.00% are recognised by several regulatory authorities worldwide [7]. 
Null Hypothesis H0: Geometric Mean Ratio (GMR) of AUEC sCTX0-m6 (GMR, RGB 14-
P / Prolia®) not contained within [80.00%, 125.00%] 
Alternative Hypothesis H1: GMR of AUEC sCTX0-m6 (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. 
2.1 Multiplicity Adjustment 
FDA submission 
Evaluation of the primary objective is uniquely based on primary efficacy endpoint; no 
multiplicity concern raises.   
EMA submission  
Similarity between RGB-14-P and Prolia® will be assessed based on the simultaneous success of 
hypothesis tests for all primary endpoints (Efficacy and Pharmacodynamics). Endpoints will then 
be seen as co-primary, thus alpha adjustment is not needed for this coprimary endpoints study. 
 


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Statistical Analysis Plan 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 27 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
3 Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
Table 3 – Populations for Analysis 
Population  
(Analysis 
Set) 
Description 
ENR 
All participants who signed the informed consent form (including screening failures). 
Participants will be reported according to their randomised treatment in each period. 
FAS 
The FAS comprises all participants to whom the IMP has been randomised. 
 
In the transition period, the FAS will be intended as all participants to whom the IMP has been re-
randomised in transition period. 
Note: subjects excluded from the main period FAS, will not be included in the transition period 
FAS.  
 
Participants will be analysed according to their randomised treatment in each period. 
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. 
Note: dropout subjects will not be excluded in the PPS due to their early discontinuation. 
 
In the transition period, the PPS consists of the main period PPS subjects who received full or 
partial dose of 3rd IMP injection; further criteria for exclusion from transition period PPS may be 
identified at the BDRM prior than DB Lock of the data from the transition period. 
Note: subjects excluded from the main period PPS, will not be included in the transition period 
PPS. 
 
Participants will be analysed according to the treatment actually received in each period. 
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 at Day 1 Treatment 
period 1.   
 
In the transition period, the SAF consists of all participants who received full or partial dose of 3rd 
IMP injection. Participants will be analysed according to the IMP they actually received as the 3rd 
dose (Treatment Period 3).     
Note: subjects excluded from the main period SAF, will not be included in the transition period 
SAF. 
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 


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Statistical Analysis Plan 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 28 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
have a relevant impact on sCTX or serum P1NP results included in the pharmacodynamic 
parameter calculation (see Section 4.3). 
 
In the transition period, the PDS consists of all participants who received full or partial dose of 3rd 
IMP injection, had at least one evaluable pharmacodynamic parameter post 3rd IMP injection and 
do not have any protocol deviations that may have a relevant impact on sCTX or serum P1NP 
results included in the pharmacodynamic parameter calculation (see Section 4.3). 
Note: in general, subjects excluded from the main period PDS due to protocol deviations, will not 
be included in the transition period PDS. Final decision will be consolidated prior to DB Lock. 
PDs with possible relevant impact on sCTX or serum P1NP will be identified prior to DB Lock of 
data from the main and the transitions period. 
Patients will be analysed according to the IMP they actually received at Day 1 Treatment Period 1 
(for main period) and Treatment Period 3 (for transition period). 
IAS 
The IAS consists of all participants in the safety population who have the pre-dose 
immunogenicity result and at least one available post-baseline immunogenicity assessment and do 
not have any protocol deviations that have a relevant impact on immunogenicity evaluations. 
 
In the transition period, the IAS consists of all participants who received full or partial dose of 3rd 
IMP injection, had at least one available immunogenicity assessment post 3rd IMP injection and 
do not have any protocol deviation that may have a relevant impact on immunogenicity 
evaluations. 
Of note: subjects excluded from the main period IAS due to protocol deviations, will not be 
included in the transition period IAS. Final decision will be consolidated prior to DB Lock. 
 
PDs with possible relevant impact on immunogenicity evaluations will be identified prior to DB 
Lock of data from the main and the transitions period. 
Patients will be analysed according to the IMP they actually received at Day 1 Treatment Period 1 
(for main period) and Treatment Period 3 (for transition period). 
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; 
P1PN = 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 
 
Unless otherwise specified, the analysis sets will serve as below: 
- 
ENR for subject disposition 
- 
FAS for demographic and baseline characteristics, medical history, medications, efficacy 
(with the exception of secondary estimand) 
- 
PPS for efficacy secondary estimand  
- 
SAF for exposure and safety 


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Statistical Analysis Plan 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
- 
PDS for pharmacodynamic 
- 
IAS for immunogenicity 
In general, in ENR and in FAS data of subjects will be listed and summarised under the planned 
treatment, independently of total amount of the treatment received; while in SAF, PPS, PDS and 
IAS, data of subjects will be listed and summarised under the treatment actually received, 
independently of total amount of the treatment received.  
Cases where a different than assigned treatment kit was injected, should be known prior to 
unblinding as these can be identified by a reconciliation process comparing the allocated kit 
number available in the IRT reports and the injected kit number reported into the EDC.  
However, it will not be known until unblinding if the injected kit was of the same treatment as the 
assigned kit.  Therefore, cases of discrepancies and corresponding handling strategies will be 
discussed at a BDRM both pre- and post-unblinding. If any subjects receive a different treatment 
at Treatment period 1 compared to Treatment period 2, the effect on the SAF, PPS, PDS and IAS 
period 2 TFLs will be discussed, and possible data handling strategies agreed.  
 
 


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Statistical Analysis Plan 
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Page 30 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4 Statistical Analyses 
4.1 General Considerations 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel procedures. 
Two deliverables are expected: one for the main and one for the transition period. In general, 
outputs delivered for the main period will contain subject data collected before the eventual 
transition period randomisation; while outputs delivered for the transition period, will contain 
data collected during both the main and transition period. More details are provided below in 
sections 4.1.5, 4.1.6 and 4.1.7. 
The overall outline of the scheduled assessment and other study procedures can be found in SoA 
(Table 10 and Table 11). The data handling conventions should be interpreted within the 
framework of the SoA. All tables, listings, and graphs will be produced to landscape orientation 
using Courier New 9pt font and will be incorporated into a MS Word document as a (RTF) rich 
text file (margins on standard A4: Margins (top, left, right, and bottom) 2.54 cm. 
4.1.1 Analysis Conventions 
Continuous data will be summarised in terms of the mean, standard deviation (SD), median, 
minimum, maximum, quartiles and number of observations, unless otherwise stated. The 
minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database.  The mean, median, lower quartile and upper quartile will be reported to 
one more decimal place than the raw data recorded in the database. The SD will be reported to 
two more decimal places than the raw data recorded in the database. In general, the maximum 
number of decimal places reported shall be four for any summary statistic. 
Categorical data will be summarised in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percentages. Any planned collapsing of categories 
will be detailed in the SAP text and the data displays. 


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Statistical Analysis Plan 
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Page 31 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts. Percentages will be calculated using n as the denominator. If sample sizes are small, the 
data displays will show the percentages, but any textual report will describe frequencies only. 
Changes from baseline in categorical data will be summarised using shift tables where 
appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places. P-
values lower than 0.001 will be presented as “<0.001”. 
Confidence intervals will be presented to one more decimal place than the raw data. 
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. 
4.1.2 
Study Days  
Study Day in Treatment Period 1 (Main Period) 
The date of IMP administration for Treatment Period 1 is defined as Day 1 Week 0. 
In Treatment Period 1, other study days are defined relative to the Study Day 1 as follow: 
• 
assessments taken before the Treatment Period 1 IMP administration: 
Relative Study Day = assessment date - Treatment Period 1 IMP administration date 
• 
assessments on or after the Treatment Period 1 IMP administration: 
Relative Study Day = assessment date - Treatment Period 1 IMP administration date + 1 
In Treatment Period 1, study days will be identified as ‘TP1DX’, as an example IMP 
administration at Week 0 will be TP1D1. 
Study Day in Treatment Period 2 (Main Period) 
Day 1 Week 26 refers the IMP administration in Treatment Period 2: in Treatment Period 2, 
Study Day 1 is defined as the date of IMP administration occurring on Treatment Period 2. 
In Treatment Period 2, study days will be identified as ‘TP2DX’, as an example IMP 
administration at Week 26 will be TP2D1. 


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Statistical Analysis Plan 
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Page 32 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
In Treatment Period 2, other study days are defined relative to the TP2D1 as follow: 
• 
assessments taken on or after Treatment Period 1 and before the Treatment Period 2 IMP 
intake, the Relative Study Day of Treatment Period 1 apply 
• 
assessments on or after the Treatment Period 2 IMP administration: 
Relative Study Day = assessment date - Treatment Period 2 IMP administration date + 1 
Study Day in Treatment Period 3 (Transition Period) 
The date of IMP administration for Transition Period is defined as Day 1 Week 52: in Transition 
Period, Study Day 1 is defined as the date of IMP administration occurring on the Transition 
Period.  
In Transition Period, study days will be identified as ‘TP3DX’, as an example IMP administration 
at Week 52 will be TP3D1. 
In Transition Period, other study days are defined relative to the TP3D1 as follow: 
• 
assessments taken on or after Treatment Periods 1 and 2 and before the Transition Period 
IMP intake, the Relative Study Day of Treatment Periods 1 and 2 apply 
• 
assessments on or after the Transition Period IMP administration: 
Relative Study Day = assessment date - Transition Period IMP administration date + 1 
4.1.3 
Study Visits  
Study visits will be presented in the format “TPX Day X – Week X”. 
In general, assessments will be listed and summarised under the visit in which they were 
collected. However more detailed rules for presenting aggregated summaries are described below 
in this SAP section 4.1.6. This general rule apply to the treatment injection visits as well in 
consideration of assessments scheduled to be performed both pre and post-dose: in other words, 
both the pre-dose physical examination and the post-dose skin examination collected on the day 
of the first injection will be listed and summarised in visit ‘TP1 Day 1 - Week 0’; with same rule 
applying on the day of the second injection.  


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
In general, if not stated otherwise, if subject came on site for week 26 visit, is not treated with 
second injection and is discontinued from the study, her week 26 collected assessments will still 
be reported under visit ‘TP2 Day1 - Week 26’.  
Details about presentation of results collected on study Week 52 are detailed below. 
Handling of study Week 52 data collection 
Study Week 52 represents TP2 Day 183 - Week 52 visit for all the subjects.  
Furthermore, for subjects enrolled into the transition period, such a visit also represents TP3 
Day1; for analyses purpose, for these subjects, visit of Week 52 will be considered as both TP2 
Day 183 - Week 52 and TP3 Day 1 - Week 52. 
In general, for subjects enrolled into the transition period: 
- 
in the study visit listing, the date of Week 52 will appear twice: once for TP2 Day183, 
once for TP3 Day1 
- 
in the listings for the assessments not directly related to the injection and performed 
before third injection, results will be presented under TP2 Day183 and corresponding 
treatment 
- 
in the main period tables for the assessments not directly related to the injection and 
performed before third injection, results will be presented under TP2 Day183 and the 
corresponding treatment 
- 
in the transition period tables for the assessments not directly related to the injection and 
performed before third injection, results will be presented under TP2 Day183 and 
corresponding treatment; in these tables, TP3 Day1 visit will not be presented 
Specific rules for reporting of the assessments scheduled at Week 52 for subjects enrolled into the 
transition period are reported in Table 4. 
 
 
 


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Statistical Analysis Plan 
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Page 34 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Table 4 – Assessments scheduled at Week 52 for subjects enrolled into the transition period 
Assessment 
Handling in listing 
Handling in table 
Procedure(s)/assessment/blood collection to be performed predosea 
- Inclusion/Exclusion Criteria Assessment for the 
Transition Period 
- Re-randomisation 
- Pre-visit Phone Call 
Listed under visit as 
received from eCRF 
data. 
Summarised in transition period 
tables only, as TP3 assessment. 
- Weight, Height, BMI 
- Physical Examination 
- Haematology and Clinical Chemistry 
- Urinalysis 
- 12-lead ECG 
- Vital Signs 
- DXA Scan Assessment (collected up until 10 
days after 3rd injection as explained in above 
section 4.2.1.1 of this SAP) 
- Lateral Spine X-ray 
- Immunogenicity (binding ADAs and NAbs) 
Sampling 
- Serum Drug Concentration Sampling 
- PD (Serum CTX and P1NP) Samplings 
Listed under visit as 
received from eCRF 
data. 
Main and transition period tables: 
summarised under TP2 Day183. 
 
Transition period tables: TP3 
Day1 visit will not be presented. 
Procedure(s)/assessment related to the dosing 
- IMP Administration 
- Participant Identification and Visit Reminder 
Card 
- Medical Device Events 
- Local Tolerance (Skin Examination)b 
Listed under visit as 
received from eCRF 
data. 
Summarised in transition period 
tables only, as TP3 
procedure/evaluation. 
a When time of assessment is collected, this will be compared to the treatment period injection date time to establish if the 
assessment was taken before injection. If time of assessment is not available then the assessment is assumed to be taken before 
injection, unless clear evidence that it wasn’t. 
b Injection site reaction assessment should be done pre-dose and approximately 1-hour post-dose. 


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Statistical Analysis Plan 
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Page 35 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.1.4 
Definition of Baseline  
Unless otherwise specified, baseline will be taken as the last available assessment prior to first 
IMP dosing on Treatment Period 1, Day 1 Week 0.  
4.1.5 
Data Listings 
All original and derived parameters will be listed. 
All listings will include scheduled and unscheduled measurements.  
Unless specified otherwise, data in listings will be organized for Treatment Periods (Treatment 
Period 1 and 2) and Transition Period. 
In general, listings will be sorted by treatment arm allocation (RGB-14-P, US licenced Prolia®), 
subject number, period, and visit (ordered by date and time within subject), as appropriate.  
Data listing number and title will be unique and not being differentiated between main and 
transition period.  
All listings will display the same number of decimals as in the source data. All raw data will be 
reported exactly as provided. Repeated and unscheduled assessments will be included in listing. 
4.1.6 
Tables 
Unless otherwise specified, summaries will be provided for scheduled assessments only.  
In case of scheduled assessments collected out of window, they will not be used in summaries if 
the deviation from scheduled window is severe, as per below defined rules. However, these data 
will be included in the listings and will serve for subject level safety evaluations. 
 Table 5 – Rules for assessments not usable in summary tables due to severe deviation from visit window 
Assessment type 
Criteria for inclusion of sample results in summaries and analysis 
DXA Scan Assessment 
(collected up until 10 
days after 2nd and 3rd 
injection as explained 
If the assessment is more than 30 days prior or after the scheduled, 
then it is not usable in summaries nor in the analyses. 
In other words, the assessments will be used in the summaries and 
analysis only if within the below defined window: 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Assessment type 
Criteria for inclusion of sample results in summaries and analysis 
in above section 4.2.1.1 
of this SAP) 
➔ Week 26: if within TP1D153 and TP1D213 (relative to the 1st 
injection) 
➔ Week 52: if within TP1D336 and TP1D396 (relative to the 1st 
injection)  
➔ Week 78: if within TP3D153 and TP3D213 (relative to the 3rd 
injection) 
Of note: if not falling in the above defined window, the assessment is 
considered severely out of schedule and considered as missing values 
and replaced with the MI techniques detailed in this SAP. 
Pharmacodynamic 
(sCTX and P1NP 
sampling) 
For Week 1 visit, result will be used in the summaries and analysis if 
obtained on or after day 7. 
For visits from Week 2 to Week 17, the result obtained on the 
nominal visit will be used for summaries and analysis (for AUEC 
calculation please refer to section 4.2.2.1 of this SAP), regardless of 
any time deviation from scheduled. 
For visits from Week 26 and subsequent visits, if the assessment is 
more than 3 times out of schedule, then it may not be usable in 
summaries nor in the analyses.  
In other words, the assessments will be used in the summaries and 
analysis only if within the below defined window: 
➔ Week 1: if on or after TP1D7 
➔ Week 2: result obtained under the nominal visit regardless of 
any deviation from scheduled  
➔ Week 4: result obtained under the nominal visit regardless of 
any deviation from scheduled  
➔ Week 8: result obtained under the nominal visit regardless of 
any deviation from scheduled  
➔ Week 12: result obtained under the nominal visit regardless of 
any deviation from scheduled  
➔ Week 17: result obtained under the nominal visit regardless of 
any deviation from scheduled nominal visit 
➔ Week 21: if within TP1D138 and TP1D162 (relative to the 1st 
injection) 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Assessment type 
Criteria for inclusion of sample results in summaries and analysis 
➔ Week 26: if within TP1D171 and TP1D195 (relative to the 1st 
injection) 
➔ Week 52: if within TP2D171 and TP2D195 (relative to the 2nd 
injection) 
➔ Week 78: if within TP3D171 and TP3D195 (relative to the 3rd 
injection) 
Immunogenicity 
(ADAs and Nabs 
sampling) and serum 
drug concentration 
In general, all results will be used in summaries and analysis under 
the nominal visit regardless of any time deviation from scheduled. 
The external laboratory will provide a comment column within the 
result file to indicate if the samples are to be excluded from analysis. 
Any other assessment 
If the assessment is more than 4-times out of schedule (in case the use 
of the 4-time tolerance produces an overlapping between two visits, 
then a 3-times out of scheduled was considered), then not usable in 
summaries nor in the analyses. 
In other words, the assessments will be used in the summaries and 
analysis only if within the below defined window: 
➔ Week 1: if happened within TP1D5 and TP1D11 (relative to 
the 1st injection) 
➔ Week 2: if happened within TP1D12 andTP1D18 (relative to 
the 1st injection) 
➔ Week 4: if happened within TP1D21 andTP1D39 (relative to 
the 1st injection) 
➔ Week 8: if happened within TP1D48 andTP1D72 (relative to 
the 1st injection) 
➔ Week 12: if happened within TP1D78 andTP1D102 (relative 
to the 1st injection) 
➔ Week 17: if happened within TP1D108 andTP1D132 (relative 
to the 1st injection) 
➔ Week 21: if happened within TP1D134 andTP1D166 (relative 
to the 1st injection) 
➔ Week 26: if happened within TP1D167 andTP1D199 (relative 
to the 1st injection) 
➔ Week 27: if happened within TP2D5 andTP2D11 (relative to 
the 2nd injection) 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Assessment type 
Criteria for inclusion of sample results in summaries and analysis 
➔ Week 28: if happened within TP2D12 andTP2D18 (relative to 
the 2nd injection) 
➔ Week 30: if happened within TP2D21 andTP2D39 (relative to 
the 2nd injection) 
➔ Week 38: if happened within TP2D74 andTP2D106 (relative 
to the 2nd injection) 
➔ Week 52: if happened within TP2D167 andTP2D199 (relative 
to the 2nd injection) 
➔ Week 53: if happened within TP3D5 andTP3D11 (relative to 
the 3rd injection) 
➔ Week 54: if happened within TP3D12 andTP3D18 (relative to 
the 3rd injection) 
➔ Week 56: if happened within TP3D26 andTP3D34 (relative to 
the 3rd injection) 
➔ Week 64: if happened within TP3D78 andTP3D102 (relative 
to the 3rd injection) 
➔ Week 78: if happened within TP3D167 andTP3D199 (relative 
to the 3rd injection) 
 
Except when considered as baseline, the repeated and unscheduled assessments will not be 
included in the summaries; however, if an assessment is not available at a scheduled visit or is 
obtained too much out of window (definition of too much out of window is provided above in 
Table 5 in this paragraph) while is collected in an unscheduled / end of study / early termination 
visit falling within the visit window for that same visit according to window above defined in 
Table 5, then the results obtained at unscheduled / end of study / early termination will be used in 
summaries under such visit; moreover if a subject is early terminating the study and the early 
termination visit is not falling in a visit window as per SoA, then assessments obtained at early 
termination visit will be presented under early termination itself. 
Below cases are provided as examples: 
- 
if a subject has vital signs collection for visit TP2 Day 15 - Week 28 performed on 
TP2D18 and has an unscheduled vital signs assessment on TP2D14, such unscheduled 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
assessment will not be used in summaries; in this case, the vital signs  for TP2 Day 15 - 
Week 28 happened within the schedule defined in Table 5and the scheduled assessment is 
therefore used in summaries - if a subject has vital signs collection for visit TP2 Day 15 - 
Week 28 performed on TP2D20 and has an unscheduled vital signs assessment on day 14, 
such unscheduled assessment will be used in summaries under TP2 Day 15 - Week 28; in 
this case, the vital signs for TP2 Day 15 - Week 28 happened outside schedule defined in 
Table 5 and the scheduled assessment cannot be used in summaries 
- 
if a subject has vital signs collection for visit TP2 Day 15 - Week 28 performed on 
TP2D21 and has an unscheduled vital signs assessment on TP2D14, such unscheduled 
assessment will be used in summaries under TP2 Day 15 - Week 28; in this case, the vital 
signs for TP2 Day 15 - Week 28 happened outside schedule defined in Table 5 and the 
scheduled assessment cannot be used in summaries; furthermore if this same subject had 
TP2 Day 30 - Week 30 on TP2D40 and no unscheduled / end of study / early termination 
between TP2D21 and TP2D39, then this subject will result having missing value at TP2 
Day 30 - Week 30 
- 
if a subject last scheduled visit was TP2 Day 30 - Week 30, then she attended early 
termination visit on TP2D50. Such TP2D50 assessments will be presented under early 
termination visit 
- 
if a subject last scheduled visit was TP2 Day 30 - Week 30, then she attended early 
termination visit on TP2D88. Such TP2D88 assessments will be presented under TP2 Day 
90 - Week 38 
Unless specified otherwise, summary tables will be presented separately for Main (Treatment 
Period 1 and 2) and Transition Period.  
Of note for the main and transition period analyses: unless otherwise specified, in the main period 
the summaries / analyses will be limited to Weeks 26 and 52, while in the transition period the 
analyses will be repeated in the subset of the subjects enrolled into the transition period and will 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
include Weeks 26, 52 and 78 for these subjects.  The data cut off (main period, or main and 
transition) will be included on the outputs. 
Within both Main and Transition Period, overall summaries will be shown for all subjects pooled 
together.  
In general, main period tables will present results for: 
- 
RGB-14-P 
- 
Prolia® 
- 
Overall (i.e., RGB-14-P and Prolia® pooled together) 
In general, transition period tables will present results for: 
- 
RGB-14-P to RGB-14-P 
- 
Prolia® to RGB-14-P 
- 
Prolia® to Prolia® 
- 
Overall (i.e., the three above mentioned arms pooled together) 
Changes from baseline in categorical data may be summarised using shift tables where 
appropriate. 
In general, for variables showing multiple possible categories, these will be displayed following 
the within variable logic criteria, for example: adverse events severity will score from Mild and 
going to grow up to a maximum of Death; where such a logic criterium does not exist (example: 
gender, ethnicity, SOC, PT), categories will be displayed by descending frequencies based on the 
RGB-14-P study arm in Treatment Periods tables; in case of two categories with same count in 
RGB-14-P study arm in Treatment Periods tables, alphabetical order will be adopted. In the end, 
the order used to show categories within variables should be the same in both Treatment Periods 
and Transition Period tables. 
4.1.7 
Figures 
Unless specified otherwise, figures will be presented separately for Main (Treatment Period 1 and 
2) and Transition Period. 


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If not stated otherwise, Main and Transition Periods will be presented with the same ordinate (y) 
and abscissa (x) as applicable. In general, all figures will be produced in black and white; 
different line types can be used for each group. Additionally, some figures may also be produced 
in colours for scientific presentations purposes. 
4.1.8 
Software 
All report outputs will be produced using SAS® version 9.4 or a later version in a secure and 
validated environment. 
4.2 Primary Endpoints Estimand Analysis 
In general, if not stated otherwise the variables in this section will be listed in the FAS for the 
main period. This will allow to have listings on all treated subjects. When producing main period 
TFLs, only data included in the main period milestone data freezing scope will be printed in 
listing, while when producing TFLs for the whole study, all the data will be printed in listings 
including data pertinent to the transition period. Detailed strategy for main and transition period 
deliverable is in section 1 of this SAP. 
4.2.1 Primary Efficacy Endpoint and Analysis 
As applicable, unless otherwise stated: 
- 
Summaries will be produced in the FAS and in the PPS in the main and transition period 
- 
Primary treatment policy estimand will be evaluated in FAS 
- 
Secondary principal stratum estimand will be evaluated in PPS  
Multiple Imputation (MI) techniques will be proposed in this SAP; these will include concepts as 
missing completely at random (MCAR), missing at random (MAR) and missing non at random 
(MNAR) [8].  
Forest plots will be produced for visual presentation of results obtained by analysing the primary 
efficacy endpoint with the different approaches presented in this SAP.  


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Forest plots will present results obtained via: 
- 
“Primary TPE – Regular missing data MCAR – Week 52 post-ICE2 assessments Prolia: 
MAR, RGB-14-P: MNAR” 
Primary treatment policy estimand evaluated in FAS, MCAR and composite estimand 
strategy for ICE2, relevant for EMA submission, details in SAP section 4.2.1.2.1.1, point 
estimate and two sided 95% CIs will be plotted 
- 
“Primary TPE – Week 52 regular missing data and post-ICE2 assessments Prolia: MAR, 
RGB-14-P MNAR” 
Primary treatment policy estimand evaluated in FAS, MNAR ‘Under the Null’ and 
composite estimand strategy for ICE2, relevant for FDA submission, details in SAP section 
4.2.1.2.1.2 
o non-inferiority of RGB 14-P compared to Prolia® 
point estimate and Lower Confidence Limit (LCL) of the one sided 95% CIs will be 
plotted 
o non-superiority of RGB 14-P compared to Prolia® 
point estimate and Upper Confidence Limit (UCL) of the one sided 95% CIs will be 
plotted 
- 
“Secondary PSE – PPS, completer, not having experienced any of the two ICEs” 
Secondary: Principal Stratum Estimand evaluated in PPS, details in SAP section 4.2.1.2.2, 
point estimate and two sided 95% CIs will be plotted  
- 
“Sensitivity TPE – Week 52 regular missing data MAR – Post-ICE2 assessments Prolia: 
MAR, RGB-14-P: MNAR” 
Sensitivity for primary treatment policy estimand evaluated in FAS, missing at random 
(MAR) and composite estimand strategy for ICE2, relevant for EMA submission, details in 
SAP section 4.2.1.3.1, point estimate and two sided 95% CIs will be plotted 
- 
“Supplementary efficacy analysis – Regular missing data MCAR – Post-ICE assessments 
excluded from analysis” 


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Supplementary analysis for primary treatment policy estimand evaluated in FAS, Mixed 
Model for Repeated Measures (MMRM) with hypothetical ICE handling strategy, details 
in SAP section 4.2.1.4, point estimate and two sided 95% CIs will be plotted for Week 52 
results 
- 
“Secondary efficacy analysis – Regular missing data MCAR – Post-ICE assessments 
included in analysis” 
Secondary efficacy MMRM, evaluated in both FAS and PPS, details in SAP section 
4.3.1.2.2, point estimate and two sided 95% CIs will be plotted for Week 52 results 
4.2.1.1 Primary Efficacy Endpoint – Definition of Endpoint 
Primary efficacy endpoint consists of percentage of Change from Baseline (%CfB) in lumbar 
spine BMD (g/cm2) at Week 52. 
Efficacy variable will be derived by data collected during the Dual Energy X-Ray 
Absorptiometry (DXA) scan. 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. DXA scans are planned at screening (imaging should be acquired and submitted for 
central independent review prior to the last week of Screening and more than one week from 
Randomisation), pre-dose at Week 26, Week 52 and Week 78 as per SoA (Table 10 and Table 
11). For all participants bone density will be measured at the lumbar spine, total hip and 
femoral neck by the BMD value.  
BMD values for the different anatomical locations will be calculated based on images by central 
laboratory and imported into the clinical database as external data.  
As DXA scan results depend on calibration of DXA scanner used to generate the results, 
calibration may shift or drift, therefore calibration of scanners is monitored using phantom data 
(IQC). Additionally, DXA scanners are not all equivalent in calibration, so that an inter-scanner 
cross-calibration is also necessary for each study (XCAL). External laboratory will then provide 
three options for the BMD: 
- 
BMD Measurement 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
- 
IQC Corrected BMD Measurement 
- 
IQC and XCAL Corrected BMD 
IQC and XCAL Corrected BMD will be used for the analyses; such values will be available in the 
external data transfer MK as per below instructions: 
- 
Lumbar Spine BMD (g/cm2): available in MK data transfer, into MKORRES variable 
when MKGRPID=‘LUMBAR SPINE’ and MKLOC=‘LUMBAR SPINE’ and 
MKTEST=‘IQC and XCAL Corrected BMD’ 
- 
Lx Vertebra BMD (g/cm2): each L1, L2, L3 and L4 vertebras BMD will be available in 
MK data transfer, into MKORRES variable when MKGRPID=‘LUMBAR SPINE’ and 
MKLOC=‘ Lx VERTEBRA’ (where x will assume values 1, 2, 3 or 4 fo r each of the 
vertebras) and MKTEST=‘IQC and XCAL Corrected BMD’ 
- 
Total Hip BMD (g/cm2): available in MK data transfer, into MKORRES variable when 
MKGRPID=‘HIP’ and MKLOC=‘FEMUR’ and MKTEST=‘IQC and XCAL Corrected 
BMD’ 
- 
Femoral neck BMD (g/cm2): available in MK data transfer, into MKORRES variable 
when MKGRPID=‘HIP’ and MKLOC=‘ FEMORAL NECK’ and MKTEST=‘IQC and 
XCAL Corrected BMD’ 
At each anatomical location and for each efficacy assessment visit of interest (Weeks 26, 52, 78, 
or ET), %CfB will be computed as follows, 
 
 
 
%CfB = 
𝐵𝑀𝐷𝑊𝑒𝑒𝑘𝑋𝑋− 𝐵𝑀𝐷𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒
𝐵𝑀𝐷𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒
∗100  
where BMDBaseline and BMDWeekXX respectively are the values of BMD assessed at baseline (last 
assessment before IMP administration) and at the Week of interest (Weeks 26, 52 or 78).  
DXA scans collected up to 10 days after the 3rd injection will still be consider as valid 
assessments for the Week 52, as well DXA scans collected up to 10 days after the 2nd injection 
will still be considered as valid assessments for the Week 26. Example: on 15 October 2022 a 
patient had 3rd injection and BMD scan, but the scan was low quality and not readable, so that a 
new scan was requested which was done on 25 October 2022; such 25 October 2022 scan is still 


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RGB-14-101 
 
Statistical Analysis Plan 
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Page 45 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
to be considered as a valid Week 52 assessment. Such particular cases will all be reviewed and 
considered, and a decision formalized at the BDRM. 
Handling of lumbar spine BMD at Week 52 will vary in the primary and secondary estimand 
strategy and in the sensitivity and robustness analyses and depending on EMA and FDA different 
approaches, detailed methods are therefore detailed in below sections 4.2.1.2, 4.2.1.3, and 4.2.1.4.   
Unless otherwise stated, missing lumbar spine BMD at any other timepoint other than Week 52 
and Week 78 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. Any decision about 
exclusion of subjects from analysis set, including cases of missing BMD baseline values, will be 
discussed, agreed, and documented in the BDRM prior to DB Lock. 
Important note 
To be noted that IQC corrections are applied to the whole pool of scans collected by a scanner 
machine, while XCAL is an inter-scanner correction applied upon availability of all the scans 
collected in the study. Both IQC and XCAL corrections are applied by the vendor. 
As explained in the introduction of this SAP, there will be two DB Locks, two sets of final TFLs 
and two CSR for the study: the main (the first) will be including data up until Week 52, the 
supplemental (the second) including transition period data, i.e., up until Week 78.  
Both at the Week 52 and Week 78 DB Locks, IQC and XCAL correction will be applied by the 
vendor.  
To be noted that IQC and XCAL corrections can change between export produced for 
Week 52 DB Lock and final export produced Week 78 DB Lock.  
This may occur in a subset of subjects whose scanners may have had shifts or drifts post Week 
52, which may potentially change the IQC correction applied in the Week 52 transfer.  
Moreover, the XCAL correction methodology requires that a ‘gold standard’ scanner is selected 
out of all scanners participating in the study for each manufacturer: Lunar and Hologic. Once the 


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RGB-14-101 
 
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Effective Date:  22 Dec 21 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
‘gold standard’ scanner is identified for Lunar and Hologic, each scanner for that manufacturer is 
then compared to the ‘gold standard’ scanner and it is then determined whether an XCAL 
correction factor needs to be applied to the individual scanners for the manufacturer. XCAL 
corrections applied in the Week 52 DB Lock export may differ from the XCAL corrections 
applied at Week 78, which may lead to Week 52 data variations as well.  
In other words, it is expected that baseline, Week 26 and Week 52 IQC and XCAL corrected 
BMDs as well as vertebrae exclusions received in the Week 52 DB Lock export may differ 
from baseline, Week 26 and Week 52 IQC and XCAL corrected BMDs as well as vertebrae 
exclusions subsequently received at Week 78 DB Lock export. 
Baseline, Week 26 and Week 52 IQC and XCAL corrected BMDs received for the Week 52 
DB Lock export will be used for Week 52 DB Lock activities, production of Week 52 final 
TFLs and production of Week 52 main CSR.  
Baseline, Week 26, Week 52 and Week 78 IQC and XCAL corrected BMDs received for the 
Week 78 DB Lock export will be used for Week 78 DB Lock activities, production of Week 78 
final TFLs and production of Week 78 transition CSR.  
4.2.1.2 Primary Efficacy Endpoint – Main Analytical Approach 
By-subject listing of BMD data will be provided.  
Visit-wise summaries of BMD data, CfB and %CfB will be provided for the treatment arms in 
main and transition period. Summaries of missing primary efficacy endpoint will be provided for 
Week 52 and Week 78. 
Missing total hip and femoral neck BMD will not be imputed and will thus result in missing 
%CfB. 
4.2.1.2.1 Primary Efficacy Endpoint – Primary estimand 
Table 2 summarises the primary analysis will be conducted to evaluate the primary endpoint of 
the study using a Treatment Policy Estimand. More in details, a model of Analysis of Covariance 
(ANCOVA) will be implemented to estimate the difference of means between the test and 
reference arms in percentage change from baseline of BMD in lumbar spine at Week 52. The 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 47 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
observed %CfB in lumbar spine BMD at Week 52 (as defined in Section 4.2.1.1) will be the 
dependent variable while the followings will be used as covariates: 
• Treatment Arm (RGB-14-P and US-licenced Prolia®, as planned (randomised) treatment) 
• Stratification factors at randomisation: 
o Previous use of bisphosphonates (yes/no) 
o Geographical region (Europe, US) 
• Baseline BMD value in lumbar spine 
• Machine type (as per DXA scan external data transfer) 
• Machine type * Baseline BMD value interaction 
As result from ANCOVA model, the effect 𝛿̂𝑇𝑃𝐸 of the binary variable Treatment Arm will be 
estimated as regression coefficients. Wald’s two-sided 95% Confidence Interval (CI) will be 
derived for the parameter estimate. 
Handling of intercurrent events 
ICE 1, the first and/or the second dose of randomised IMP is not administered, will be handled 
under treatment policy strategy: all obtained data points will be included in the analysis, in line 
with the ITT principle. 
ICE 2 will consist of the participant receiving other medication alongside the IMP, which affects 
the primary variable, i.e., prohibited therapies as per SAP section 6.2.8. 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. 
Details about strategy implementation for EMA and FDA submissions are outlined here below. 
Descriptive analysis of the number, proportion and timing of intercurrent events (ICEs) will be 
presented. 


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4.2.1.2.1.1 EMA submission 
To test the hypothesis of equivalence, the 𝛿̂𝑇𝑃𝐸 95% CIs, as obtained by the ANCOVA model 
described in section 4.2.1.2.1, will be studied. If the LCL of the two-sided 95% CI around 𝛿̂𝑇𝑃𝐸 
will be greater than n 
 and the UCL will be less than 
, the null hypothesis will be rejected.  
Missing data without experiencing ICE2 will be assumed to be MCAR and will not be imputed. 
Assessments of the primary endpoints observed after occurrence of ICE2 will be disregarded, i.e., 
artificially set as missing, and will be replaced with MI techniques.  
Different assumptions will be made for handling of ICE2 in each of the two arms. Under Prolia® 
group, data artificially set as missing after ICE2 occurrence will be assumed to be MAR and 
imputed assuming they would have behaved like subjects in the same arm had they not taken 
prohibited medication. Under the RGB-14-P group, Week 52 data artificially set as missing after 
ICE2 occurrence will be imputed using MNAR method ‘Under the Null’: after ICE2 primary 
efficacy data are assumed to worsen from “MAR” by an amount of equivalence margin “delta” 
[9][10]. The 
 will be used as the “delta” for the ICE2 in the RGB-
14-P group [11].  
MI will be performed through SAS PROC MI, variables used to impute Week 52 missing values 
will be the dependent variables from ANCOVA model defined at section 4.2.1.2.1; additionally, 
Week 26 data will be used as well in the SAS PROC MI as a post-randomization predictive 
variable; in that contest the post-ICE2 Week 26 BMD will be imputed as well within the SAS 
PROC MI itself, with MAR approach for both the treatment arms. 
Below steps will be followed (note: the steps below will be executed on a copy of the BMD 
%CfB column variable, while the original will be maintained as well): 
Step 1) 
In a copy of the whole original efficacy dataset, the Week 26 and Week 52 %CfB 
observed after ICE2 occurrence will be set as missing 
Step 2) 
Two datasets, one including only Prolia® subject and another one including only 
RGB-14-P, will be filtered from the dataset resulting from Step 1 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
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Effective Date:  22 Dec 21 
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Page 49 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Step 3) 
In the Prolia® dataset created in Step 2, Week 52 %CfB missing or assessed after 
ICE2 occurrence will be imputed as MAR. SAS PROC MI will be executed with 
FCS method, 50 complete datasets will be created, seed 252679 will be used, 
variables used to impute missing values will be the stratification factors (previous 
use of bisphosphonates and geographical region), baseline BMD, machine type 
and Week 26 lumbar spine BMD %CfB 
Step 4) 
In the RGB-14-P dataset created in Step 2, Week 52 %CfB missing or assessed 
after ICE2 occurrence will be imputed as MNAR. SAS PROC MI will be executed 
with FCS method, 50 complete datasets will be created, seed 252679 will be used, 
variables used to impute missing values will be the stratification factors (previous 
use of bisphosphonates and geographical region), baseline BMD, machine type and 
Week 26 lumbar spine BMD %CfB. MNAR statement will be used including 
ADJUST option with SHIFT as sub option, allowing a shift of -1.45 to be applied 
to the imputed Week 52 values 
Step 5) 
From the dataset created at Steps 3 and 4, only data imputed because of ICE2 
occurrence will be retained, while data that were originally missing will be reverted 
back as missing. The two resulting datasets will then be compiled in a unique 
dataset 
Step 6) 
The primary efficacy ANCOVA model as defined at section 4.2.1.2.1 will be 
executed by imputation on dataset obtained in Step 5 
Step 7) 
Estimates from the Step 6 will then be combined through SAS MIANALYZE, 
alpha will be set at 5%. Combined estimation of the difference RGB 14-P – Prolia 
will be examined together with the corresponding two-sided 95% CI. Equivalence 
of RGB 14-P compared to Prolia® will be claimed if the LCL will be greater than 
 and the UCL will be less than 
. 
As a title of example, a SAS code to implement the steps is provided in section 6.4.2. 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 50 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
As sensitivity analysis, missing data will be imputed in accordance with techniques proposed by 
Jakobsen et al (2017) [4], which will be considered as described in section 4.2.1.3: if the 
proportion of non-complete cases is below 5%, sensitivity analysis will be not conducted.  
4.2.1.2.1.2 FDA submission 
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 MI method.  Specifically, for the first test, i.e., test of non-inferiority, 
missing week 52 values for the RGB-14-P group will be imputed under the corresponding 
 
; for the second test, i.e., test of non-superiority, missing 
week 52 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 
randomised subjects with baseline BMD will be included in the analysis.  
In other words, to test the hypothesis of equivalence, two one-sided tests at alpha=0.05 will be 
conducted with the following null hypotheses of non-inferiority and non-superiority: 
- 
Non inferiority of RGB 14-P compared to Prolia® H0: δTPE ≤ 
≤ 
 
- 
Non superiority of RGB 14-P compared to Prolia® H0: δTPE ≥ 
 
Equivalence with respect to the primary efficacy endpoint is demonstrated if both null hypotheses 
are rejected.  
For FDA submission, missing primary efficacy post baseline data will be imputed with MI 
techniques. Furthermore, assessments of the primary endpoints observed after occurrence of ICE2 
will be disregarded, i.e., artificially set as missing, and will be imputed with same MI techniques 
as applied to regular missing data. 
Prolia® group subjects with missing values (originally or post-ICE2 assessments) will be 
assumed to be MAR and imputed assuming they would have behaved like subjects in the same 
arm had they not have a missing value or taken prohibited medication. 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 51 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
RGB-14-P group subjects’ with missing Week 52 values (originally or post-ICE2 assessments) 
will be imputed using MNAR method ‘Under the Null’: missing primary efficacy data are 
assumed to worsen from “MAR” by an amount of equivalence margin “delta” [9][10]. The 
 will be used as the “delta” for the RGB-14-P group [11].  
MI will be performed through SAS PROC MI, variables used to impute Week 52 missing values 
will be the dependent variables from ANCOVA model defined at section 4.2.1.2.1; additionally, 
Week 26 data will be used as well in the SAS PROC MI as a post-randomization predictive 
variable; in that contest the missing Week  26 (originally or post-ICE2 assessments), will be 
imputed as well within the SAS PROC MI itself, with MAR approach for both the treatment 
arms. 
Below steps will be followed (note: the steps below will be executed on a copy of the BMD 
%CfB column variable, while the original will be maintained as well): 
Step (1) In a copy of the whole original efficacy dataset, the Week 26 and Week 52 %CfB 
observed after ICE2 occurrence will be set as missing 
Step (2) Two datasets, one including only Prolia® subject and another one including only 
RGB-14-P, will be filtered from the dataset resulting from Step 1 
Step (3) In the Prolia® dataset created in Step 2, Week 52 %CfB missing or assessed after 
ICE2 occurrence will be imputed as MAR. SAS PROC MI will be executed with 
FCS method, 50 complete datasets will be created, seed 252679 will be used, 
variables used to impute missing values will be the stratification factors (previous 
use of bisphosphonates and geographical region), baseline BMD, machine type 
and Week 26 lumbar spine BMD %CfB 
Step (4) In the RGB-14-P dataset created in Step 2, Week 52 %CfB missing or assessed 
after ICE2 occurrence will be imputed as MNAR. SAS PROC MI will be 
executed with FCS method, 50 complete datasets will be created, seed 252679 
will be used, variables used to impute missing values will be the stratification 
factors (previous use of bisphosphonates and geographical region), baseline 
BMD, machine type and Week 26 lumbar spine BMD %CfB. MNAR statement 
CCI


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
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Effective Date:  22 Dec 21 
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Page 52 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
will be used including ADJUST option with SHIFT as sub option, allowing a 
shift to be applied to the Week 52 values imputed. Shift will be of 
 when 
testing non-inferiority and 
 when testing non-superiority 
Step (5) MI datasets resulting from Steps 3 and 4 will be compiled in a unique dataset, 
with Prolia® having been imputed under MAR and RGB-14-P under MNAR 
assumption 
Step (6) The primary efficacy ANCOVA model as defined at section 4.2.1.2.1 will be 
executed in the dataset obtained in Step 5 by imputation, so to get results from 
each of the 50 complete datasets 
Step (7) Estimates obtained in Step 6 will then be combined through SAS MIANALYZE, 
alpha will be set at 10%. Combined estimation of the difference RGB 14-P – 
Prolia will be examined together with the corresponding one-sided 95% CI: 
non-inferiority of RGB 14-P compared to Prolia® 
non-inferiority will be claimed if the LCL will be greater than n 
 
non-superiority of RGB 14-P compared to Prolia® 
non-superiority will be claimed if the UCL will be less than 
. 
 
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 at the 5% level each; considering the use of MI, all randomised 
subjects with a baseline measurement will be included in the analysis. 
As a title of example, a SAS code to implement the steps is provided in section 6.4.3. 
4.2.1.2.2 Primary Efficacy Endpoint – Secondary estimand 
As described in Table 2, the secondary analysis will be conducted to evaluate the primary 
endpoint of the study using a Principal Stratum Estimand (PSE).  
PSE strategy relates to a target population of interest, taken as the principal stratum, in which 
both ICEs would not occur. The clinical question of interest relates to the treatment effect only 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 53 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
within the principal stratum. PSE is based on potential ICEs occurrence, i.e., subjects who would 
have ICE occurrence if assigned to either treatment arm.  
Let U denote the principal stratum defined by the joint potential PPSC (Per-Protocol and 
Completer) and PSE (i.e., not having experienced the two ICEs as defined in Table 1) status had a 
subject been assigned to RGB-14-P and US-licenced Prolia®, 𝑈= {𝑆1, 𝑆0} = {𝑠𝑠, 𝑠𝑠̅, 𝑠̅𝑠, 𝑠̅𝑠̅}. 
There are four principal strata: 
- 
“Always PPSC & PSE” (𝑈= 𝑠𝑠):(𝑈= 𝑠𝑠): Participant who would comply with study 
(i.e., be PPSC & PSE) under both RGB-14-P and US-licenced Prolia®. 
- 
“PPSC & PSE with RGB-14-P only” (𝑈= 𝑠𝑠̅):(𝑈= 𝑠𝑠̅): Participant who would be PPSC 
& PSE if assigned to RGB-14-P, but would not if assigned to US-licenced Prolia®. 
- 
“PPSC & PSE with US-licenced Prolia® only” (𝑈= 𝑠̅𝑠):(𝑈= 𝑠̅𝑠): Participant who would 
be PPSC & PSE if assigned to US-licenced Prolia®, but would not if assigned to 
RGB-14-P. 
- 
“Never PPSC & PSE” (𝑈= 𝑠̅𝑠̅):(𝑈= 𝑠̅𝑠̅): Participant who would not be PPSC nor PSE 
regardless of the treatment group being assigned to. 
Under the assumptions of Stable Unit Treatment Values Assumption (SUTVA) and random 
assignment of the current study, the Survivor Average Causal Effect (SACE) estimand of the 
difference of means between the RGB-14-P and US-licenced Prolia® arms in percentage change 
from baseline of BMD is composed of two parts, as follows 
 
𝛿𝑆𝐴𝐶𝐸= 𝛿𝑃𝑆𝑇+ 𝑩𝑰𝑨𝑺= 𝛿𝑃𝑆𝑇+ 𝝅𝒔̅𝒔
𝒑𝟎
𝜷𝟎−𝒑𝟏−𝒑𝟎+ 𝝅𝒔̅𝒔
𝒑𝟏
𝜷𝟏, 
where: 
- 
𝛿𝑃𝑆𝑇: principal stratum estimate of the effect (difference) in mean (from ANCOVA). 
- 
𝜋𝑠̅𝑠: marginal proportion of PPSC & PSE with US-licenced Prolia® only 
- 
𝑝0: proportion of being observed PPSC & PSE subjects in the US-licenced Prolia® 
- 
𝑝1: proportion of being observed PPSC & PSE subjects in the RGB-14-P 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 54 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
- 
𝛽0: is the difference in average potential outcome under US-licenced Prolia® arm between 
the stratum “PPSC & PSE with US-licenced Prolia® only” and the stratum “always PPSC 
& PSE” 
- 
𝛽1: is the difference in average potential outcome under RGB-14-P arm between the 
stratum “PPSC & PSE with RGB-14-P only” and the stratum “always PPSC & PSE” 
As for the secondary estimand analysis for this bioequivalence study, no deviations are expected 
in the two arms from the stratum of from “always PPSC & PSE”, therefore 𝛽0 = 0 and 𝛽1= 0 will 
be considered. In other words, 𝛿𝑆𝐴𝐶𝐸= 𝛿𝑃𝑆𝑇 is assumed for secondary estimand analysis. 
Parameters 𝛽0 and 𝛽1 , as well as 𝜋𝑠̅𝑠 , will be made to vary as part of the sensitivity tipping point 
as described in section 4.2.1.3.3 of this SAP. 
A model of Analysis of Covariance (ANCOVA) will be used to estimate 𝛿𝑃𝑆𝑇: the observed 
%CfB in lumbar spine BMD at Week 52 (as defined in Section 4.2.1.1) will be the dependent 
variable while the followings will be model covariates: 
• Treatment Arm (RGB-14-P and US-licenced Prolia®, as planned treatment) 
• Stratification factors for randomisation: 
o Previous use of bisphosphonates (yes/no) 
o Geographical region (Europe, US) 
• Baseline BMD value in lumbar spine 
• Machine type (as per DXA scan external data transfer) 
• Machine type * Baseline BMD value interaction 
As result from ANCOVA model, the estimated effect 𝛿̂𝑃𝑆𝑇 of the binary variable treatment arm 
will be obtained as regression coefficients. Wald’s two-sided 95% CI will be derived for the 
parameter estimate. 
As a title of example, a SAS code is provided in section 6.4.1. 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 55 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
To test the hypothesis of equivalence, the 𝛿̂𝑃𝑆𝑇 95% CIs will be studied. If the LCL of the 95% 
CIs around 𝛿̂𝑃𝑆𝐸 will be greater than 
 than 
 and the UCL will be less than 
 the null hypothesis 
will be rejected. 
If the proportion of non-complete cases in subjects PPS & PSE is higher than 5%, 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. Approach for MI will 
be similar to one used for primary efficacy primary estimand for FDA submission, which is 
treated in section 4.2.1.2.1.2. 
4.2.1.3 Primary Efficacy Endpoint – Sensitivity Analyses 
4.2.1.3.1 Primary Efficacy Endpoint – Primary estimand sensitivity analysis for EMA 
submission 
For EMA submission, missing primary efficacy post baseline data will be imputed as a sensitivity 
estimation. As sensitivity analysis, missing data will be imputed in accordance with techniques 
proposed by Jakobsen et al (2017) [4]: if the proportion of non-complete cases is below 5%, 
sensitivity analysis will be not conducted. 
Missing data will be assumed to be MAR and imputed using fully conditional specification (FCS) 
method via SAS PROC MI. Additionally, likewise for the primary endpoint primary estimand 
analysis as outlined in section 4.2.1.2.1.1, assessments of the primary endpoints observed after 
occurrence of ICE2 will be disregarded, i.e., artificially set as missing, and will be replaced with 
MI techniques. Different assumptions will be made for handling of ICE2 in each of the two arms. 
Under Prolia® group, data artificially set as missing after ICE2 occurrence will be assumed to be 
MAR and imputed assuming they would have behaved like subjects in the same arm had they not 
taken prohibited medication. Under the RGB-14-P group, Week 52 data artificially set as missing 
after ICE2 occurrence will be imputed using MNAR method ‘Under the Null’: after ICE2 
primary efficacy data are assumed to worsen from “MAR” by an amount of equivalence margin 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 56 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
“delta” [9][10]. The equivalence margin of 
 will be used as the “delta” for the RGB-14-P 
group [11].  
MI will be performed through SAS PROC MI, variables used to impute Week 52 missing values 
will be the dependent variables from ANCOVA model defined at section 4.2.1.2.1; additionally, 
Week 26 data will be used as well in the SAS PROC MI as a post-randomization predictive 
variable; in that contest the missing Week  26 (originally or post-ICE2 assessments) will be 
imputed as well within the SAS PROC MI itself, with MAR approach for both the treatment 
arms. 
 Below steps will be followed (note: the steps below will be executed on a copy of the BMD 
%CfB column variable, while the original will be maintained as well): 
Step 1) 
In a copy of the whole original efficacy dataset, the Week 26 and Week 52 %CfB 
observed after ICE2 occurrence will be set as missing 
Step 2) 
Two datasets, one including only Prolia® subject and another one including only 
RGB-14-P, will be filtered from the dataset resulting from Step 1 
Step 3) 
In the Prolia® dataset created in Step 2, Week 52 %CfB missing or assessed after 
ICE2 occurrence will be imputed as MAR. SAS PROC MI will be executed with 
FCS method, 50 complete datasets will be created, seed 252679 will be used, 
variables used to impute missing values will be the stratification factors (previous 
use of bisphosphonates and geographical region), baseline BMD, machine type and 
Week 26 lumbar spine BMD %CfB 
Step 4) 
In the RGB-14-P dataset created in Step 2, Week 52 %CfB missing or assessed 
after ICE2 occurrence will be imputed as MAR. SAS PROC MI will be executed 
with FCS method, 50 complete datasets will be created, seed 252679 will be used, 
variables used to impute missing values will be the stratification factors (previous 
use of bisphosphonates and geographical region), baseline BMD, machine type and 
Week 26 lumbar spine BMD %CfB. To be able to impute ‘Under the Null’ the 
Week 52 post ICE2 occurrence values, the MNAR statement will be used including 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 57 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
ADJUST option with SHIFT and ADJUSTOBS as sub options, allowing a shift of 
-1.45 to be applied to only the value imputed after occurrence of ICE2. 
Step 5) 
MI datasets resulting from Steps 3 and 4 will be compiled in a unique dataset 
Step 6) 
The primary efficacy ANCOVA model as defined at section 4.2.1.2.1 will be 
executed by imputation on complete dataset obtained in Step 5 
Step 7) 
Estimates from the Step 6 will then be combined through SAS MIANALYZE, first 
type error alpha will be set at 5%. Combined estimation of the difference RGB 14-
P – Prolia will be examined together with the corresponding two-sided 95% CI. 
Equivalence of RGB 14-P compared to Prolia® will be suggested if the LCL will 
be greater than n 
 and the UCL will be less than 
 
As a title of example, a SAS code to implement the steps is provided in section 0. 
4.2.1.3.2 Primary Efficacy Endpoint – Primary estimand sensitivity tipping point for FDA 
submission 
For FDA submission, robustness of the main estimator will be assessed by using two-dimensional 
tipping point analyses allowing assumptions about missing Week 52 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. Again, 
assessments of the primary endpoints observed after occurrence of ICE2 will be disregarded, i.e., 
artificially set as missing, and will be imputed in the tipping point analysis with same MI 
techniques as applied to regular missing data. 
The analysis finds a (tipping) point in this spectrum of assumptions, at which conclusions change 
from being favorable to the experimental treatment to being unfavorable. After such a tipping 
point is determined, clinical judgment can be applied as to the plausibility of the assumptions 
underlying this tipping point. Tipping point analysis is a method of exploring the influence of 
missingness on the overall conclusion of the treatment difference by shifting imputed missing 
values in the test group towards the reference group until the study results are reversed. Tipping 
point is evaluated based on a series of shift parameters. 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 58 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Different assumptions will be made for missing values (and post-ICE2 assessments) in each of 
the two arms. SAS PROC MI will be utilised with MNAR statement including ADJUST option 
with SHIFT as sub option to allow the Week 52 outcomes in the two treatment arms to vary 
independently. 
To stress both non-inferiority and non-superiority null hypotheses, a broad range of shifts will be 
applied to the two arms, so to obtain a quasi-quantitative ‘delta’ variation. 
For MI procedure, analysis of MI data and results combination for each imputation, similar 
techniques will be used as presented in section 4.2.1.2.1.2, details will follow in the below.  
Tipping point analysis will be executed following two approaches. If equivalence is established in 
the two approaches, it will be concluded that the MI method used for handling missing (and post-
ICE2 assessments) is not impacting the study results interpretation; however, if equivalence is not 
consistently established with both the two approaches, then the tipping points reversing study 
conclusions will be evaluated from medical point of view to determine if such scenarios are 
clinically plausible. 
Under both approaches, MI will be performed through SAS PROC MI. Variables used to impute 
Week 52 missing values will be the dependent variables from ANCOVA model defined at section 
4.2.1.2.1; additionally, Week 26 data will be used as well in the SAS PROC MI as a post-
randomization predictive variable; in that contest the missing Week  26 (originally or post-ICE2 
assessments) will be imputed as well within the SAS PROC MI itself, with MAR approach for 
both the treatment arms. 
Tipping point analysis approach 1 
Week 52 Prolia® MI under MAR assumption (i.e., shift = 0), RGB 14-P MI assumed MNAR (i.e., 
shifts under the null hypothesis). 
MAR assumption applied to Prolia® (i.e., shift = 0), while in RGB 14-P arm shifts will be 
applied ranging from 'delta' (' (
 when testing non-inferiority, 
y, 
 when testing non-
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 59 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
superiority) to approximately 5 times delta (-7.45 when testing non-inferiority, 7.45 when testing 
non-superiority).  
Below steps will be followed (note: the steps below will be executed on a copy of the BMD 
%CfB column variable, while the original will be maintained as well): 
Step 1) 
In a copy of the whole original efficacy dataset, the Week 26 and Week 52 %CfB 
observed after ICE2 occurrence will be set as missing 
Step 2) 
Two datasets, one including only Prolia® subject and another one including only 
RGB-14-P, will be filtered from the dataset resulting from Step 1 
Step 3) 
In the Prolia® dataset created in Step 2, Week 52 %CfB missing or assessed after 
ICE2 occurrence will be imputed as MAR. SAS PROC MI will be executed with 
FCS method, 50 complete datasets will be created, seed 252679 will be used, 
variables used to impute missing values will be the stratification factors (previous 
use of bisphosphonates and geographical region), baseline BMD, machine type and 
Week 26 lumbar spine BMD %CfB 
Step 4) 
In the RGB-14-P dataset created in Step 2, Week 52 %CfB missing or assessed 
after ICE2 occurrence will be imputed as MNAR. SAS PROC MI will be 
executed with FCS method, 50 complete datasets for each applied shift will be 
created, seed 252679 will be used, variables used to impute missing values will 
be the stratification factors (previous use of bisphosphonates and geographical 
region), baseline BMD, machine type and Week 26 lumbar spine BMD %CfB. 
MNAR statement will be used including ADJUST option with SHIFT as sub 
option, allowing a shift to be applied to the Week 52 values imputed. Different 
shifts will be applied as part of this tipping point analysis: shifts will vary from 
om  
 to -7.45 when testing non-inferiority, from 
om 
 to 7.45 when testing non-
superiority, by incremental value of 1.  
Step 5) 
MI datasets resulting from Steps 3 and 4 will be compiled in a unique dataset for 
each shift applied. 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 60 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Step 6) 
Separately for each RGB-14-P shift level, the primary efficacy ANCOVA model 
as defined at section 4.2.1.2.1 will be executed by imputation on complete dataset 
obtained from Step 5. 
Step 7) 
Estimates from the Step 6 will then be combined through SAS MIANALYZE, by 
each RGB-14-P shift level, alpha will be set at 10%. Combined estimation of the 
difference RGB 14-P – Prolia will be examined together with the corresponding 
one-sided 95% CI: 
non-inferiority of RGB 14-P compared to Prolia® 
non-inferiority will be confirmed if the LCL will be greater than n 
 
non-superiority of RGB 14-P compared to Prolia® 
non-superiority will be confirmed if the UCL will be less than 
 
Step 8) 
If non-inferiority (non-superiority) is confirmed under all shifts, the procedure 
will end, and it will be concluded that approach 1 suggests that the method used 
for MI of missing (and post-ICE2 assessments) is not impacting the results 
interpretation; 
If non-inferiority (non-superiority) is not confirmed under all shifts, then the 
procedure will continue to Step 9 below 
Step 9) 
If the non-inferiority (non-superiority) conclusion is reverted, then the ‘area’ 
thresholds where such conversion is observed, which will have extent of 1, will 
be further examined in deeper detail; Steps 3 to 7 will be repeated; in Step 4 RGB 
14-shifts will be made to vary from lower to upper ‘area’ thresholds by 
incremental value of 0.1; this will allow to identify a stricter ‘area’ threshold 
where study conclusion are reversed; such stricter ‘area’ will have extent of 0.1 
and will be investigated in deeper detail as per below Step 10 
Step 10) Steps 3 to 7 will be repeated again; in Step 4 RGB 14-shifts will be made to vary 
within the stricter ‘area’ thresholds identified in above Step 9; shifts will be made 
to vary from lower to upper stricter ‘area’ thresholds by incremental value of 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 61 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
0.01; this will allow to identify the tipping point reversing the study conclusion 
with a detail of two decimal places 
Results obtained while running the approach 1 will be tabulated, including the shift applied to the 
RGB 14-P, the point estimate obtained for the primary endpoint together with the two-sided 90% 
Cis and the standard error. When testing non-inferiority, observed LCL for the different RGB 14-
P will be plotted, observed UCL will be plotted when testing non-inferiority. A forest plot will be 
present as well: point estimate and 90% Cis will be plotted for all the different RGB 14-P shifts 
under the non-inferiority and non-superiority tests.  
Execution of above-described approach 1 will be supported by SAS macro available at section 
6.4.5 of this SAP. Such macro was developed based on an example available from SAS user 
guide [20]. SAP section 6.4.5 also provides sample SAS code for the required plots. 
Tipping point analysis approach 2 
Week 52 Prolia® and RGB 14-P MI assumed MNAR (i.e., shifts under the null hypothesis). 
MNAR shifts will be applied to both Prolia® and RGB 14-P arm shifts ranging from ‘delta’ to 
approximately 5 times delta. 
When testing non-inferiority, shifts in the range from 
 to 7.45 will be applied to Prolia® 
while shifts in the range from -7.45 to 
7.45 to 
 will be applied to RGB 14-P. 
Conversely, when testing non-superiority, shifts in the range from -7.45 to 
7.45 to 
 will be applied 
to Prolia® while shifts in the range from 
 to 7.45 will be applied to RGB 14-P.Below steps 
will be followed (note: the steps below will be executed on a copy of the BMD %CfB column 
variable, while the original will be maintained as well): 
Step 1) 
In a copy of the whole original efficacy dataset, the Week 26 and Week 52 %CfB 
observed after ICE2 occurrence will be set as missing 
Step 2) 
Two datasets, one including only Prolia® subject and another one including only 
RGB-14-P, will be filtered from the dataset resulting from Step 1 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 62 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Step 3) 
In the Prolia® dataset created in Step 2, Week 52 %CfB missing or assessed after 
ICE2 occurrence will be imputed as MNAR. SAS PROC MI will be executed with 
FCS method, 50 complete datasets will be created, seed 252679 will be used, 
variables used to impute missing values will be the stratification factors (previous 
use of bisphosphonates and geographical region), baseline BMD, machine type and 
Week 26 lumbar spine BMD %CfB. MNAR statement will be used including 
ADJUST option with SHIFT as sub option, allowing a shift to be applied to the 
Week 52 values imputed. Different shifts will be applied as part of this tipping 
point analysis: shifts will vary from 
rom 
 to 7.45 when testing non-inferiority, from 
-7.45 to 
7.45 to 
 when testing non-superiority, by incremental value of 1. 
Step 4) 
In the RGB-14-P dataset created in Step 2, Week 52 %CfB missing or assessed 
after ICE2 occurrence will be imputed as MNAR. SAS PROC MI will be 
executed with FCS method, 50 complete datasets will be created, seed 252679 
will be used, variables used to impute missing values will be the stratification 
factors (previous use of bisphosphonates and geographical region), baseline 
BMD, machine type and Week 26 lumbar spine BMD %CfB. MNAR statement 
will be used including ADJUST option with SHIFT as sub option, allowing a 
shift to be applied to the Week 52 values imputed. Different shifts will be applied 
as part of this tipping point analysis: shifts will vary from -7.45 to 
7.45 to 
 when 
testing non-inferiority, from 
 to 7.45 when testing non-superiority, by 
incremental value of 1.  
Step 5) 
MI datasets resulting from Steps 3 and 4 will be compiled in a unique dataset 
Step 6) 
Separately for each combination of Prolia® and RGB-14-P shift level, the 
primary efficacy ANCOVA model as defined at section 4.2.1.2.1 will be executed 
by imputation on complete dataset obtained from Step 5 
Step 7) 
Estimates from the Step 6 will then be combined through SAS MIANALYZE, by 
each RGB-14-P shift level, alpha will be set at 10%. Combined estimation of the 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 63 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
difference RGB 14-P – Prolia will be examined together with the corresponding 
one-sided 95% CI: 
non-inferiority of RGB 14-P compared to Prolia® 
non-inferiority will be confirmed if the LCL will be greater than n 
 
non-superiority of RGB 14-P compared to Prolia® 
non-superiority will be confirmed if the UCL will be less than 
 
Step 8) 
If non-inferiority (non-superiority) is confirmed under all shift combinations, the 
procedure will end, and it will be concluded that approach 2 suggests that the 
method used for MI of missing (and post-ICE2 assessments) is not impacting the 
results interpretation 
If non-inferiority (non-superiority) is not confirmed under all shifts, then the 
procedure will continue to Step 9 below 
Step 9) 
If the non-inferiority (non-superiority) conclusion is reverted, then the ‘area(s)’ 
thresholds where such conversion is observed, which will have extent of 1, will 
be further examined in deeper detail; Steps 3 to 7 will be repeated in each area 
where the conversion is observed; in Steps 3 and 4, within each identified ‘area’, 
Prolia® and RGB 14-shifts will be made to vary from lower to upper ‘area’ 
thresholds by incremental value of 0.1; this will allow to identify stricter ‘area(s)’ 
threshold where study conclusion are reversed; such stricter ‘area(s)’ will have 
extent of 0.1 and will be investigated in deeper detail as per below Step 10 
Step 10) Steps 3 to 7 will be repeated again; in Steps 3 and 4, within each identified 
stricter ‘area’, Prolia® and RGB 14-P shifts will be made to vary within the 
stricter ‘area’ thresholds identified in above Step 9; shifts will be made to vary 
from lower to upper stricter ‘area’ thresholds by incremental value of 0.01; this 
will allow to identify the tipping points reversing the study conclusion with a 
detail of two decimal places 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 64 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Results obtained while running the approach 2 will be tabulated, including the shift applied to 
Prolia® and RGB 14-P, the point estimate obtained for the primary endpoint together with the 
two-sided 90% CIs and the standard error. For different combinations of Prolia® and RGB 14-P 
shifts: 
- 
observed LCL will be plotted when testing non-inferiority, UCL when testing non-
superiority 
- 
forest plots will also be present, plotting point estimate and 90% CIs under the non-
inferiority and non-superiority tests 
Execution of above-described approach 2 will be supported by SAS macro available at section 
6.4.6 of this SAP. Such macro was developed based on an example available from SAS user 
guide [20]. SAP section 6.4.6 also provides sample SAS code for the required plots. 
4.2.1.3.3 Primary Efficacy Endpoint – Secondary estimand sensitivity tipping point analysis 
Due to the nature of study design, robustness of the estimator will be assessed by implementing 
in a Causal Inference framework, as proposed by Lou et al. [5]. More in detail, principal 
stratification approach will be followed.  
The BIAS component of the 𝛿𝑆𝐴𝐶𝐸 formula will be studied, please refer to formula and 
terminology presented in section 4.2.1.2.2 of this SAP.  
A tipping point sensitivity analysis will be conducted to evaluate the robustness of the conclusion 
based on the observed principal stratum [PST] estimator under different scenarios, by varying the 
values of 𝛽0, 𝛽1 and 𝜋𝑠̅𝑠 within clinically meaningful ranges. Boundaries for the range of 𝜋𝑠̅𝑠 can 
be easily derived as  
𝜋𝑠̅𝑠 ∈[max(0, 𝑝0 −𝑝1) , min (𝑝0, 1 −𝑝1)]. 
The proportion of PST with US-licenced Prolia® only is bounded, but the selection effects (𝛽0, 
𝛽1) are not. 
The robustness analysis will be conducted, below steps will be followed: 


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Related to:  SOP-GDO-WW-019 
 
Page 65 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Step 1) 
Compute 𝑝̂0 and 𝑝̂1 and compute the 𝛿̂𝑝= 𝑝̂1 −𝑝̂0 and derive the two-sided 90% 
confidence interval of 𝛿̂𝑝 using Yates’s continuity correction. If the 90% CI is 
included in the specific equivalence margin, tipping point analysis can be 
performed. For this study, the specific equivalence margin for the difference of 
proportion of PSE subjects is set as ± 15% 
Step 2) 
Estimate 𝛿̂𝑃𝑆𝑇 and Wald’s 95% CI by ANCOVA model (𝛿𝑃𝑆𝑇  as estimated by the 
secondary estimand analysis described in section 4.2.1.2.2 of this SAP) 
Step 3) 
Compute the boundaries for 𝜋𝑠̅𝑠 as previously defined and identify a few cut 
point inside the range to perform tipping point analysis (for example if the range 
of 𝜋𝑠̅𝑠 is between 0 and 15%, it is suggested to cover the interval with 0%, 5%, 
10% and 15%). Furthermore, derive 𝜋̂𝑠𝑠̅ as: 
𝜋𝑠𝑠̅ = 𝑝̂1 −𝑝̂0 + 𝜋𝑠̅𝑠 
Step 4) 
For each value of 𝜋𝑠̅𝑠,a clinical meaningful range is set for 𝛽0 and 𝛽1 (for 
example, between ±35%) 
Step 5) 
Compute 𝛿̂𝑆𝐴𝐶𝐸 as defined below with its 95% CI: because the sensitivity 
parameters are considered as “fixed,” the 90% CI for an estimator of the SACE can 
simply be constructed by shifting the CI of the observed 𝛿𝑃𝑆𝑇  (as estimated by the 
secondary estimand analysis described in section 4.2.1.2.2 of this SAP) by the 
BIAS 
Step 6) 
Figure 3 shows an example of tipping point plot. A plot will be produced for each 
value of a series that cover the whole 𝜋𝑠̅𝑠. Horizontal and vertical axes 
respectively represent values for 𝛽0 and 𝛽1. Considering the value of 𝜋𝑠̅𝑠 and for 
each value of 𝛽0 and 𝛽1, 𝛿̂𝑆𝐴𝐶𝐸 and its 95% are derived. If the LCL for the set of 
𝛽0, 𝛽1 and  𝜋̂𝑠̅𝑠 is greater than n 
 and UCL is less than 
 the point is plotted 
as green, while red otherwise. The black point is 𝛿̂𝑃𝑆𝑇 where the BIAS quantity is 
zero due to 𝛽0 = 𝛽1 = 0 
CCI
CCI


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Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
3URMHFW'RFXPHQW9HUVLRQ1R'RFXPHQW(IIHFWLYH'DWH'DWHRIODVWVLJQDWXUH
73*'2::


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Step 7)
If most of the multiple plots, which cover the range of variation of ߨ௦ҧ௦ǡ  will not 
show large red areas close to the PST estimate black point, the equivalence 
conclusion would be considered robust. The equivalence conclusion reverses only 
if the selection effects under RGB 14-P and US licenced Prolia® are very 
unbalanced (i.e., if the absolute value of ߚ଴െߚଵ is large). This will happen if 
RGB 14-P and US licenced Prolia have very different safety and efficacy 
profiles 
Step 8)
The associated green/red value related to any ߜመௌ஺஼ாvalues will be listed and 
quantitative summaries will be provided 

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Such robustness analysis may be executed in software R [22]. 
 3ULPDU\(IILFDF\(QGSRLQW±6XSSOHPHQWDU\$QDO\VHV
The supplementary estimand of BMD %CfB at Week 52 will utilise 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.  


Parexel International 
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Statistical Analysis Plan 
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Effective Date:  22 Dec 21 
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Page 67 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Data points captured after the ICE will be left out from the FAS analysis. The same ICEs will be 
applied as for the primary and secondary estimands.  
Primary endpoint will be analysed by using MMRM with the following factors:. 
• Treatment (RGB-14-P and US-licenced Prolia®, as planned treatment) 
• Stratification factors for randomisation: 
o Previous use of bisphosphonates (yes/no) 
o Geographical region (Europe, US) 
• Baseline BMD value 
• Machine type (as per DXA scan external data transfer) 
• Machine type * Baseline BMD value interaction 
• Study Week (Week 26 and Week 52 will be included in the model) 
• Study Week (Week 26 and Week 52) * Treatment interaction 
Unstructured covariance matrix will be used. In case of convergence issues, alternative structures 
will be considered in the following order: Autoregressive(1), Compound Symmetry, Toeplitz; 
until convergence is met. 
Missing data will be assumed to be MCAR and will not be imputed.  
As a title of example, a SAS code to implement the steps is provided in section 6.4.7. 
4.2.2 
Primary Pharmacodynamic Endpoint and Analysis 
Of note: pharmacodynamic results are received from external vendor laboratory; in some 
instances, sCTX results were received with the two test codes ZCTXG and ZCTX1; in these 
instances, based on instructions received from laboratory, the results received under code 
ZCTXG is to be considered as latest and more accurate and used for summaries, analysis and any 
derivation detailed in this SAP; both results obtained under ZCTXG and ZCTX1 will be 
displayed in the data listings, with a clear identification key for results received under code 
ZCTXG and under code ZCTX1. 


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Statistical Analysis Plan 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.2.2.1 Primary Pharmacodynamic Endpoint – Definition of Endpoint 
AUEC of %CfB sCTX0-m6 until Week 26 is the primary pharmacodynamic variable. 
sCTX PD markers will be measured and compared as specified at the endpoint. Blood samples 
will be collected for measurement of serum concentrations of sCTX as per SoA (Table 10 and 
Table 11). Baseline is defined as the concentration values of sCTX derived by serum sampling 
collected pre-dose at Day 1 Week 0.  
As sCTX values are expected to decrease over time following injection, the CfB will be derived 
and interpreted as a reduction from baseline. %CfB in serum sCTX will then be computed as 
follows, 
%CfB sCTX = 𝑠𝐶𝑇𝑋𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒− 𝑠𝐶𝑇𝑋𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡
𝑠𝐶𝑇𝑋𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
∗100 
where 𝑠𝐶𝑇𝑋baseline and 𝑠𝐶𝑇𝑋timepoint respectively are concentration values at baseline (including 
pre-dose at Day 1, Week 0) and at post-baseline timepoint.  
The %CfB AUEC after first dose until Week 26 in sCTX0-m6 will be estimated as key PD 
parameter for the primary endpoint. 
The AUEC of %CfB sCTX(0-m6) will be calculated as the area under/over 0 after the first dose 
administration (Day 1 Week 0) until week 26.  
AUEC of %CfB sCTX(0-m6) is calculated as follows: 
𝐴𝑈𝐸𝐶(0-m6) = ∫
𝐸(𝑡)𝑑𝑡
𝑤𝑒𝑒𝑘 26
0
 
The trapezoidal method will be employed for all trapezoids arising from %CfB sCTX. The area 
under the %CfB-time curve will be divided into a series of trapezoids, each bounded by two 
consecutive time points and corresponding %CfB sCTX values. 
For each trapezoid, the area will be calculated via the formula: 
Piecewise area = (d2 – d1) * (C1 + C2) / 2 
where d1 and d2 are the time points at the boundaries of the trapezoid and C1 and C2 are the 
corresponding %CfB sCTX values at those time points. The AUEC value is obtained by 
summing the areas of all the trapezoids between the initial time point (day1) and the final time 


Parexel International 
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RGB-14-101 
 
Statistical Analysis Plan 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 69 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
point (Week 26) Example for %CfB AUEC derivation is provided in appendix section 
6.4.8;actual days will be used for the calculation of the AUEC. 
4.2.2.2 Primary Pharmacodynamic Endpoint – Main Analytical Approach 
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 presented as BLQ in 
listing. In summary tables and graphically representation, including derivation of AUEC, values 
BLQ will be imputed as LLOQ.  The individual serum concentration of sCTX, %CfB and AUEC 
of %CfB will be listed and summarised in tabular and graphical format by treatment group at 
each planned sampling time using descriptive statistics.  
Analysis will be performed on the PDS population. 
To evaluate the %CfB AUEC sCTX0-m6 (required as primary endpoint for EMA and secondary 
for FDA), the treatment comparison will be made using the ANCOVA with natural 
log-transformed AUEC data as the dependent variable while the followings will be model 
covariates: 
• Treatment Arm. 
• Stratification factors for randomisation: 
o Previous use of bisphosphonates (yes/no) 
o Geographical region (Europe, US) 


Parexel International 
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Statistical Analysis Plan 
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Related to:  SOP-GDO-WW-019 
 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
• Log of baseline sCTX 
LS means for %CfB AUEC sCTX0-m6 will be back transformed to derive geometric means and 
presented with the corresponding LS GMR with their corresponding 95% CIs. Geometric LS 
mean ratios will be derived by back transforming the LS mean difference between RGB-14-P and 
Prolia® (RGB-14-P - Prolia®) and presented as ratio (GMR). Back transformed LS mean and 
GMR will be presented as percentages, as well as the corresponding CIs. Delta method was 
applied to back transform geometric mean standard error used for the computation of 
corresponding 95% CIs. As an example, SAS code is provided in section 6.4.9. 
Pharmacodynamic equivalence will be concluded if the 95% CI of the treatment GMR is 
contained within the 80% to 125% equivalence margin. 
4.2.2.3 Primary Pharmacodynamic Endpoint – Sensitivity Analyses 
Not Applicable. 
4.2.2.4 Primary Pharmacodynamic Endpoint – Supplementary Analyses 
Not Applicable. 
4.3 Secondary Endpoints and Analysis 
4.3.1 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints are listed in section 1.1, Table 1. 
As applicable, unless otherwise stated, secondary efficacy analyses will be executed in FAS and 
PPS in the main and transition period.  


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Page 71 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.3.1.1 Secondary Efficacy – Definition of Endpoint(s) 
4.3.1.1.1 %CfB in total hip BMD at Weeks 26, 52 and 78 
As derivations and data handling are very similar to those necessary for the primary endpoint, this 
secondary endpoint was described in section 4.2.1.1; please refer to that section for detailed 
instructions. 
4.3.1.1.2 %CfB in lumbar spine BMD at Weeks 26 and 78 
As derivations and data handling are very similar to those necessary for the primary endpoint, this 
secondary endpoint was described in section 4.2.1.1; please refer to that section for detailed 
instructions. 
4.3.1.1.3 %CfB in femoral neck BMD at Weeks 26, 52 and 78 
As derivations and data handling are very similar to those necessary for the primary endpoint, this 
secondary endpoint was described in section 4.2.1.1; please refer to that section for detailed 
instructions. 
4.3.1.1.4 Vertebral fragility fracture incidence 
Information on vertebral fractures will be centrally collected through the evaluation of lateral 
thoraco-lumbar spine X-ray planned at screening, Weeks 52 and 78, as per SoA (Table 10 and 
Table 11). For central assessment of vertebral fractures by lateral spine X-ray, the Genant visual 
semiquantitative grading scale will be used [12], Genant scores range 0 – 3 for presence and 
severity of vertebral fractures (0 = normal, 1 = mild, 2 = moderate, 3 = severe). A value of 0 will 
be interpreted as no vertebral fracture, while values higher than 0 will be interpreted as presence 
of a vertebral fracture with severity indicated by the score itself. Genant score is received into the 
MO X-ray external data transfer, when variable MOTESTCD = ANASCORE the associated 
MOORRES contains the Genant score. Any vertebral fracture emerging or worsening in the 
Genant score on or after first IMP injection, fracture will be considered for this endpoint. 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Furthermore, collected AEs will be scrutinised by the Medical Monitor to flag vertebral fracture 
events. A reconciliation should happen between vertebral fracture events as flagged into the X-
ray external data transfer and events logged as AEs into the EDC, as any fracture (symptomatic 
and asymptomatic) occurring during the study should 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.  
For each of the timepoints (Weeks 52 and 78), a binary variable will be derived, on a 
subject-by-subject basis, as follow: 
- 
No (0): no new episodes and no worsening from baseline of vertebral fragility fracture 
until Week XX 
- 
Yes (1): presence of new episodes or worsening from baseline of vertebral fragility 
fracture until Week XX 
where, Week XX is the time point of interest.  
In order to mitigate the risk associated with non-evaluable X-ray on certain vertebras (i.e., the 
assessment is received as “NOT ASSESSABLE” for a vertebra from the external vendor), as an 
additional sensitivity analysis, the worst case scenario is considered and such NOT 
ASSESSABLE results will be considered as new fractures on the relevant vertebra. 
Of note: two datasets are received from external vendor for x-ray reading, these are MO and 
SMO; as per vendor instructions SMO corresponds to secondary read data that are not to be 
included in the statistical analysis; therefore, for any derivation based on x-ray reading described 
in this SAP, the dataset MO will be the only one considered; data results received in SMO will be 
displayed in the data listings with a clear identification key for results coming from MO versus 
SMO. 
4.3.1.1.5 Non-vertebral fragility fracture incidence 
Information on any non-vertebral fractures while in the study will be recorded as AEs, collected 
AEs will be scrutinised by Medical Monitor to flag non-vertebral fracture events. The diagnosis 


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Statistical Analysis Plan 
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Page 73 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
of non-vertebral fractures will not require central X-ray reading and will be based on local 
radiological reports.  
For each of the timepoints (Weeks 52 and 78), a binary variable will be derived as follow: 
- 
No (0): no AE episodes of non-vertebral fragility fracture until Week XX 
- 
Yes (1): AE episodes of non-vertebral fragility fracture until Week XX 
where, Week XX is the time point of interest.  
4.3.1.2 Secondary Efficacy – Main Analytical Approach 
Secondary efficacy analyses will be executed based on the on FAS and PPS. 
MI will be conducted for %CfB in lumbar spine BMD at Week 78, as per below section 4.3.1.2.2. 
No imputation of missing data is foreseen for other secondary endpoints. 
4.3.1.2.1 %CfB in total hip BMD at Weeks 26, 52 and 78 
BMD, CfB and %CfB of secondary BMD endpoints, %CfB will be estimated for each treatment 
arm and 95% CI derived for each time point. BMD, CfB and %CfB will be summarised in FAS 
and PPS. 
Furthermore, the endpoints %CfB in total hip BMD at Weeks 26 and 52 will be analysed by 
using mixed model for repeated measures (MMRM) with the following factors: 
• Treatment (RGB-14-P and US-licenced Prolia®, as planned treatment) 
• Stratification factors for randomisation: 
o Previous use of bisphosphonates (yes/no) 
o Geographical region (Europe, US) 
• Baseline BMD value 
• Machine type (as per DXA scan external data transfer) 
• Machine type * Baseline BMD value interaction 
• Study Week 
• Study Week * Treatment interaction 


Parexel International 
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Statistical Analysis Plan 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 74 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Unstructured covariance matrix will be used. In case of convergence issues, alternative structures 
will be considered in the following order: Autoregressive(1), Compound Symmetry, Toeplitz; 
until convergence is met. MMRM will be executed without MI applied, without special handling 
of ICEs. 
By-subject listing will be provided.  
4.3.1.2.2 %CfB in lumbar spine BMD at Weeks 26, 52 and 78 
Similar analysis as detailed in section 4.3.1.2.1. 
In addition, for FDA, a sensitivity tipping point analysis will be conducted to assess the 
robustness of the results at Week 78: a similar analysis will be performed as the one described on 
this SAP at section 4.2.1.3.2 will be performed by using Week 78 BMD data. As the transition 
period consists of three study arms, the arm ‘Prolia to Prolia’ will be considered as the reference 
arm and the two arms ‘RGB-14-P to RGB-14-P’ and ‘Prolia to RGB-14-P’ will be test arms and 
will be compared to the ‘Prolia to Prolia’ reference. Again, assessments of the primary endpoints 
observed after occurrence of ICE2 will be disregarded, i.e., artificially set as missing, and will be 
imputed in the tipping point analysis with same MI techniques as applied to regular missing data. 
Different assumptions will be made for missing values (and post-ICE2 assessments) in each of 
the three arms. SAS PROC MI will be utilised with MNAR statement including ADJUST option 
with SHIFT as sub option to allow the Week 78 outcomes in the three treatment arms to vary 
independently.  
For the method implementation, similar steps will be followed as described in section 4.2.1.3.2, 
including both approach 1 and approach 2; Week 52 lumbar spine BMD %CfB will be included 
in the FCS REG statement of the PROC MI in the Steps 3 and 4  predictive variable for the 
missing (originally or post-ICE2 assessments) Week 78 outcomes. 
Results obtained while running the approach 1 and approach 2 will be tabulated, including the 
shift applied to reference arm ‘Prolia to Prolia’ and to the test arms, the point estimate obtained 
for the primary endpoint together with the two-sided 90% CIs and the standard error. For 
different combinations of reference and test arms shifts: 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
- 
observed LCL will be plotted when testing non-inferiority, UCL when testing non-
superiority 
- 
forest plots will also be present, plotting point estimate and 90% CIs under the non-
inferiority and non-superiority tests 
4.3.1.2.3 %CfB in femoral neck BMD at Weeks 26, 52 and 78 
Similar analysis as detailed in section 4.3.1.2.1. 
4.3.1.2.4 Vertebral fragility fracture incidence  
All data on Vertebral fractures will be listed. A summary table will also be presented with 
number of subjects who experienced at least one fracture in the study (starting from 
randomisation) and total amount of post-randomisation fractures. 
Incidence of fracture will be estimated as the proportion (also presented as percentage) of 
subjects with at least one post-randomisation fracture, and a two-sided 95% CI will be computed. 
Average difference and its 95% CI will be also computed. 
4.3.1.2.5 Non-vertebral fragility fracture incidence 
Similar analysis as detailed in section 4.3.1.2.4. 
4.3.1.3 Secondary Efficacy – Sensitivity Analyses 
Not Applicable. 
4.3.1.4 Secondary Efficacy – Supplementary Analyses 
Not Applicable. 
4.3.2 
Secondary Pharmacodynamic Endpoints 
4.3.2.1 Secondary Pharmacodynamic – Definition of Endpoint(s) 
Of note: pharmacodynamic results are received from external vendor laboratory; in some 
instances, P1NP results are received with the two test codes ZP1NG and ZP1NB; in these 


Parexel International 
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Statistical Analysis Plan 
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Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 76 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
instances, based on instructions received from laboratory, the results received under code ZP1NG 
is to be considered as latest and more accurate and used for summaries, analysis and any 
derivation detailed in this SAP; both results obtained under ZP1NG and ZP1NB will be displayed 
in the data listings, with a clear identification key for results received under code ZP1NG and 
under code ZP1NB. 
4.3.2.1.1 %CfB in serum P1NP at Weeks 4, 26, 52 and 78. 
For %CfB derivation of this secondary pharmacodynamic endpoint, same formula will be used as 
for sCTX %CfB, please refer to section 4.2.2.1. 
4.3.2.1.2 %CfB in sCTX at Weeks 4, 26, 52 and 78. 
For sCTX %CfB derivation, please refer to section 4.2.2.1. 
4.3.2.2 Secondary Pharmacodynamic – Main Analytical Approach 
Secondary pharmacodynamic analyses will be executed on PDS. 
4.3.2.2.1 %CfB in serum P1NP at Weeks 4, 26, 52 and 78. 
Descriptive analysis of P1NP, CfB and %CfB at each visit will be presented. Furthermore, a by-
subject listing will be provided. P1NP concentrations below the limit of quantification (BLQ) will 
be presented as BLQ in listing. In summary tables, values BLQ will be imputed as LLOQ. 
4.3.2.2.2 %CfB in sCTX at Weeks 4, 26, 52 and 78. 
Descriptive analysis of sCTX, CfB and %CfB at each visit will be presented. Furthermore, a by-
subject listing will be provided. 
4.4 Immunogenicity Analysis and Serum drug concentrations 
4.4.1 Immunogenicity 
Immunogenicity analyses will be executed on IAS, unless otherwise specified. 


Parexel International 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.4.1.1 Immunogenicity binding ADAs and NAbs – Definition of Endpoint(s) 
Antibodies to denosumab (ADA) and neutralising antibodies (Nabs) will be evaluated in serum 
samples collected at Weeks 0, 2, 4, 26, 28, 30, 52, 54, 56 and 78.  
Serum immunogenicity samples will be assessed for ADAs and NAbs according to the following 
stepwise analytical approach, visit wise: 
1. Screening analysis (assay): all immunogenicity samples are analysed in an ADA screening 
assay, this will give a result of positive/negative, which tells if the samples are potentially 
positive for ADA or not 
2. For those who had a positive screening result, confirmatory analysis is performed: 
confirmatory assay giving a result of positive/negative, which tells with certainty that the 
sample is positive for ADA or not 
3. Confirmed ADA positive samples will be titrated  
4. Confirmed ADA positive samples will be analysed in NAb assay, which may result to be 
either positive or negative  
4.4.1.2 Immunogenicity – Main Analytical Approach 
All immunogenicity results (ADA Screening positive or negative, ADA positive or negative, ADA 
titres, NAb positive or negative) will be listed by subjects and treatment group, at each visit where 
they are assessed for main and transition period for full analysis set.  
Incidence of binding ADAs and Nabs in samples by visit and titre ranges will be summarised for 
the main (0-w52) and transition period (0-w78) for each time points, based on IAS.  
ADA status of subjects 
Overall, subjects will be labelled as ADA negative or positive as per the logic outlined in Table 6.  
Table 6 – Overall ADA status classification 
Subject overall 
classification  
Baseline* result 
Post-dose visit results 


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 (up to week 52 for the main period; up to week 
78 for the transition period) 
Negative 
Negative 
Negative  
Negative 
Positive 
Negative/ Positive (no significant ADA titer 
increase from baseline at any post-baseline 
timepoint )  
Positive  
Negative 
Positive (any titre level, observed at least at one 
post-baseline timepoint) 
Positive  
Positive 
Positive (significant ADA titer increase from 
baseline, observed at least at one post-baseline 
timepoint) 
Switch-induced and boosted positives, if any, will be evaluated based on the individual 
immunogenicity response kinetics by Sponsor in the CSR. 
*Baseline is the last result obtained before the first injection 
 
In those subjects with baseline ADA positivity, a significant ADA titer increase from baseline is 
defined as minimum 4-fold increase in titre ratio, corresponding to a 75% increase. 
Titer ratio = Post-dose titer / Baseline titer (last assessment available pre first dosing) 
Titer ratio ≥ 4 will be interpreted as significant ADA titer increase from baseline. 
 
If necessary, data will be reviewed by the immunogenicity laboratories personnel who will 
discuss on a case-by-case basis the special features and exceptions to the logics above described; 
if these decisions will be evaluated prior than unblinding, these will be communicated in a 
blinded way to the main study team, handling strategies defined in the final BDRM / DRM report 
as applicable. 
 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
NAb status 
Subjects are not expected to be NAb positive at pre-treatment, exceptional cases of subjects NAb 
positive at baseline and other data issues will be reviewed by the immunogenicity laboratories 
personnel who will discuss on a case-by-case basis the special features and exceptions to the 
logics above described; if these decisions will be evaluated prior than unblinding, these will be 
communicated in a blinded way to the main study team, handling strategies defined in the final 
BDRM / DRM report as applicable. 
Overall, subjects will be labelled as NAb negative or positive as per the below logic outlined in 
Table 7. 
Table 7 – Overall NAb status classification 
Subject overall 
classification  
Baseline* 
result 
Post-dose visit results 
 (up to week 52 for the main period; up to week 78 
for the transition period) 
Negative 
Negative/ 
not tested 
Negative 
Positive 
Negative/ 
not tested 
Positive  
Unexpected, if will be 
observed, will be 
discussed at the BDRM 
Positive 
Negative / Positive 
*Baseline is the last result obtained before the first injection  
Nab status of subjects will be summarised for the main period by treatment arms and overall.  
4.4.1.3 Immunogenicity – Supplementary Analysis 
.Persistent versus transient ADA response 


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For overall ADA positive subjects, determination of Persistent versus transient ADA response 
will be studied based on indications from Shankar (2014) [17]. 
Persistent ADA response is defined as:  
1) ADA positivity detected at two or more sampling time points where the first and last 
ADA-positive samples (irrespective of any negative samples in between) are separated by 
a period of 16 weeks (112 days) or longer 
or 
2) ADA positivity detected in the last available sampling time point 
or 
3) Last ADA positivity detected is not followed by a negative sample dated 16 weeks (112 
days) or longer after such positivity.  
 
In other words, persistent ADA response is defined: 
- 
when a subject has at least two post baseline positive results and (date of last post baseline 
positive result – date of first post baseline positive result) + 1 is ≥ 112 days, then the 
subject will be flagged as with persistent ADA response 
- 
when the last available assessment for the subject indicates positive ADA, then the subject 
will be flagged as with persistent ADA response 
- 
if the last post baseline positive result for a subject is not followed by a negative result 
distanced 112 days or more from such positive result, then the subject will be flagged as 
with persistent ADA response 
- 
in any other case, then the subject will be flagged as with transient ADA response  
In main period summary, all the data up to the pre-dose week 52 assessment will be used. 
Example cases are provided in appendix 6.4.10, Table 13. 
Transition period ADA and Nab shift of status 


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For subjects included in the transition period, a shift table will be produced which will show 
shifts in the overall ADA and Nab positive / negative status when switching from main to 
transition treatment. For ADA, the persistent and transient responses . 
4.4.2 Serum drug concentrations – Supporting immunogenicity 
Serum drug concentrations will be listed, as received from vendor, by subjects and treatment 
group, at each visit where they are assessed for main and transition period. Denosumab 
concentration data may be used for interpretation of immunogenicity, safety, efficacy aspects of 
study, but will not be evaluated statistically. Parexel will not perform any statistical analysis nor 
summaries for serum drug concentrations nor parameters. 
 
4.5 Safety Analyses 
Safety variables are: 
• 
Exposure 
• 
Adverse event (AE) assessments 
• 
12-lead electrocardiograms (ECG): PR interval, QRS interval, QT interval, QTC interval 
and correction type 
• 
Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
• 
Physical examinations 
• 
Clinical laboratory tests (haematology, clinical chemistry, and urinalysis parameters) 
• 
Concomitant medication assessments 
• 
Number and intensity of injection site reaction 
In general, if not stated otherwise, the safety variables will be listed in the SAF for the main 
period. This will allow to have listings on all treated subjects. When producing main period 
TFLs, only data included in the main period milestone data freezing scope will be printed in 
listing, while when producing TFLs for the whole study, all the data will be printed in listings 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
including data pertinent to the transition period. Detailed strategy for main and transition period 
deliverable is in section 1 of this SAP. 
4.5.1 
Extent of Exposure 
IMP dosing information will be listed by subject and includes: 
- 
Anatomical Location (upper arm, abdomen, thigh) 
- 
Laterality (left, right, other/specification) 
- 
Route (subcutaneous) 
- 
Administration date 
- 
Administration start time (24h HH:MM) 
- 
Kit number 
Summaries will be provided based on FAS for number of subjects treated and not treated with 
each scheduled injection. 
4.5.2 
Adverse Events 
An AE is any untoward medical occurrence in a study subject administered an IMP which does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign (including a clinically significant abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an IMP, whether or not considered 
related to the IMP. Adverse events may include the onset of new illness and the exacerbation of 
pre-existing conditions. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, 
e.g., those occurring during treatment-free periods (including Screening or post-treatment Follow-
up periods), in association with study-related procedures and assessments. 
Concomitant illnesses, which existed before entry into the clinical study, will not be considered 
AEs unless they worsen during the study. Pre-existing conditions will be recorded as part of the 
subject’s medical history. 


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Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 24.0 or higher. Safety population data sets (SAF) will be used for safety analysis. 
A treatment emergent adverse event (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. 
In the Main and Transition Period, TEAEs will be additionally assigned to the treatment to which 
the AE was emergent. When time of onset is available, time of onset will be used for the 
derivation of the treatment emergent flag. AE emerging on an injection day will be assumed to be 
emergent to such injection treatment period, unless there is clear evidence through times 
comparison that the event started prior than the injection. 
AEs with incomplete start and end dates are not expected. In case of any AEs with incomplete 
start and end dates, below rules will apply: 
• Adverse events with completely unknown start date will be considered as TEAEs 
• Adverse event with unknown start day and month but with known start year will be 
considered: 
o as TEAEs if the start year coincides or is after the dosing year 
o as non TEAEs if start year is before the dosing year 
• Adverse events with unknown start day but with known start month and year will be 
considered: 
o as TEAEs if the start month and year coincide or are after the dosing month and 
year 
o as non TEAEs if start month and year are before the month and year of first dosing  
• Adverse events with completely unknown end date will be considered as ongoing (not 
recovered/ not resolved) on the day of last contact with the subject. 
For any AEs, severity was scored in a five-point scale as mild, moderate, severe, life threatening 
and death. To be noted that both the wording “severity” and “intensity” were interchangeably 
used in the CSP and eCRF, with the same meaning.  


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Local tolerance will be evaluated through skin examination, events of intolerance will be 
regarded as ISR. The grading of ISRs will be based on the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5. Injection site reactions with a grading of ≥ 1 are expected to 
be recorded as AEs in the eCRF AE log form. Local tolerance listing will be provided, while 
ISRs will be listed and also included in the TEAEs summaries.  
  
Separate summaries will be produced for the AEs and TEAEs emerging in main and transition 
period regarding the below outputs: 
• An overview on the number and percentage of subjects (and number of events) with: 
o Any AE (only applicable for the main period summaries) 
o Any TEAE  
o Any TEAE severe or with worse severity 
o Any treatment related TEAE  
o Any treatment related TEAE severe or with worse severity  
o Any serious TEAE 
o Any serious TEAE severe or with worse severity 
o Any treatment related serious TEAE 
o Any treatment related serious TEAE severe or with worse severity 
o Any non-serious TEAE 
o Any AE leading to subject discontinuation (only applicable for the main period 
summaries) 
o Any TEAE leading to subject discontinuation  
o Any treatment related TEAE leading to subject discontinuation  
o Any fracture TEAE 
o Any fracture TEAE severe or with worse severity 
o Any treatment related fracture TEAE 
o Any treatment related fracture TEAE severe or with worse severity 
o Any serious fracture TEAEs 


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o Any serious fracture TEAEs severe or with worse severity 
o Any treatment related serious fracture TEAE 
o Any treatment related serious fracture TEAE severe or with worse severity 
o Deaths 
o Any AE leading to death (only applicable for the main period summaries) 
o Any TEAEs leading to death 
o Any treatment related fatal serious TEAEs 
o Any injection site reactions 
o Any injection site reactions severe or with worse severity 
o Any injection site reactions of CTCAE grade ≥ 3 
• Number and percentage of subjects for each TEAE, and non-serious TEAE categorised by 
treatment, SOC and PT 
• Number and percentage of subjects for each TEAE severe or with worse severity, 
categorised by treatment, SOC and PT 
• Number and percentage of subjects for each TEAE categorised by treatment, SOC, PT, 
and worst severity 
• Number and percentage of subjects for each treatment related TEAE categorised by 
treatment, SOC and PT 
• Number and percentage of subjects for each treatment related TEAE severe or with worse 
severity categorised by treatment, SOC and PT  
• TEAEs in ≥ 3% of subjects by treatment, SOC and PT  
• Treatment related TEAEs in ≥ 3% of subject by treatment, SOC and PT 
• TEAEs in ≥ 5% of subject by treatment, SOC and PT 
• Treatment related TEAEs in ≥ 5% of subject by treatment, SOC and PT 
• Non-serious AEs in ≥ 3% of subject by treatment, SOC and PT  
• Non-serious AEs in ≥ 5% of subject by treatment, SOC and PT  
A detailed list of all AEs, including TEAEs, adverse reactions (i.e., AEs related with the IMP), 
SAEs, ISR and fractures will be created. 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
AEs listing will be presented by treatment group and will include as a minimum: subject 
identifier, age, adverse event (SOC, PT, and verbatim term), date of onset, date of resolution, 
severity, seriousness, action taken, outcome and causality.  
Adverse event summaries will be ordered by descending order of total frequency (across all study 
parts treatment groups combined) for SOC, and PT within SOC. In the event of PTs with equal 
total frequencies, the relevant PTs will be sorted alphabetically.  
Note for subjects enrolled in the transition period: TEAEs emerging prior to third injection will 
be summarised in main tables only, even though lasting during the transition period as well, these 
events will not be counted in the transition tables; TEAEs emerging on or after the third injection 
will be summarised in transition tables only. 
If an AE starts in the main period and worsens in severity during the transition period, study sites 
will communicate in eCRF the end date for the AE with the first severity and will register in 
eCRF a new AE with the worse severity for transition period. 
If a subject reports the same TEAE more than once within that SOC and PT, the TEAE with the 
highest severity will be used in the corresponding severity summaries. Similarly, the worst 
causality (most related to treatment) will be attributed and used in the by-causality summaries. If 
severity or causality is missing, a conservative approach for AE assessment (taking into account 
the worst case) will be followed.  
If a device incident or device deficiency cause an AE or SAE during the study, the unblinded 
study team member will complete the Product Complaint Form. Upon the relevant study period 
unblinding, such forms will be shared to the statistical team for processing. Listing for any device 
incident or device deficiency will be created. 
4.5.2.1 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
Summaries detailed below will be provided for deaths, SAEs and other significant AEs presented 
by treatment group: 
- 
Number and percentage of subjects for each treatment emergent SAE, categorised by SOC 
and PT 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
- 
Number and percentage of subjects for each treatment emergent SAE severe or with 
worse severity, categorised by SOC and PT 
- 
Number and percentage of subjects for each treatment emergent SAE, categorised by 
SOC, PT, and worst severity 
- 
Number and percentage of subjects for each treatment related SAE, categorised by SOC 
and PT 
- 
Number and percentage of subjects for each treatment related SAE severe or with worse 
severity, categorised by SOC and PT 
- 
Number and percentage of subjects for each TEAE leading to subject discontinuation, 
categorised by SOC and PT 
- 
Number and percentage of subjects for each related TEAE leading to subject 
discontinuation, categorised by SOC and PT 
- 
Number and percentage of subjects for each treatment emergent fracture AE, categorised 
by SOC and PT 
- 
Number and percentage of subjects for each treatment emergent fracture AE severe or 
with worse severity, categorised by SOC and PT 
- 
Number and percentage of subjects for each treatment emergent fracture AE, categorised 
by SOC, PT, and worst severity 
- 
Number and percentage of subjects for each treatment related fracture AE, categorised by 
SOC and PT 
- 
Number and percentage of subjects for each treatment related fracture AE severe or with 
worse severity, categorised by SOC and PT 
- 
Number and percentage of subjects for each treatment emergent serious fracture AE, 
categorised by SOC and PT 
- 
Number and percentage of subjects for each treatment emergent serious fracture AE 
severe or with worse severity, categorised by SOC and PT 
- 
Number and percentage of subjects for each treatment emergent serious fracture AE, 
categorised by SOC, PT, and worst severity 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
- 
Number and percentage of subjects for each treatment related serious fracture AE, 
categorised by SOC and PT 
- 
Number and percentage of subjects for each treatment related serious fracture AE severe 
or with worse severity, categorised by SOC and PT 
- 
Number and percentage of subjects for each fatal SAE, categorised by SOC and PT 
- 
Number and percentage of subjects for each treatment related fatal SAE, categorised by 
SOC and PT 
- 
Number and percentage of subjects for each injection site reaction, categorised by SOC 
and PT  
- 
Number and percentage of subjects for each injection site reaction severe or with worse 
severity, categorised by SOC and PT 
- 
Injection Site Reactions of CTCAE grade ≥ 3 by Treatment, System Organ Class and 
Preferred Term 
For deaths, SAEs and other significant AEs the following listing will be provided: 
- 
A by-subject listing of all deaths that occurred during the study, including details such as 
cause of death from eCRF page Death 
- 
A by-subject listing of adverse events leading to death 
- 
A by-subject listing of related adverse events leading to death 
- 
A by-subject listing of all serious adverse events  
- 
A by-subject listing of all related serious adverse events  
- 
A by-subject listing of all fracture adverse events  
- 
A by-subject listing of all related fracture adverse events  
- 
A by-subject listing of adverse events leading to discontinuation  
- 
A by-subject listing of related adverse events leading to discontinuation  
- 
A by-subject listing of all adverse events severe or with worse severity 
- 
A by-subject listing of all related adverse events of severe or with worse severity 
- 
A by-subject listing of all injection site reactions. 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.5.3 
Additional Safety Assessments 
4.5.3.1 Clinical Laboratory Evaluation 
The tests detailed in Table 8 will be performed by the central laboratory. All study-required 
laboratory assessments will be performed by a central laboratory, except for: 
- 
Dipstick urinalysis at all visits 
- 
Immunogenicity and serum drug concentration samples (assessed by Sponsor) 
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.  
For clinical study report purposes, the values from the central laboratory will be considered. 
Local laboratory results are required in the event that the central laboratory results are not 
available in time for IMP administration as indicated in the SoA (section 6.2.10 and Table 11) 
and/or for response evaluation. 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. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Investigators will receive central laboratory safety report in paper, and they must document their 
review of each laboratory within the paper safety report itself, including assessment of clinical 
significance. No clinical significant assessment will be registered in central laboratory eCRF 
page, however clinically significant abnormal values will be logged as AEs into the AE eCRF 
page. Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded. 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Table 8 - Protocol-Required Safety 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 
Magnesium 
Phosphorus 
AST 
ALT 
Alkaline phosphatase 
GGT 
Total and direct bilirubin 
Total Protein 
Albumin 
Total cholesterol 
Triglyceride 
LDH 
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 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Laboratory Assessments 
Parameters 
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 
 
By-subject listing will be provided for all subjects enrolled by visit, including changes from 
baseline and reference range. Laboratory values will be summarised for all visits scheduled in 
Main and Transition period. Unscheduled visits will be listed only, unless contribute to baseline 
measurement or replace a missing visit assessment as detailed in section 4.1.6 of this SAP. 
Abnormal (for haematology, clinical chemistry or urinalysis) results will be also provided as by-
subject listing. 
All values outside the clinical reference ranges will be flagged in the data listing. The abnormal 
values will be flagged with ‘Low’ for values below the lower limit of the clinical reference range 
and ‘High’ for values above the upper limit of the clinical reference range and included in the 
listing. Moreover, lab results will be compared with corresponding normal ranges and following 
categories will be derived and presented in listing:  
- 
NR [within Normal Range] 
- 
OoR ≤ 2x NR [Out of Range ≤ 2x NR in both directions] 
- 
OoR ≤ 5x NR [OoR >2x to ≤ 5x NR in both directions] 
- 
OoR > 5x NR [OoR > 5x NR in both directions] 
The following summaries will be provided for all parameters: 
- 
A summary of results by treatment arm and visit 
- 
A summary of the change from baseline by treatment arm and visit.  
- 
Shift tables by treatment group and visit will be provided for all parameters to compare a 
subject’s baseline laboratory evaluation relative to the visit’s observed value; in shift 
tables the denominator for the percentages will be based on observations non-missing for 
baseline and the pertinent visit.   


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o hematology and clinical chemistry shift table to evaluate whether a particular 
laboratory test value was normal, low or high for each visit value relative to the 
baseline value presented as well as normal, low or high  
o hematology and clinical chemistry shift table to evaluate whether a particular 
laboratory test value was within NR, OoR ≤ 2x NR, OoR ≤ 5x NR or OoR > 5x 
NR for each visit value relative to the baseline value presented as well as NR, 
OoR ≤ 2x NR, OoR ≤ 5x NR or OoR > 5x NR 
o urinalysis shift table to evaluate whether a particular laboratory test value was 
normal, or abnormal for each visit value relative to the baseline value presented 
as well as normal or abnormal 
4.5.3.2 Vital Signs, Physical Findings and Other Observations Related to Safety 
4.5.3.2.1 Vital Signs 
Vital signs will be assessed as shown in the SoA (Table 10 and Table 11). The following vital 
signs measurements will be obtained: 
- 
Body temperature (C° or F°) and temperature measurement location (axilla, tympanic 
membrane and forehead) 
- 
Respiratory Rate (breaths/min) 
- 
Heart Rate (beats/min) 
- 
Blood pressure and subject position during assessment (sitting, standing and supine) 
o Systolic blood pressure (SBP) (mmHg) 
o Diastolic blood pressure (DBP) (mmHg) 
Temperature values recorded as °F will be summarised as °C using the function below: 
°𝐶= (°𝐹−32) × 5
9 
For body temperature measurements in degrees of Fahrenheit, both °F and °C values and units 
will be reported in line listing. Body temperature values obtained from different body parts will 


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be summarised separately by measurement location in the order of axilla, tympanic membrane, 
and forehead.  
Vital signs data will be listed by subject including changes from baseline. Descriptive statistics 
for absolute values and changes from baseline will be presented by Treatment Period, Treatment 
Arm, visit and overall. 
4.5.3.2.2 ECG 
Standard safety 12-lead ECGs will be performed as shown in the SoA (Table 10 and Table 11). 
The following ECG parameters will be recorded: 
• PR-interval (msec). 
• QRS-complex (msec). 
• QT-interval (msec). 
• QTcF (msec) or QTcB (msec) or QTc ’other’ (msec). 
The ECG will be evaluated by the Investigator as normal/abnormal and clinically/not clinically 
significant.  
All ECG parameters will be listed by subject including changes from baseline. Descriptive 
statistics (n, mean, SD, median, minimum, maximum) for absolute values and changes from 
baseline will be presented by study part, treatment group and overall.  
Three QTc types may be collected: QTcF, QTcB and Other QTc; these will be summarized as 
three parameters, with CfB being calculated only when the post-baseline QTc type matches the 
baseline one. 
4.5.3.2.3 Physical Examination 
Physical examinations will be performed as shown in the SoA (Table 10 and Table 11). 
The physical examination includes an assessment of general appearance and a review of systems 
(head, eyes, ears, nose, mouth - oral cavity – throat – neck, thyroid gland, lymphatic gland, 
dermatologic, respiratory system, cardiovascular system, gastrointestinal, extremities, 
musculoskeletal and neurological system). 


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For each time point, an overall interpretation will be recorded by the Investigator as normal, 
abnormal not clinically significant, or abnormal clinically significant. 
A summary of the number and percentage of subjects in each category (normal, abnormal NCS 
and abnormal CS) will be provided by Treatment Period, Treatment Arm, visit and overall. 
By-subject listing will be provided for all subjects.  
4.5.3.2.4 Overdose 
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. 
4.5.3.2.5 Pregnancy test 
A Pregnancy test will be executed as shown in the SoA (Table 10 and Table 11) in subjects, even 
though pregnancy is not expected (postmenopausal population). By-subject listing will be 
provided for all subjects.  
4.6 Other Analyses 
4.6.1 
Other Variables and/or Parameters 
4.6.1.1 Health Economics 
Not applicable. 
4.6.1.2 Patient Reported Outcome (PRO) Measures 
Not applicable. 
4.6.2 
Subgroup Analyses 
No subgroup analyses are planned. 
For the summaries and analyses, the term ‘Centre’ will be used to define each investigator site. 
Otherwise specified, analyses will not be presented by centre or geographical region. 


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4.6.3 
Pharmacokinetics, Pharmacokinetic-Pharmacodynamic Relationships 
Serum drug concentrations at immunogenicity measurement time points will be listed as 
supporting data for immunogenicity evaluation (possible drug interference). 
4.7 Interim Analysis  
No interim analysis will take place. 
4.8 Changes to Protocol-planned Analyses 
Analyses described in this SAP are in alignment with the study protocol. 


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5 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 [13], [14], [15], 
sample size was calculated from the following parameters: 
• The primary parameter is the %CfB in lumbar spine BMD 
• Two-sided 95% CIs of the difference between the study arms must be contained within the 
 
• 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) 
• The expected (true) common standard deviation is 3.44 
Based on the above assumptions the total evaluable sample size required for efficacy comparison 
with a margin of 
 power of 90% is 362 (181 per arm) 
With regards to the PD co-primary endpoint, healthy volunteer data [15] was used for the sample 
size calculations due to the lack of information on AUEC sCTX0-m6 derived from the subject 
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. 
CCI
CCI


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Calculating with 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 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) provides the probability for a sample size (N) of 60 and 66 participants to observe at 
least 1 participant per AE, considering different frequencies of AE. 
Table 9 - 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. 
 


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6 Supporting Documentation 
 
6.1 Appendix 1: List of Abbreviations 
List and define all acronyms and abbreviations used in the document here.  Abbreviations should 
be spelled out in full, and the abbreviation indicated in parentheses at first appearance in the text.  
Abbreviations should appear in alphabetical order. 
Abbreviation / Acronym 
Definition / Expansion 
%CfB 
Percentage of Change from Baseline 
𝛿𝑃𝑆𝑇 
𝛿principal stratum 
ADA 
Anti-Drug Antibodies 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUEC 
Area Under the Effective Curve 
BDRM 
Blinded Data Review Meeting 
BDRR 
Blinded Data Review Report 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
BP 
Blood Pressure 
Bpm 
Beats per minute 
BUN 
Blood Urea Nitrogen 
CfB 
Change from Baseline 
CI 
Confidence interval 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 


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Abbreviation / Acronym 
Definition / Expansion 
CS 
Clinically Significant 
CSP 
Clinical Study Protocol 
CTCAE 
Common Terminology Criteria for Adverse Events 
DB Lock 
Database Lock 
DBP 
Diastolic Blood Pressure 
DXA 
Dual Energy X-Ray Absorptiometry 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
ENR 
Enrolled Analysis Set 
EOS 
End-of-study 
EST 
Erythrocyte Sedimentation Rate 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GDO 
Global Data Operations 
GGT 
Gamma-Glutamyl Transferase 
GLMM 
Generalised Linear Mixed Models 
HbcAg 
Hepatis B core antigen 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
IAS 
Immunogenicity Analysis Set 


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Abbreviation / Acronym 
Definition / Expansion 
ICE 
Intercurrent Events 
ICF 
Informed Consent Form 
IgC 
Immunoglobulin 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IRIS 
Inconclusive Results or Insufficient Sample volume 
IQC 
Calibration of DXA scanners using phantom data 
ITT 
Intent To Treat 
LCL 
Lower Confidence Limit 
LDH 
Lactate Dehydrogenase 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
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 
NA 
Not available 
NAb 
Neutralising Antibodies 
NCS 
Not clinically significant 
NK 
Not known 
NR 
Normal Range 
P1NP 
Prokollagen Typ 1 N-terminales Propeptid 


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Abbreviation / Acronym 
Definition / Expansion 
PD 
Pharmacodynamic 
PDS 
Pharmacodynamic analysis set 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PPS 
Per-Protocol Analysis Set 
PPSC 
Per-Protocol and Completer 
PSE 
Principal Stratum Estimand 
PST 
Principal Stratum 
PT 
Preferred Term 
PTH 
Parathyroid Hormone 
QT 
The QT interval is measured from the beginning of the QRS 
complex to the end of the T wave 
QTc 
Corrected QT interval 
QTcB 
QT corrected using Bazett’s formula 
QTcF 
QT corrected using Fridericia’s formula 
RBC 
Red Blood Cell Count 
SACE 
Survivor Average Causal Effect 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus-2 
SBP 
Systolic blood pressure 
sCTX 
Serum type I collagen C-telopeptide 
SD 
Standard deviation or single dose 
SE 
Standard error of the mean 
SoA 
Schedule of Assessments 


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Abbreviation / Acronym 
Definition / Expansion 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
SUTVA 
Stable Unit Treatment Values Assumption 
TEAE 
Treatment-emergent adverse event 
TPE 
Treatment Policy Estimand 
TSH 
Thyroid-Stimulating Hormone 
TTATP 
Time to ADA Treatment induced or boosted Positivity 
UCL 
Upper Confidence Limit 
US 
United States 
WBC 
White Blood Cell Count 
XCAL 
DXA Inter-scanner cross-calibration 
 
 
 
 


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6.2 Appendix 2: Supporting Study Information 
In general, if not stated otherwise, the variables in this section will be listed in the FAS for the 
main period. This will allow to have listings on all randomized subjects. When producing main 
period TFLs, only data included in the main period milestone data freezing scope will be printed 
in listing, while when producing TFLs for the whole study, all the data will be printed in listings 
including data pertinent to the transition period. Detailed strategy for main and transition period 
deliverable is in section 1 of this SAP. 
6.2.1 
Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided in the 
ENR, from screening to study completion.  
By-subject listing will include: 
- 
ICF date and response by subject 
- 
Visit Dates 
- 
Randomisation listing, including: 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. 
- 
Subject’s discontinuation, including the date of study exit, duration of treatment (i.e., number 
of IMP doses received) and reason for discontinuation. 
- 
Subjects excluded from each analysis sets, including the reason for exclusion. 
Summaries will include number and percentage of: 
- 
Screened subjects 
- 
Randomised subjects 
- 
Treated subjects 
- 
Subjects completed the study 
- 
Subjects withdrawn and reason for end of treatment and end of study 


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6.2.2 
Demographics 
Descriptive statistics (see section 4.1.1) for demographics and anthropometric variables will be 
listed and summarised in the FAS.   
Demographic variables include:  
- 
Age (years) 
- 
Sex (Female) 
- 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other/Specification) 
- 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
Anthropometric variables include:  
- 
Height (cm) 
- 
Weight (kg) 
- 
BMI (kg/m2)  
Weight will be listed both as originally collected and in kg. Weight values collected as lb will be 
converted in kg (kg = 2.20462 * lb) for analyses. Height will be listed both as originally collected 
and in cm. Height values collected as in will be converted in cm (cm = 2.54 * in) for analyses. 
6.2.3 Baseline and Disease Characteristics 
In the study, sites will enter the osteoporosis diagnosis in the medical history page for subjects 
with a known prior diagnosis of osteoporosis. For those subjects who received osteoporosis 
diagnosis during the study screening period, the diagnosis will not be recorded neither as a 
medical history nor as an AE event. Subjects will then be flagged as: 
- 
‘Subjects with prior osteoporosis diagnosis’ if the osteoporosis diagnosis is in the medical 
history page 
- 
‘Subjects with new osteoporosis diagnosis’ if the osteoporosis diagnosis is not in the 
medical history page 


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Above flag will be reviewed and confirmed by medical monitor. Summaries will be provided to 
provide number of subjects with prior or new diagnosis. 
Serology will be tested at screening, including HBV, HCV and HIV. In the FAS, results will be 
listed; summary table will be presented for number of subjects reactive to each tested virus. 
6.2.4 Treatment Compliance 
Not applicable. 
6.2.5 Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
of a study protocol.  
In the FAS, a summary of the number and percentage of subjects with a major protocol deviation 
by study period, and treatment will be provided for each country/site and overall. By-subject 
listing of all protocol deviations will be provided. 
The COVID-19 pandemic requires specific attention on the protocol deviations that may impact 
the conduct of the study and the follow-up of the subjects. The number and percentage of subjects 
who experienced at least one COVID-19 deviation will be described together with the major 
protocol deviation table. Also, protocol deviations that are specifically related to COVID-19 will 
also be described in a separate table and identified in the listing of deviations. 
Blinded assessment at the end of Main Treatment Period  
Deviations will be reviewed and classified in a blinded fashion at the Blinded Data Review 
Meeting (BDRM) prior to unblinding at the end of Main Treatment Period. The BDRM will be 
performed to confirm that the database is ready to be hard locked for the Treatment Periods 1 and 
2, all protocol deviations addressed with the assigned classification (i.e., Minor/Major) together 
with their overall effect on a subject, and to agree assignment of each subject to the analysis 
populations. During BDRM, all protocol deviations and their possible impacts will be discussed 
between Parexel and the Sponsor and will be assessed as “minor” or “major”. 
Major protocol deviations are defined as those deviations from the protocol likely to have an 
impact on the perceived efficacy and/or safety of study treatments.  


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Major protocol deviations and any action to be taken regarding the exclusion of subjects or 
affected data from specific analyses are defined in the project-specific Protocol Deviation 
Specification. 
Major protocol deviations and protocol deviations affecting efficacy and/or safety can lead to the 
exclusion of a subjects from the PPS. Reasons for excluding subjects from any study populations 
will be reported and described in the BDRM Report that will be finalised before unblinding 
procedures for study reporting. Listing of assignment of each subject to each analysis set will be 
provided. 
Blinded assessment at the end of Transition Period  
Deviations from the Transition Period will as well be reviewed and classified in a blinded fashion 
in a BDRM prior to final Data Base Lock. The BDRM will be performed to confirm that the 
database is ready to be fully hard locked, all protocol deviations addressed with the assigned 
classification (i.e., Minor/Major) together with their overall effect on a subject. It is expected that 
PDs collected during the Transition Period will not modify assignment of each subject to the 
analysis populations as these were decided at the BDRM for the main study part. 
6.2.6 Medical and Surgical History and Concurrent Illnesses 
In the FAS, medical and surgical history data will be listed by subject including visit, description 
of the disease/procedure, MedDRA system organ class (SOC) and preferred term (PT) (MedDRA 
version 24.0 or higher), start date and stop date (or ongoing if applicable).  
6.2.7 Prior/Concomitant Medications 
In the Main and Transition Period, prior medications are those that started and stopped prior to 
the first dose of IMP. Concomitant medications are those taken after first dosing (including 
medications that started prior to dosing and continued after). In the Main and Transition Period, a 
concomitant flag will be additionally created to identify the treatment to which the medication 
was concomitant: 


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- 
Concomitant medication in the main period is defined as any medication ongoing at the 
first dose of IMP or with a start date on or after the first dose of IMP and before the third 
injection 
- 
Concomitant medication in the transition period is defined as any medication ongoing at 
third injection or with a start date on or after the third injection 
If medication start and/or stop dates are missing or partial, the dates will be compared as far as 
possible with the date of first IMP dosing. Medications will be assumed to be concomitant, unless 
there is clear evidence (through comparison of partial dates) to suggest that the medication 
stopped prior to the first IMP dosing. If there is clear evidence to suggest that the medication 
stopped prior to the first IMP dosing, the medication will be assumed to be Prior.  
Prior and concomitant medications will be coded according to the World Health Organisation 
Drug Dictionary latest version. 
In the FAS, prior and concomitant medications will be listed by subject and will include the 
following information: reported term, trade name, the route of administration, dose, frequency, 
start date/time, stop date/time and indication. Prior and concomitant medications will also be 
summarised by ATC level 4 term and trade name, for the main and transition period.  
6.2.8 Prohibited therapies 
Unless required for AE/SAE management, the medications and interventions which are listed 
below are prohibited during the study period: 
• 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. 


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• Tibolone, oral or topical (e.g., transdermal, intravaginal) oestrogen, antioestrogens, SERMs 
and aromatase-inhibitors. 
• Calcitonin or its derivates and calcimimetics (such as cinacalcet or etelcacetide). 
• 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. 
As far as possible, prohibited therapies will be flagged programmatically based on ATC and 
MedDRA codes, as applicable, however final list of the prohibited therapies will be reviewed and 
confirmed by the medical monitor at the BDRM, at which time subjects who assumed prohibited 
therapies will be clearly flagged. 
In the FAS, prohibited therapies will be listed by subject. 
6.2.9 Concomitant Procedures 
In the Main and Transition Period, procedures that started and stopped prior to the first dose of 
IMP will be considered as prior procedures. Concomitant procedures are those happening after 
first dosing (including procedures that started prior to dosing and continued after). In the Main 
and Transition Period, a concomitant flag will be additionally created to identify the treatment to 
which the procedure was concomitant: 
- 
Concomitant procedure in the main period is defined as any procedures ongoing at the 
first dose of IMP or with a start date on or after the first dose of IMP and before the third 
injection 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 110 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
- 
Concomitant procedure in the transition period is defined as any procedures ongoing at 
third injection or with a start date on or after the third injection. 
If procedures start and/or stop dates are missing or partial, the dates will be compared as far as 
possible with the date of first IMP dosing. Procedures will be assumed to be concomitant, unless 
there is clear evidence (through comparison of partial dates) to suggest that the procedure stopped 
prior to the first IMP dosing. If there is clear evidence to suggest that the procedure stopped prior 
to the first IMP dosing, the procedure will be assumed to be Prior.  
Prior and concomitant procedures will be coded according to the MedDRA latest version. 
In the FAS, prior and concomitant procedures will be listed by subject and will include the 
following information: procedures name, SOC, PT, start date, stop date, type of indication 
(adverse event, medical history, prophylaxis, other) and indication.  


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 111 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
6.2.10 Schedule of Activities 
Table 10 – 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 
 
 
 
 
 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 112 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
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 
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 
 
 
 
 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 113 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
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 
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 
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 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 114 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
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 
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). 
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. 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 115 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
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 pre-dose 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.   
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. 
m. Assessments to be done pre-dose and 1 hour post-dose. 
n. 
Injection site reaction assessment should be done pre-dose and approximately 1 hour post-dose, 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.   
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. 
 
 
 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 116 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Table 11 – 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 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 117 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
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 
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 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 118 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
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 
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. 
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. 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 119 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
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 pre-dose 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. 
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 pre-dose and approximately 1 hour post-dose, 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. 
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. 
 
 


Parexel International 
 
Statistical Analysis Plan 
 
Project Document Version No.: X.X; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  dd Mmm yy 
Related to:  SOP-GDO-WW-019 
Page 120 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.3 Appendix 3: Data Handling Conventions 
6.3.1 Missing Date Imputation  
To account for missing time in date/time when deriving duration variables, the following 
approaches will be used: 
• Time points with unknown start times (where the date is known) will be imputed with a 
time of 00:00 h or treatment administration time 
• Time points with unknown end times (where the date is known) will be imputed with a 
time of 23:59 h  
• Unknown time part will be shown as “-” in listings (meaning not known, missing in 
source) 
6.3.1.1 Missing/Incomplete AE Start Date  
Missing / incomplete AE start dates will be printed in listing, unknown part will be shown as “-” 
in listings (meaning not known, missing in source). Handling of partial AE dates for the sake of 
determining whether an AE is TEAE are presented in section 4.5.2. 
6.3.1.2 Missing/Incomplete AE End Date  
Same consideration as presented in section 6.3.1.1. 


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 121 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4 Appendix 4: Sample SAS code 
In this appendix, examples of SAS codes are provided; these are intended to guide programmers and it is expected these will be adapted 
in phase of analysis. 
6.4.1 Secondary Estimand – ANCOVA sample SAS code is provided as general example and will be adapted in phase of analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
  
 
 
 
 
 
     
 
 
 
RUN
RUN;  
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 122 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.2 ICE2 Multiple Imputation for EMA – sample SAS code (code is provided as general example and will be adapted in phase 
of analysis) 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 123 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
 
  
  
 
  
  
 
 
  
  
  
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 124 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 
 
 
 
 
  
 
 
CCI
CCI
CCI
CCI
CCI
CCI


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 125 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.3 Multiple Imputation for FDA – sample SAS code (code is provided as general example and will be adapted in phase of 
analysis) 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 126 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
  
 
 
 
 
 
  
  
 
  
  
 
  
  
 
  
  
 
 
  
  
  
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 127 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  
  
 
  
  
 
  
  
 
 
  
  
  
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 128 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 
 
 
 
  
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 129 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.4 Multiple Imputation for EMA Sensitivity analysis – sample SAS code (code is provided as general example and will be 
adapted in phase of analysis) 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 130 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
  
 
 
 
 
 
  
  
 
  
  
 
  
  
 
  
  
 
 
  
  
  
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
    
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 131 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.5 Tipping point for FDA Sensitivity analysis – Approach 1 (code is provided as general example and will be adapted in phase 
of analysis) 
  
 
 
             
 
                   
 
                      
 
                   
 
                         
 
                         
                      
 
            
 
                   
 
 
 
 
 
 
   
   
 
 
 
 
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 132 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 
 
 
 
 
   
   
 
 
   
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 133 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
  
  
 
 
  
  
 
 
 
  
  
  
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
 
 
 
 
 
  
  
 
 
   
   
 
 
 
 
 
 
 
 
 
 
  
 
   
   
 
      
      
 
      
      
 
      
      
 
      
      
 
   
   
 
 
  
  
 
   
   
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 134 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
      
      
 
   
   
 
 
 
 
 
 
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 135 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.5.2 Use of macro and plots production (code is provided as general example and will be adapted in phase of analysis) 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 136 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 
 
 
 
 
 
 
 
   
   
 
   
   
 
   
   
 
   
   
 
  
 
 
 
 
  
  
 
  
  
 
  
  
 
  
  
 
 
 
 
  
  
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 137 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.6 Tipping point for FDA Sensitivity analysis – Approach 2 (code is provided as general example and will be adapted in phase 
of analysis) 
6.4.6.1 Macro sample SAS code  
 
 
             
 
                   
          
 
                              
 
                         
 
                         
 
            
  
 
                   
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
 
   
   
 
 
   
   
 
 
   
   
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 138 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
 
 
   
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 139 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
 
  
  
  
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
 
 
 
 
 
  
  
 
 
 
   
   
 
      
      
 
      
      
 
   
   
 
 
 
   
   
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 140 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 
 
 
 
  
 
   
   
 
      
      
 
      
      
 
      
      
 
      
      
 
   
   
 
 
  
  
 
   
   
 
      
      
 
   
   
 
  
 
  
  
 
   
  
 
      
      
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 141 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 142 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.6.2 Use of macro and plots production (code is provided as general example and will be adapted in phase of analysis) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 143 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 144 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
  
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
   
 
   
   
 
   
   
 
   
   
 
  
 
 
  
  
 
  
  
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 145 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
  
  
 
  
  
 
 
  
  
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
 
Page 146 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.7 Supplementary Estimand – sample SAS code (code is provided as general example and will be adapted in phase of 
analysis) 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Parexel International 
Gedeon Richter Plc. 
 
RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
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Effective Date:  22 Dec 21 
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Page 147 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.8 Derivation of AUEC of %CfB in sCTX from baseline to Week 26 – sample SAS code (code is provided as general example 
and will be adapted in phase of analysis) 
Table 12 contains data for a possible case, with a value of sCTX at each scheduled timepoint up to Week 26.  
The piecewise linear function 𝑓(𝑡)𝑓(𝑡) for a sample subject is plotted in Figure 5 and the resulting AUEC of sCTX from baseline to 
Week 26 is highlighted in blue.  
 
Table 12 – sCTX example data 
Day 
Week 
sCTX (ng/mL) 
sCTX CfB (ng/mL) 
sCTX %CfB 
Integral 
1 
0 
0.334 
0 
0 
0 
8 
1 
0.069 
0.265 
79.341317365 
277.69461078 
15 
2 
0.068 
0.266 
79.640718563 
834.13173653 
30 
4 
0.066 
0.268 
80.239520958 
2033.2335329 
60 
8 
0.056 
0.278 
83.233532934 
4485.3293413 
90 
12 
0.082 
0.252 
75.449101796 
6865.5688623 
120 
17 
0.099 
0.235 
70.359281437 
9052.6946108 
150 
21 
0.064 
0.27 
80.838323353 
11320.658683 
183 
26 
0.082 
0.252 
75.449101796 
AUEC = 13899.401198 
 


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Figure 4 – sCTX example data from baseline up to Week 26 
 
 


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Figure 5 – %CfB AUEC in sCTX example data from baseline up to Week 26 
 
 


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Page 150 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
The following SAS example code was utilised to approximate the integral for example data: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
    
    
 
    
    
 
    
    
 
    
    
  
    
    
 
    
    
 
 
 
    
    
 
    
    
 
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Parexel International 
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RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
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Page 151 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.9 Primary Pharmacodynamic Endpoint ANCOVA model and GMR derivation – sample SAS code (code is provided as 
general example and will be adapted in phase of analysis ) 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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Parexel International 
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RGB-14-101 
 
Statistical Analysis Plan 
Project Document Version No.: 1.0; Document Effective Date:  Date of last signature 
TP-GDO-WW-016-09 
 
 
Effective Date:  22 Dec 21 
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Page 152 of 154 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
6.4.10 ADA persistent versus transient response – Example cases 
Table 13 – ADA persistent versus transient response, in main and transition period – Example cases 
Case 
# 
Baseline 
Period 1 
Period 2 
Week 52 
Evaluation 
Period 3 
Week 78 
Evaluation 
Week2 
Week4 
Week26 
week28 
week30 
week52 
Week 54 
Week 56 
Week 78 
1 
Negative 
Any 
Any 
Any 
Positive 
Positive 
Positive 
Persistent 
Negative 
Negative 
Negative 
Persistent 
2 
Negative 
Any 
Any 
Any 
Positive 
Negative 
Positive 
Persistent 
Negative 
Negative 
Negative 
Persistent 
3 
Negative 
Negative 
Negative 
Negative 
Positive 
Negative 
Missing 
Persistent 
Missing 
Missing 
Missing 
Persistent 
4 
Negative 
Negative 
Negative 
Negative 
Positive 
Positive 
Missing 
Persistent 
Missing 
Missing 
Missing 
Persistent 
5 
Negative 
Negative 
Negative 
Positive 
Missing 
Missing 
Missing 
Persistent 
Missing 
Missing 
Missing 
Persistent 
6 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Persistent 
Negative 
Negative 
Negative 
Transient 
7 
Negative 
Positive 
Positive 
Negative 
Negative 
Negative 
Negative 
Transient 
Positive 
Negative 
Negative 
Persistent 
8 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Negative 
Transient 
Positive 
Negative 
Negative 
Persistent 
9 
Negative 
Negative 
Negative 
Negative 
Positive 
Negative 
Negative 
Transient 
Negative 
Positive 
Negative 
Persistent 
10 
Negative 
Negative 
positive 
Negative 
Positive 
Negative 
Negative 
Persistent 
Negative 
Negative 
Negative 
Persistent 
11 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Persistent 
Positive 
Negative 
Negative 
Transient 
12 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Persistent 
Positive 
Positive 
Negative 
Transient 
13 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Persistent 
14 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Missing 
Missing 
Persistent 
15 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Negative 
Missing 
Persistent 
16 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Negative 
Negative 
Transient 
17 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Negative 
Transient 
 


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7 References 
Guidelines and scientific papers: 
[1] Guideline, ICH Harmonised Tripartite E3: "Structure and content of clinical study reports E3." Recommended for Adoption at Step 4 
(1995). 
[2] Guideline, ICH Harmonised Tripartite E9: "Statistical principles for Clinical Trials." Recommended for Adoption at Step 4 (1998). 
[3] Guideline, ICH Harmonised Tripartite E9(R1) "Addendum on estimands and sensitivity analysis in clinical trials to the guideline on 
Statistical principles for Clinical Trials." Recommended for Adoption at Step 4 (2019). 
[4] 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. 
[5] 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. 
[6] Borgheini, G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin. Ther. 2003, 25, 
1578–1592. 
[7] Gozzo, Lucia, Filippo Caraci, and Filippo Drago. "Bioequivalence, drugs with narrow therapeutic index and the phenomenon of 
biocreep: A critical analysis of the system for generic substitution." Healthcare. Vol. 10. No. 8. MDPI, 2022. 
[8]  Pedersen, Alma B., et al. "Missing data and multiple imputation in clinical epidemiological research." Clinical epidemiology (2017): 
157-166. 
[9] Koch GG. (2008). Comments on ‘Current issues in non inferiority trials’. Statistics in Medicine, 27:333 342. 
[10] Kenward MG, Molenberghs G, Thijs H. (2003). Pattern mixture models with proper time dependence. Biometrika , 90:53 71. 
[11] Tan, Ping-Tee, et al. "A review of the use of controlled multiple imputation in randomised controlled trials with missing outcome 
data." BMC Medical Research Methodology 21.1 (2021): 1-17. 


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[12] 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. 
[13]  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. 
[14]  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. 
[15] 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. 
[16] https://clinicaltrials.gov/ct2/show/results/NCT2053753?view=results. 
[17] Shankar, Assessment and reporting of the clinical immunogenicity of therapeutic Proteins and peptides – Harmonised terminology 
and tactical recommendations, AAPS 16 (4) 2014. 
Software: 
[18] SAS® Version 9.2 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS Institute Inc. SAS and all other SAS 
Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.  
[19] SAS/STAT 15.2® User’s Guide The MI Procedure 
[20] SAS/STAT 15.2® User’s Guide The MIANALYZE Procedure 
[21] SAS/STAT 15.2® User’s Guide 
[22] R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, 
Austria. URL https://www.R-project.org/. 


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Reason for signing: Approved
Name: 
Role: 
Date of signature: 13-Dec-2023 07:43:34 GMT+0000
Reason for signing: Approved
Name: 
Role: 
Date of signature: 13-Dec-2023 08:46:17 GMT+0000
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Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan Addendum 
Project Document Version No.: 2.0; Document Effective Date:  Date of last sig.  
 CONFIDENTIAL 
TP-GDO-WW-169-01 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 1 of 9 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Gedeon Richter Plc. 
RGB-14-101 
A Randomised, Double-blind, Multicentre Phase III Study to Assess the Efficacy and 
Safety ofRGB-14-P Compared to Prolia® in Women with Postmenopausal Osteoporosis 
Statistical Analysis Plan Addendum 
Parexel Project Number: 252679 
 
 


Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan Addendum 
Project Document Version No.: 2.0; Document Effective Date:  Date of last sig.  
 CONFIDENTIAL 
TP-GDO-WW-169-01 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 2 of 9 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
SPONSOR SIGNATURE PAGE 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
Gedeon Richter Plc. 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
 
 
Gedeon Richter Plc. 
 
Signatures obtained electronically. 
 
 
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Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan Addendum 
Project Document Version No.: 2.0; Document Effective Date:  Date of last sig.  
 CONFIDENTIAL 
TP-GDO-WW-169-01 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 3 of 9 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
Parexel Signature Page 
Signature(s) below confirm that the Statistical Analysis Plan Addendum was developed in accordance with 
SOP-GDO-WW-019 and that it is approved for release. 
This document has been approved and signed electronically on the final page by the following:  
 
 
 
 
Signatory 
Author 
 
  
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Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan Addendum 
Project Document Version No.: 2.0; Document Effective Date:  Date of last sig.  
 CONFIDENTIAL 
TP-GDO-WW-169-01 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 4 of 9 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
TABLE OF CONTENTS 
 
1 
CHANGES TO THE STATISTICAL ANALYSIS PLAN......................................... 6 
1.1 
Primary Pharmacodynamic Endpoint – Main Analytical Approach ........................................ 6 
1.2 
Primary Efficacy Endpoint – Primary estimand sensitivity tipping point for FDA submission
 
7 
1.3 
Pharmacokinetic Concentrations .............................................................................................. 7 
1.4 
Adverse Events ......................................................................................................................... 8 
1.5 
Medical History and Concurrent Illnesses ............................................................................... 8 
 
 
 


Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan Addendum 
Project Document Version No.: 2.0; Document Effective Date:  Date of last sig.  
 CONFIDENTIAL 
TP-GDO-WW-169-01 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 5 of 9 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
REVISION HISTORY 
 
 
Version No. 
Effective Date 
Summary of Change(s) 
1.0 
Date of last signature 
New document 
2.0 
Date of last signature 
Updated to add a section for summary of PK results 
Updated to add a section for additional summaries of AE and 
additional AE tables 
Updated to add a section for summary of medical history and 
concomitant illness. 
 
 
 
 
 
 


1 
CHANGES TO THE STATISTICAL ANALYSIS PLAN 
1.1 
Primary Pharmacodynamic Endpoint – Main Analytical Approach 
Section 4.2.2.2 of the statistical analysis plan (SAP) version 1.0 stated that to evaluate the %CfB 
AUEC sCTX0-m6 (required as primary endpoint for EMA and secondary for FDA), the treatment 
comparison will be made using the ANCOVA with natural log-transformed AUEC data as the 
dependent variable while the followings will be model covariates: 
• Treatment Arm 
• Stratification factors for randomisation: 
o Previous use of bisphosphonates (yes/no) 
o Geographical region (Europe, US) 
• Log of baseline sCTX 
 
LS means for %CfB AUEC sCTX0-m6 will be back transformed to derive geometric means and 
presented with the corresponding LS GMR with their corresponding 95% CIs. Geometric LS mean 
ratios will be derived by back transforming the LS mean difference between RGB-14-P and Prolia® 
(RGB-14-P - Prolia®) and presented as ratio (GMR). Back transformed LS mean and GMR will 
be presented as percentages, as well as the corresponding CIs. Delta method was applied to back 
transform geometric mean standard error used for the computation of corresponding 95% CIs. 
A supplementary analysis will now be performed as followed: To evaluate the %CfB AUEC 
cSCTX0-m6, the treatment comparison will be made using the ANCOVA with the AUEC data as 
collected as the dependent variable while the following will be model covariates: 
• Treatment Arm 
• Stratification factors for randomisation: 
o Previous use of bisphosphonates (yes/no) 
o Geographical region (Europe, US) 
• Baseline of sCTX 
 
LS means for %CfB AUEC sCTX0-m6 will be presented with their corresponding 95% confidence 
intervals (CIs). The LS mean difference between RGB-14-P and Prolia® (RGB-14-P - Prolia®) 
and the corresponding 95% CI will also be presented. 
The change is being made as, although sCTX values are expected to decrease over time following 
injection, some patients had an increase from baseline in sCTX values (indicated as negative values 
– see formula in section 4.2.2.1 of SAP version 1.0) and a log-transformation would exclude these 
data from analysis.    
 
 


Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan Addendum 
Project Document Version No.: 2.0; Document Effective Date:  Date of last sig.  
 CONFIDENTIAL 
TP-GDO-WW-169-01 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 7 of 9 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
1.2 
Primary Efficacy Endpoint – Primary estimand sensitivity tipping point for FDA 
submission 
Two additional tipping point plots will be produced to present the tipping point results of Approach 
1 and Approach 2 mention in section 4.2.1.3.2 of the SAP version 1.0.  
The first figure will display the sensitivity two-dimensional tipping point multiple imputation – 
approach 1 – non inferiority and the sensitivity two-dimensional tipping point multiple imputation 
– approach 2 – non inferiority. The second figure will display the sensitivity two-dimensional 
tipping point multiple imputation – approach 1 – non superiority and the sensitivity two-
dimensional tipping point multiple imputation – approach 2 – non superiority.  
For each figure, the horizontal axis will cover the “Shift to RGB” ranging from -7.45 to +7.45, and 
the vertical axis will cover the “Shift to Prolia” ranging from -7.45 to +7.45.  
Claims of non-inferiority/non-superiority met will be displayed by green circles, or red circles 
otherwise. 
The new figures are being produced to assess the tipping points of the of non-inferiority/non-
superiority claims more easily.  
1.3 
Pharmacokinetic Concentrations 
Serum concentrations for RGB-14-P and Prolia will be summarised by study day on the full 
analysis set. The following descriptive statistics will be presented for serum concentrations 
obtained at each study day: n, number of concentration values below the limit of quantification 
(nBLQ), (where the lower limit of quantification is defined as 1ng/mL) mean, SD, coefficient of 
variation (CV%) (calculated as the [standard deviation divided by the mean]*100), geometric mean 
(calculated as: exp(µ); where µ is the mean of the data on the log transformed values), geometric 
CV% (calculated as: gCV% =SQRT[exp(s²) -1]*100; where s is the standard deviation of the log 
transformed values), minimum, median and maximum. 
The following rules will be followed with regards to the number of decimal places/significant 
figures and presentation of data in tables of concentration data: 
• The mean, geometric mean and median will be tabulated to one more decimal place 
compared to the source data, and the standard deviation (SD) will be tabulated to two more 
decimal places compared to the source data, but with a maximum of four decimal places. 
• Minimum and maximum values will be tabulated to the same precision as the source data, 
but with a maximum of four significant digits. 


Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan Addendum 
Project Document Version No.: 2.0; Document Effective Date:  Date of last sig.  
 CONFIDENTIAL 
TP-GDO-WW-169-01 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 8 of 9 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
• CV% and gCV% will be presented to one decimal place. 
   
This new table is being produced to support the Listing of serum drug concentration. 
1.4 
Adverse Events 
Section 4.5.2 of the SAP details the summaries to be produced for TEAEs. The following additional 
summaries will be produced for the overview of the number and percentage of subjects (and 
number of events) for the TEAEs emerging in the main and transition period for the safety analysis 
set: 
• Any TEAE leading to discontinuation of IMP 
• Any treatment related TEAE leading to discontinuation of IMP 
 
A new output will be produced for: 
 
• Number and percentage of subjects for each TEAE leading to discontinuation of IMP 
categorised by SOC and PT 
• Number and percentage of subjects for treatment related TEAE leading to discontinuation 
of IMP categorised by SOC and PT 
 
The new categories of adverse events and new table are being added to further characterise the 
safety profile. 
1.5 
Medical History and Concurrent Illnesses 
Section 6.2.6 of the SAP states that medical and surgical history data will be listed. Two additional 
summary tables will now be produced for medical and surgical history, and concomitant illness. 
Medical history is defined as any disease with a start and end date prior to the date of first dose of 
IMP. Concomitant illness is defined as any disease with an end date on or after the date of the first 
dose of IMP. Any disease with missing end date and marked as ‘Ongoing’ will also be considered 
as concomitant illness.   
The following additional summary tables will be produced in the main and transition period for the 
full analysis set: 
 
• Medical history by SOC and PT 
• Concomitant illness by SOC and PT  
 


Parexel International 
Gedeon Richter Plc. 
RGB-14-101 
Statistical Analysis Plan Addendum 
Project Document Version No.: 2.0; Document Effective Date:  Date of last sig.  
 CONFIDENTIAL 
TP-GDO-WW-169-01 
 
 
Effective Date:  22 Dec 21 
Related to:  SOP-GDO-WW-019 
Page 9 of 9 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
The new outputs are being added to further characterise the medical history and concomitant illness 
of the subjects randomised in the study. 


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Reason for signing: Approved
Name: 
Role: 
Date of signature: 10-Apr-2024 12:28:59 GMT+0000
Reason for signing: Approved
Name: 
Role: 
Date of signature: 10-Apr-2024 13:54:07 GMT+0000
Reason for signing: Approved
Name: 
Role: 
Date of signature: 10-Apr-2024 14:59:45 GMT+0000
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