A Randomized, Double-blind, Multicenter Integrated Phase I/III Study in Postmenopausal Women With Osteoporosis to Compare the Pharmacokinetics, Pharmacodynamics, Efficacy, Safety and Immunogenicity of GP2411 (Proposed Biosimilar Denosumab) and Prolia® (EU-authorized)
Phase: PHASE3
Conditions: Postmenopausal Women With Osteoporosis
Sponsor: Sandoz

Biopharmaceuticals Clinical Development 
GP2411 
Clinical Trial Protocol CGP24112301 / NCT03974100
A randomized, double-blind, multicenter integrated phase 
I/III study in postmenopausal women with osteoporosis to 
compare the pharmacokinetics, pharmacodynamics, 
efficacy, safety and immunogenicity of GP2411 (proposed 
biosimilar denosumab) and Prolia® (EU-authorized) 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2018-003523-11 
Version number: 
06, incorporating amendment 6 
Clinical Trial Phase: 
Integrated phase I/III 
Release date: 
30-Oct-2020
Property of Hexal AG and Sandoz Inc. 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Hexal AG and Sandoz Inc. 
Clinical Trial Protocol Template version 1.0 (01-Dec-2017) 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 6 (released on 30-Oct-2020) ......................................................................... 12 
Amendment 5 (released on 21-Feb -2020) ........................................................................ 14 
Local Amendment 4 (released on 10-Sep-2019) for Japan only ....................................... 18 
Local Amendment 3 (released on 28-Jun-2019) for Czech Republic only ....................... 19 
Amendment 2 (released on 15-Mar-2019) ........................................................................ 20 
Amendment 1 (released on 10-Dec-2018) ........................................................................ 25 
Protocol summary .............................................................................................................. 26 
1 
Introduction ....................................................................................................................... 32 
1.1 
Background ............................................................................................................ 32 
1.2 
Purpose .................................................................................................................. 33 
2 
Objectives and endpoints ................................................................................................... 33 
3 
Study design ...................................................................................................................... 35 
4 
Rationale ............................................................................................................................ 36 
4.1 
Rationale for study design ..................................................................................... 36 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 37 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 37 
4.4 
Purpose and timing of interim analyses ................................................................. 37 
4.5 
Risks and benefits .................................................................................................. 37 
4.5.1 
Blood sample volume ............................................................................ 38 
5 
Population .......................................................................................................................... 38 
5.1 
Inclusion criteria .................................................................................................... 38 
5.2 
Exclusion criteria ................................................................................................... 39 
6 
Treatment ........................................................................................................................... 41 
6.1 
Study treatment ...................................................................................................... 41 
6.1.1 
Investigational and comparator drugs ................................................... 41 
6.1.2 
Additional study treatments .................................................................. 41 
6.1.3 
Treatment arms/group ........................................................................... 42 
6.1.4 
Treatment duration ................................................................................ 42 
6.2 
Other treatment(s) .................................................................................................. 43 
6.2.1 
Concomitant therapy ............................................................................. 43 

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6.2.2 
Prohibited medication ........................................................................... 43 
6.2.3 
Restriction for study patients ................................................................ 43 
6.3 
Patient numbering, treatment assignment, randomization ..................................... 44 
6.3.1 
Patient numbering ................................................................................. 44 
6.3.2 
Treatment assignment, randomization .................................................. 44 
6.4 
Treatment blinding ................................................................................................ 45 
6.5 
Dose escalation and dose modification.................................................................. 47 
6.6 
Additional treatment guidance ............................................................................... 47 
6.6.1 
Treatment compliance ........................................................................... 47 
6.6.2 
Recommended treatment of adverse events .......................................... 47 
6.6.3 
Emergency breaking of assigned treatment code .................................. 48 
6.7 
Preparation and dispensation ................................................................................. 48 
6.7.1 
Handling of study treatment and additional treatment .......................... 48 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 49 
7 
Informed consent procedures ............................................................................................ 49 
8 
Visit schedule and assessments ......................................................................................... 50 
8.1 
Screening ............................................................................................................... 53 
8.1.1 
Information to be collected on screening failures ................................. 54 
8.2 
Patient demographics/ other baseline characteristics ............................................ 54 
8.3 
Efficacy/ Pharmacodynamics ................................................................................ 54 
8.3.1 
DXA scan collection, processing and analytical methods .................... 54 
8.3.2 
Bone metabolism biomarkers ................................................................ 55 
8.3.3 
Appropriateness of efficacy assessments .............................................. 56 
8.4 
Pharmacokinetics ................................................................................................... 56 
8.4.1 
Pharmacokinetics blood sample collection and handling ..................... 56 
8.4.2 
Analytical methods for pharmacokinetics ............................................. 56 
8.4.3 
Appropriateness of pharmacokinetic measurements ............................. 57 
8.5 
Safety ..................................................................................................................... 57 
8.5.1 
Physical examination and vital signs .................................................... 57 
8.5.2 
Laboratory evaluations .......................................................................... 58 
8.5.3 
Immunogenicity .................................................................................... 60 
8.5.4 
Fractures ................................................................................................ 61 
8.5.5 
Injection site reactions........................................................................... 61 
8.5.6 
Electrocardiogram (ECG) ..................................................................... 61 
8.5.7 
Pregnancy and assessments of fertility ................................................. 62 
8.5.8 
Appropriateness of safety measurements .............................................. 62 

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8.6 
Additional assessments .......................................................................................... 62 
8.6.1 
Clinical outcome assessments (COAs) ................................................. 62 
9 
Study discontinuation and completion .............................................................................. 62 
9.1 
Discontinuation ...................................................................................................... 62 
9.1.1 
Discontinuation of study treatment ....................................................... 62 
9.1.2 
Withdrawal of informed consent ........................................................... 63 
9.1.3 
Early termination visit ........................................................................... 64 
9.1.4 
Lost to follow-up ................................................................................... 64 
9.1.5 
Early study termination by the sponsor ................................................. 64 
9.2 
Study completion and post-study treatment .......................................................... 65 
10 Safety monitoring and reporting ........................................................................................ 65 
10.1 
Definition of adverse events and reporting requirements ...................................... 65 
10.1.1 
Adverse events ...................................................................................... 65 
10.1.2 
Serious adverse events .......................................................................... 67 
10.1.3 
SAE reporting........................................................................................ 68 
10.1.4 
Pregnancy reporting .............................................................................. 68 
10.1.5 
Reporting of study treatment errors including misuse/ abuse ............... 69 
10.2 
Additional safety monitoring ................................................................................. 69 
11 Data collection and database management ........................................................................ 69 
11.1 
Data collection ....................................................................................................... 69 
11.2 
Database management and quality control ............................................................ 70 
11.3 
Site monitoring ...................................................................................................... 70 
12 Data analysis and statistical methods ................................................................................ 71 
12.1 
Analysis sets .......................................................................................................... 72 
12.2 
Patient demographics and other baseline characteristics ....................................... 73 
12.3 
Treatments ............................................................................................................. 74 
12.4 
Pharmacokinetics and pharmacodynamics ............................................................ 74 
12.4.1 
Pharmacokinetics .................................................................................. 74 
12.4.2 
Pharmacodynamics ............................................................................... 74 
12.5 
Analysis of the primary endpoint(s) ...................................................................... 75 
12.5.1 
Definition of primary endpoint(s) ......................................................... 75 
12.5.2 
Statistical model, hypothesis, and method of analysis .......................... 75 
12.5.3 
Handling of missing values/discontinuations........................................ 79 
12.5.4 
Sensitivity analyses ............................................................................... 80 
12.5.5 
Supplementary analyses ........................................................................ 81 
12.6 
Analysis of secondary endpoints ........................................................................... 81 

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12.6.1 
Efficacy endpoints ................................................................................. 81 
12.6.2 
Safety endpoints .................................................................................... 81 
12.6.3 
Pharmacokinetics .................................................................................. 83 
12.6.4 
Pharmacodynamics ............................................................................... 83 
12.7 
Interim analyses ..................................................................................................... 84 
12.8 
Sample size calculation.......................................................................................... 84 
12.8.1 
Assumptions of sample size calculation ............................................... 84 
12.8.2 
Margin derivation for %CfB in LS-BMD ............................................. 85 
12.8.3 
Combined sample size calculation ........................................................ 86 
12.8.4 
Supplementary analysis of primary endpoint ........................................ 86 
13 Ethical considerations and administrative procedures ...................................................... 87 
13.1 
Regulatory and ethical compliance ........................................................................ 87 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 87 
13.3 
Publication of study protocol and results............................................................... 87 
13.4 
Quality control and quality assurance.................................................................... 87 
14 Protocol adherence ............................................................................................................ 88 
14.1 
Protocol amendments............................................................................................. 88 
15 References ......................................................................................................................... 89 
16 Appendices ........................................................................................................................ 92 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 33 
Table 6-1 
Investigational/ comparator drug .......................................................... 41 
Table 6-2 
Blinding and unblinding plan ................................................................ 46 
Table 8-1 
Assessment schedule ............................................................................. 51 
Table 8-2 
Laboratory assessments ......................................................................... 58 
Table 8-3 
Injection site reaction grading ............................................................... 61 
Table 10-1 
Guidance for capturing the study medication errors including 
misuse/ abuse ........................................................................................ 69 
Table 12-1 
List of primary endpoints ...................................................................... 71 
Table 12-2 
List of secondary endpoints with equivalence testing ........................... 72 
Table 12-3 
Pharmacokinetic parameters ................................................................. 74 
Table 12-4 
Pharmacodynamic parameters .............................................................. 75 
Table 12-5 
Hierarchical testing strategy for FDA ................................................... 75 
Table 12-6 
Hierarchical testing strategy for EMA .................................................. 75 
Table 12-7 
Hierarchical testing strategy for PMDA ............................................... 76 

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Table 12-8 
Missing data patterns for %CfB in LS-BMD for TP1 FAS .................. 79 
Table 12-9 
Assumptions for sample size calculation .............................................. 84 
Table 12-10 
%CfB in LS-BMD at 12 months for denosumab 60 mg compared 
to placebo in three published clinical trials ........................................... 85 
Table 12-11 
Meta-analysis of treatment effects of denosumab - placebo ................. 85 
Table 12-12 
Testing specifications for combined requirements ............................... 86 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 35 
 

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List of abbreviations 
%CfB 
Percentage change from baseline 
25 (OH) vitamin D 
25-hydroxyvitamin D 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
anti-HBc 
anti-Hepatitis B core antibody 
anti-HBs 
anti-Hepatitis B surface antibody 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUCinf 
Area under the serum concentration-time curve extrapolated to infinity 
AUEC 
Area under the effect versus time curve 
BDRM 
Blind Data Review Meeting 
BMD 
Bone mineral density 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulation 
CI 
Confidence interval 
Cmax 
Maximum serum concentration (of a drug) 
CMO & PS 
Chief Medical Office and Patient Safety 
COA 
Clinical outcome assessments 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report/ Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
Collagen C-telopeptide 
CV 
Coefficient of variation 
CZ 
Czech Republic 
dL 
Deciliter 
DXA 
Dual energy X-ray Absorptiometry 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials database 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FN-BMD 
Femoral neck bone mineral density 

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FSH 
Follicle-stimulating hormone 
g 
Gram 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
h 
Hour 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INN 
International Nonproprietary Names 
INR 
International Normalized Ratio 
IOF 
International Osteoporosis Foundation 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
JP 
Japan 
kDa 
Kilodalton 
kg 
Kilogram(s) 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification 
LS-BMD 
Lumbar spine bone mineral density 
LSM 
Least-squares means 
MAR 
Missing at random 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram(s) 
mL 
Milliliter(s) 
MMRM 
Mixed-model repeated measures 
NAb 
Neutralizing antibodies 
NCI 
National Cancer Institute 
ng 
Nanogram(s) 
NYHA 
New York Heart Association (Functional Classification) 
ONJ 
Osteonecrosis of the jaw 
PD 
Pharmacodynamic(s) 
PDS 
Pharmacodynamics analysis set 
PFS 
Pre-filled syringe 
PINP 
Procollagen I N-terminal propeptide 
PK 
Pharmacokinetic(s) 

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PKS 
PK analysis set 
PMDA 
Pharmaceuticals and Device Agency 
PMO 
Postmenopausal osteoporosis 
PPS 
Per-Protocol Set 
PT 
Prothrombin time 
QMS 
Quality Management System 
RANK 
Receptor Activator of Nuclear factor Kappa-B 
RANKL 
Receptor Activator of Nuclear factor Kappa-B Ligand 
s.c. 
Subcutaneous 
SAE 
Serious adverse event 
SAF 
Safety Set 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SmPC 
Summary of Product Characteristics 
SMQ 
Standardized MedDRA Query 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TH-BMD 
Total hip bone mineral density 
TP1 
Treatment Period 1 
TP2 
Treatment Period 2 
WBC 
White blood cell(s) 
WHO 
World Health Organization 
µL 
Microliter 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
Any drug (an active drug or an inactive drug, such as a placebo) which is used 
as a comparator to the investigational drug being tested in the trial 
Dosage 
Dose of the study treatment given to the patient in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Enrollment 
Point/ time of patient entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Investigational 
drug 
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance” 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage. 
Medication 
number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system 
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a single 
dose part and a multiple dose part, or a part in patients with established 
disease and in those with newly-diagnosed disease. 
Patient 
An individual with the condition of interest and who has consented to participate 
in this study 
Period 
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the planned completion 
of all study drug administration and assessments; at this time all study drug 
administration is discontinued and no further assessments are planned 
Randomization 
number 
A unique identifier assigned to each randomized patient, corresponding to a 
specific treatment arm assignment 
Screen Failure 
A patient who did not meet one or more criteria that were required for 
participation in the study  
Study completion 
Point/time at which the patient came in for a final evaluation visit or when study 
drug was discontinued whichever is later 
Study medication 
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug(s), control(s) or non-investigational 
medicinal product(s) 
Study treatment 
discontinuation 
When the patient permanently stops taking study treatment prior to the defined 
study treatment completion date 
Patient number 
A number assigned to each patient who enrolls in the study. When combined 
with the center number, a unique identifier is created for each patient in the 
study. 
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study 

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Withdrawal of 
consent 
Withdrawal of consent from the study is defined as when a patient does not 
want to participate in the study any longer, and does not want any further visits 
or assessments, and does not want any further study related contact, and does 
not allow analysis of already obtained biologic material 
 

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Clinical Trial Protocol (Version No. 06) 
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Amendment 6 (released on 30-Oct-2020) 
Amendment rationale 
The purpose of this amendment is to address the following: 
x Implement FDA´ advice information request on Investigational New Drug application (IND 
135707) dated 30-Apr-2020 on missing data 
x Evaluation of the impact of the COVID-19 pandemic including retrospective serological 
testing for SARS-CoV-2 antibodies may be performed. This is to assure data robustness 
through potential sensitivity analyses for LS-BMD, PK and PD  and adverse events 
reporting to assess a possible impact from SARS-CoV-2 on these endpoints 
x Update of statistical testing strategy from one overall study testing strategy to three separate 
testing strategies to address different health authority requirements 
Furthermore, editorial changes were made to correct inconsistencies within this protocol. 
Study status 
At the time of this protocol amendment, the study has finished recruitment with overall 527 
patients enrolled globally.   
Main Changes to the protocol 
Changes based on FDA feedback on missing data 
x Inclusion of more details for MMRM model in Section 12.5.2.1 
x Inclusion of summary statistics on missing data patterns in Section 12.5.3 
x Additional details on missing data handling for the primary analysis of %CfB in LS-BMD 
in Section 12.5.3.1 
x Inclusion of training provided to the investigators for prevention of missing data in 
Section 11.3 
x Inclusion of laboratory normal range for albumin in Section 5.2 
x Inclusion of sensitivity analysis to assess robustness of MAR assumption for MMRM 
primary analysis of %CfB in LS-BMD in Section 12.5.4 
Changes related to COVID-19 pandemic 
x Risk assessment related to COVID-19 due to study medication included in Section 4.5 Risks 
and Benefits 
x Included retrospective serological testing for SARS-CoV-2 antibodies may be performed in 
Section 8.5.2 
x Updated Table 8-1 assessment schedule  
x 
 
 
 
PI

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Other changes 
Update of use of research results (data) collected for study evaluation prior to withdrawal of 
informed consent in Section 9.1.2 
Statistical testing strategy updated from one overall testing strategy in the study to three separate 
testing strategies to address different health authority requirements 
• Reference to detailed testing strategy included in Section 12 
• Testing strategy details updated in Section 12.5.2  
Description of summary statistics moved to statistical introduction section to ensure 
applicability and consistency across sub-sections 
• Inclusion of description of summary statistics in Section 12 
• Removal of description of summary statistics in Sections 12.2, 12.6.3 and 12.6.4 
• Removal of summary statistic of frequency of concentrations below LLOQ in Section 
12.6.3 and 12.6.4 
Clarification on missing or duplicated summary statistics 
• Inclusion of summary statistics of AUEC of %CfB in CTX concentrations after the first 
dose in Section 12.5.2.2 
• Inclusion of summary statistics of AUCinf and Cmax in Section 12.5.2.3 
• Removal of repeated summary statistics of PD concentrations in Section 12.6.4 
Clarification of assignment of analyses as sensitivity, supportive or supplementary analysis in 
Sections 12.5.2.1, 12.5.4, 12.5.5, and 12.8.4. 
Specification of sensitivity analyses to assess impact of stratification errors in Section 12.1 
moved to statistical analysis plan. 
Move of PD analysis description to PD section 
• Move of handling of CTX concentrations below LLOQ in summary statistics from Section 
12.5.3 to Section 12.6.4 
• Move of PD secondary endpoint description from Section 12.6.1 to Section 12.6.4 
Focus of laboratory safety analysis by grade on low/ normal/ high classification instead of 
CTCAE grading in Section 12.6.2 
Specification of ECG analyses in Section 12.6.2 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
This amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities (HA) for approval or notification as required 
according to local regulations. The changes described in this amended protocol are substantial.  

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Amendment 5 (released on 21-Feb -2020) 
Amendment rationale 
The purpose of this amendment is to address the following: 
• Changes requested by FDA and other updates in the data analysis section: FDA advice on 
Investigational New Drug application (IND 135707) of 25-Jul-2019 following the second 
review of the protocol v02 (released on15-Mar-2019). This also led to clarifications of other 
statistical topics including overall study testing strategy. 
• Changes of calcium assessment: To further ensure the safety of patients, exclusion criterion 
#15 is updated; allowing only patients with normal albumin values to enter into the study.  
As a consequence, the assessment of calcium levels is shifted from the parameter serum 
albumin adjusted calcium to the parameter serum calcium (equals total serum calcium) 
throughout the entire study. 
• The vitamin D repletion and the processing time for the central laboratory samples could 
take more than 28 days. To avoid unnecessary repeated DXA and blood sampling for 
rescreening, the screening period is extended from 28 days to 35 days. Patients with vitamin 
D deficiency are allowed to be treated at the investigator’s discretion with an appropriate 
vitamin D dose in addition to the per protocol scheduled vitamin D supplementation during 
the screening period.  
The changes in local amendments 3 (for Czech Republic, released on 28-Jun-2019) and local 
amendment 4 (for Japan, released on 10-Sept-2019) are added in this global amendment 5; and 
editorial changes are made to correct inconsistencies within the protocol.  
Study status 
At the time of this protocol amendment, the study has recruited more than 200 patients globally.  
Changes to the protocol 
Changes Requested by FDA 
Analysis set for primary analysis of percentage change from baseline (%CfB) in lumbar spine 
bone mineral density (LS-BMD) for FDA and PMDA is changed from per protocol set (PPS) 
to treatment period 1 full analysis set (TP1 FAS) in Section 12.5: 
• Analysis set for the primary analysis of %CfB in LS-BMD was updated from PPS to TP1 
FAS including now all patients with at least one post-baseline LS-BMD value (including 
Week 26 assessment) 
Reduction of sample size from 522 patients to 492 patients in Section 3, Section 5 and 
Section 12.8: 
• Following a change in primary analysis set from PPS to TP1 FAS the drop-out rate was 
adjusted from 25% to 15%.   
• In addition, SD estimate of %CfB in LS-BMD at Week 52 was updated from 3.96 to 4.08 
deriving the SD as pooled SD over the 3 historical published trials instead of using weights 
based on variance of difference in mean between denosumab and placebo. 

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Modification of TP1 FAS in Section 12.1: 
• Analysis set definition of TP1 FAS was narrowed down to have at least one available post-
baseline LS-BMD value regardless of available post-baseline PD or PK values. 
Change of primary analysis set for %CfB in LS-BMD in Section 12.5 and Section 12.8.4: 
• For FDA and PMDA primary analysis set was changed from PPS to TP1 FAS with PPS as 
sensitivity analysis. 
• Following a decrease in sample size the power for the sensitivity analysis on PPS using a 
(-1.45, 1.45) margin was estimated to be at least 84%. 
Clarification of rationale for different stratification factors in Protocol summary, Section 6.3.2 
and Section 12.5.2: 
• Rationale for each stratification factor was provided in more detail to allow for a more in-
depth understanding on why stratification factors were implemented and in which endpoint 
analysis they need to be accounted for. 
• For the primary analysis of %CfB in LS-BMD prior bisphosphonate use (yes/ no) was 
included into the model as a potential source of heterogeneity that cannot be assured to be 
completely controlled through the use of inclusion/exclusion criteria. Age group (<65 years/ 
≥65 years) was removed from the model as age can best be assumed to have a linear effect 
on LS-BMD and therefore using the %CfB in LS-BMD as primary endpoint and including 
LS-BMD Baseline value as covariate should already account for the change in LS-BMD 
with age. 
Changes of calcium assessment 
The following changes in the reporting of calcium values were implemented: 
• The assessment of calcium values throughout the study was shifted from “albumin adjusted 
serum calcium” to “calcium”. 
• Cut-off values for hypocalcemia and hypercalcemia were added in exclusion criterion #15 
in Protocol Summary and Section 5.2:  
• Hypocalcemia was defined as calcium less than 2.10 mmol/L [8.42 mg/dL]. 
• Hypercalcemia was defined as calcium more than 2.62 mmol/L [10.50 mg/dL). 
• The same cut-off values are applied for the evaluation of the adverse events hypocalcemia 
and hypercalcemia. 
• SI and conventional units are both provided for calcium test as well as other laboratory 
parameters. 
Other main changes 
Screening period was prolonged from 28 days to 35 days in Figure 3-1, Table 8-1, Section 3 
and Section 8.1. 
Clarification on safety laboratory assessments: 
• Wordings were updated in Section 8.5. 

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Clarification on retest of vitamin D during the screening was added: 
• Exclusion criterion #14 in Protocol Summary and Section 5.2. 
Clarification on repletion of calcium during the screening was added: 
• Exclusion criterion #15 in Protocol Summary and Section 5.2.  
• Section 8.5.2, repletion rules were specified 
Clarification on safety lab values: 
• SI reference values were added in  Section 5.2. 
A +1 day window was added to Visit 3 to facilitate site visit schedules in Table 8-1.  
Clarification on analytical method for pharmacokinetics: 
• Wordings were updated in Section 8.4.2. 
Further unblinded sponsor staff was specified in Section 6.4: 
• Compliance Clinical Operations staff was added 
Clarification on physical examination: 
• Documentation of physical examination in eCRF was specified in Table 8-1 and Section 
8.5.1 
Clarification of purpose of interim analysis in Section 4.4 and Section 12.7: 
• Purpose of interim analysis was clarified to provide an early read-out of the primary 
analyses without affecting validity of subsequent analyses. 
Clarification of hierarchical testing strategy in Section 12.5.2: 
• With different HAs requiring testing of different primary endpoints, the overall study testing 
strategy was clarified. 
Change of layout of description of testing requirements for different HAs in Section 12: 
• To avoid duplication and ensure no misunderstanding testing requirements for different 
HAs are now presented in tabular format. 
Removal of description of application of analysis set from Section 12.1: 
• To avoid duplication and potential inconsistency application of different analysis sets is now 
described in Sections 12.5 and 12.6 only. 
Removal of reference to BDRM in Section 12.1: 
• Sponsor internal data review process was adapted to an ongoing blind data review instead 
of a single blind data review meeting (BDRM) before database lock. Protocol deviations 
leading to exclusion  will be defined in the SAP version finalized before database lock. 
Implementation of analysis set TP2 RAS in Section 12.1: 
• Patient disposition for patients re-randomized to TP2 will be presented for all patients re-
randomized to TP2 regardless of any post-baseline efficacy, PD or PK value, requiring the 
implementation of a new analysis set. 

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Removal of description of non-mandatory listings in Section 12.5 and Section 12.6: 
• Scope of non-mandatory listings will be defined in the SAP with related documents and was 
removed from protocol. 
Removal of sensitivity analysis on TP1 FAS for PK and PD endpoints in Sections 12.5 and 
Section 12.6: 
• Sensitivity analysis on TP1 FAS for PK and PD endpoints was deemed to be of limited 
value given the decreased accuracy in deriving parameters with missing values or relevant 
protocol deviations and was therefore removed from the protocol. 
Harmonization of description of analysis sets in Section 12.1: 
• Description of analysis sets was aligned to use the same wording when the same criteria 
was to be met. 
• Clarification was provided that for analyses on the TP1 FAS patient would be allocated to 
the strata as randomized in the IRT and not as stored in the clinical database. 
Removal of description of margin for CTX in Section 12.8: 
• For equivalence testing on PD endpoint AUEC of %CfB in CTX after first dose the standard 
bioequivalence margin of (0.80, 1.25) will be used with no study specific adaptions and 
therefore confusing statement removed from protocol. 
Clarification on Trial Feedback Questionnaire (TFQ) in Section 8.6.1: 
• Sentence on transfer of any spontaneous information on AE to safety database removed as 
not applicable, i.e. no option to enter free text in the TFQ. 
 

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Local Amendment 4 (released on 10-Sep-2019) for Japan only 
Amendment rationale 
The purpose of this amendment is to address the feedback from Pharmaceuticals and Medical 
Devices Agency (PMDA) deficiency letter on CGP24112301 Clinical Trial Notification 
received on 23-Aug-2019, 03-Sep-2019 and 09-Sep-2019. Changes in the protocol based on 
local amendment 4 are applicable for Japan only. 
Natural vitamin D was specified in the following section: 
• Additional study treatment in Section 6.1.2. 
Romosozumab was listed as a standalone approved drug excluded for prior or ongoing 
osteoporosis treatment: 
• Protocol summary, Key exclusion criteria 
• Exclusion criterion #8 in Section 5.2. 
• Prohibited medication in Section 6.2.2. 
An additional laboratory test at Day -4 was added for testing of albumin adjusted serum calcium 
levels in Japanese patients switching from activated vitamin D to natural vitamin D at Visit 1 
in the Assessments Schedule, Table 8-1 and screening, Section 8.1. 
Japanese brand name was added to the respective sections. 

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Local Amendment 3 (released on 28-Jun-2019) for Czech Republic only 
Amendment rationale 
The purpose of this local amendment is to respond to the deficiency letter (sukls99642/2019) 
issued by Czech Republic Health Authority on 6-Jun-2019. Changes in the protocol based on 
local amendment 3 will be implemented in the Czech Republic only. 
Inclusion criterion #2 in Section 5.1 
• A test for serum follicle-stimulating hormone (FSH) to confirm menopause at Screening 
was added to inclusion criterion #2. 
• Table 8-1 Assessment Schedule was updated to include the FSH test 
Laboratory evaluations in Section 8.5.2 
• Urine sediment test by microscopy was added at regular intervals 
• Screening in Section 8.1 was updated to include the urine sediment test 

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Amendment 2 (released on 15-Mar-2019) 
Amendment rationale  
The main purpose of this amendment is to respond the feedback from the European Medicines 
Agency (EMA) follow-up scientific advice of 13-Dec-2018 and Food and Drug Administration 
(FDA) advice on investigational drug application (IND 135707) of 06-Feb-2019 following their 
review of the study protocol. 
In addition, severity grading of adverse events, which was not defined by the Common 
Terminology Criteria for Adverse Events (CTCAE) classification is clarified. Severity grading 
of injection site reactions was updated to align with the CTCAE classification. The 
communication guideline of immunogenicity results was specified. 
Furthermore, editorial changes were made to correct inconsistencies within this protocol. 
Study Status 
At the time of this protocol amendment, the study has not yet started. 
Changes to the protocol 
Requested changes from Health Authorities (EMA and FDA)  
Increase of sample size in Section 12: 
• The sample size calculations were updated to change the confidence interval for the LS-
BMD for the FDA requirements to use a 95% confidence interval (previously a 90% 
confidence interval) in the similarity assessment of the primary endpoint. This results in a 
change in the total sample size from 436 to 522 throughout the protocol (Figure 3-1 was 
updated). 
Inclusion criterion #5 in Section 5.1: 
• The regions, total hip and femoral neck, were removed for BMD measurement to assess 
patient eligibility; inclusion will be based solely on LS-BMD in terms of T-score. This is 
in line with the fact that the study primary endpoint is based on a percent change from 
baseline in BMD specifically at the lumbar spine. 
Additional exclusion criterion #6 in Section 5.2: 
• Exclusion of patients with active healing fractures was added.  
Exclusion criterion #7 in Section 5.2: 
• Washout period for previous tibolone, oral or transdermal estrogen and selective estrogen 
receptor modulators, was extended from 6 months to 12 months prior to screening. 
Additional study treatment in Section 6.1.2:  
• For calcium and vitamin D supplementation, dosage as per investigator discretion has 
been replaced with at least 1000 mg of elemental calcium and 800 IU vitamin D 
supplementation daily from screening until the end of the study. 
DXA assessment in Section 8.3.1: 
• DXA assessments of hip joint (total hip and femoral neck) were standardized in terms of 
using the same side of the body (left). 

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Assessment of nonvertebral fractures in Section 8.5.4:  
• Instruction to use local radiology report for nonvertebral fractures was added. 
Study discontinuation and completion in Section 9.1.1 and Section 9.2: 
• The recommendation for transitioning patients to alternative antiresorptive osteoporosis 
therapy was further emphasized.  
Safety monitoring and reporting in Section 10.1.3: 
• Reporting of all potential serious risks to the FDA in accordance with 21 CFR 312.32 (c) 
was specified. 
Stratification factor of “prior bisphosphonate use” added: 
• Prior bisphosphonate use (oral and parenteral route) was added to the stratification scheme 
to account for potential study population heterogeneity due to this prior therapy (changes 
in Section 3 Study design; Section 6.1.3 Treatment arms/groups; Section 6.3.2 Treatment 
assignment, randomization; and Section 12.5.2 Statistical model, hypothesis, and method 
of analysis). 
• With the introduction of an additional stratification factor, the list of factors and covariates 
in the statistical models has been carefully reconsidered and updated to avoid possible 
model instability through confounding. The primary analysis will not include region in the 
statistical model. This model should provide a stable main analysis, which is robust to any 
possible imbalances. A separate sensitivity analysis will be conducted to demonstrate 
homogeneity of the regions (LS-BMD and AUEC CTX). 
PK and ADA sampling time point at Week 22 added: 
• A PK sampling time point at Week 22 was added to better capture the PK profile. An 
ADA sampling time point at Week 22 was also added to ensure that an ADA sample is 
obtained at every sampling time point in line with PK sampling, (changes in Table 8-1 
Assessment schedule; Section 8.4.1 Pharmacokinetics blood sample collection and 
handing; Section 8.5.3.1 Immunogenicity blood sample collection and handling). 
PD sampling time point at Day 2 added: 
• A PD sampling time point at Day 2 was added to better capture the PD profile (changes in 
Table 8-1 Assessment schedule (all visit numbers were updated accordingly); Section 
8.3.2.1 Biomarker blood sample collection and processing. 
PD comparability index removed: 
• The PD comparability index may not be powerful to detect differences between test and 
reference product, therefore this approach was deleted from the protocol (change in 
Section 12.5.4 Sensitivity and Supportive analyses).  
AUEC clarification: 
• The AUEC definition was refined as the area under the baseline using all evaluable time 
points after the first 60 mg s.c. dose until CTX values return and cross the baseline for the 
first time, without including any rebound effects (specification on AUEC calculation in 
Section 12.4 Pharmacokinetics and pharmacodynamics). The rebound area has been 
included as sensitivity analyses in Section 12.5.4.  

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Definition of analysis sets in Section 12.1: 
• A new analysis set, Randomized Analysis Set (RAS), which included all randomized 
patients whether they are treated or not was added. The RAS will be used for disposition 
tables to include all patients who were randomized. 
• The Treatment Period 1 Full Analysis Set (FAS) definition in Section 12.1 was updated to 
include only patients who received at least one treatment with study medication and for 
whom there is some efficacy or PD data available. 
• The Per Protocol Set (PPS) definition in Section 12.1 was split into two analysis sets: an 
efficacy PPS which focuses on the protocol adherence, related to the LS-BMD 
measurements and safety, and a Pharmacodynamics (PD) analysis set (PDS) which 
focuses on the protocol adherence,  related to the CTX measurements and safety.  
Clarification of handling of missing percent change from baseline (%CfB) LS-BMD values in 
the efficacy primary analysis: 
• A clarification on the handling of missing %CfB LS-BMD values was added in 
Section 12.5.3 for the efficacy primary analysis. It is further clarified that a sensitivity 
analysis will be provided which does allow for the inclusion of patients with missing LS-
BMD values in Section 12.5.4. 
Margin justification was clarified in Section 12.8.2: 
• For clarification, the wording for the margin justification was updated to “A margin of 
1.45% retains at least 70% of the minimum treatment effect (FDA approach)”. 
Clarification on grading of adverse events by CTCAE 
Injection site reactions in Section 8.5.5: 
• Instruction to grade the severity of injection site reactions was updated according to the 
CTCAE classification in Table 8-3. 
Adverse events in Section 10.1.1:  
• The severity grading was introduced for adverse events, which were not defined by the 
CTCAE classification. 
Inclusion of the immunogenicity results communication guidance 
• The instruction on the communication of immunogenicity results was added in Section 
8.5.3.1. 
Editorial changes 
Study design in Section 3:  
• Visit number 15 instead of 13 for Week 52 was corrected. 
Population in Section 5: 
• Inclusion criterion #6 was updated for clarification of X-ray. 
• Exclusion criterion #7 was updated to cross reference to exclusion criterion #25. 
Investigational and comparator drugs in Section 6.1.1:  
• Polysorbate 20 concentration was corrected to 0.01% in Table 6-1. 

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Screening in Section 8.1:  
• ECG assessment was added to be consistent with Table 8-1.  
Pharmacokinetics in Section 8.4:  
• For clarification previous pharmacokinetics Section 8.5.2 moved to Section 8.4. 
Consequently, all subsequent subsections under Section 8 were renumbered. 
Appropriateness of pharmacokinetic measurements in Section 8.4.3:  
• PK assessment justification was added.  
Laboratory evaluations in Section 8.5.2: 
• Out of range laboratory values evaluations were further specified. 
• Hypocalcemia evaluation is further clarified. 
Immunogenicity in Section 8.5.3: 
• Immunogenicity risk of study drugs was specified. 
Pregnancy and assessment of fertility in Section 8.5.7:  
• Wording was updated to be consistent with Section 10.1.4 Pregnancy reporting.  
Data analysis and statistical methods in Section 12:  
• The confidence interval for the PK endpoint for PMDA was corrected to 90. 
• For readability, the terminology of the natural logarithm function “ln” was replaced by 
“log” throughout the protocol. Log was added to the list of abbreviations to make it clear 
that the natural logarithm is still meant.  
Pharmacokinetics and pharmacodynamics in Section 12.4: 
• The PK and PD parameters were moved to the newly introduced Section 12.4 
Pharmacokinetics and pharmacodynamics.  Consequently, all subsequent subsections 
under Section 12 were renumbered.  
Handling of missing values/ censoring/ discontinuations in Section 12.5.3:  
• It is now specified that the visit windows that will lead to exclusion from analysis set will 
be defined in the Blinded Data Review Meeting. 
• An explanation how to handle LLOQ values for the PK and PD parameter calculation was 
provided. 
Efficacy endpoints in Section 12.6.1:  
• Fracture rates were moved from the efficacy endpoints for Treatment Period 1 and 
Treatment Period 2 and became part of the safety assessments 
Safety endpoints in Section 12.6.2:  
• Specification of what laboratory outputs are to be provided was clarified. 
Pharmacokinetics in Section 12.6.3:  
• Clarification that the ratio of geometric means with associated confidence intervals will be 
provided as a secondary PK endpoint relevant for EMA only.  
Pharmacodynamics in Section 12.6.4:  

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• More details on the bioequivalence assessment of the secondary PD endpoint have been 
provided.  

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Amendment 1 (released on 10-Dec-2018) 
Amendment rationale 
The amendment is to address the request for information from the US Food and Drug 
Administration (FDA) based on the GP2411 Investigational New Drug review (submitted 30th-
Nov-2018). The main purpose of this amendment is editorial changes to ensure the correct 
terminology is appropriately used when referring to US-licensed Prolia and EU-authorized 
Prolia as well as the regulatory determination of “highly similar”, which will be made by the 
FDA at a later time. 
Study status 
At the time of this protocol amendment, the study has not yet started. 
Changes to the protocol 
Section 4.5 Risks and benefits: 
• Section was edited to reflect the appropriate use of wording to describe the results of 
comparative analytical studies for GP2411. 
Throughout this clinical protocol, wording has been edited to ensure the appropriate 
terminology is used when referring to US-licensed Prolia and EU-authorized Prolia or in 
general, to biosimilar development: 
• The term “originator” product has been implemented throughout this protocol where 
appropriate to refer in general to biosimilar development. 
• US-licensed Prolia and EU-authorized Prolia are used (together or separately) when 
more specific detail is necessary with regard to GP2411 and this study.  
• The term “comparator” is used to refer to EU-authorized Prolia that is used in this study. 

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Protocol summary 
Protocol number 
CGP24112301 
Full Title 
A randomized, double-blind, multicenter integrated phase I/III study in 
postmenopausal women with osteoporosis to compare the 
pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity 
of GP2411 (proposed biosimilar denosumab) and Prolia® (EU-authorized) 
Brief title 
Study investigating PK, PD, efficacy, safety, and immunogenicity of 
biosimilar denosumab (GP2411) in patients with postmenopausal 
osteoporosis 
Sponsor 
Hexal AG, Industriestr. 25, 83607 Holzkirchen, Germany  
Sandoz Inc., 100 College Road West, Princeton, NJ 08540, USA (for US) 
Investigation type 
Biosimilar 
Study type 
Interventional 
Study phase 
Integrated Phase I/III 
Purpose and 
rationale 
The purpose of this study is to demonstrate similar PK, PD, efficacy, safety, 
and immunogenicity of GP2411 and EU-authorized Prolia for up to 52 weeks 
in postmenopausal women with osteoporosis, following two 60 mg 
subcutaneous injections every 6 months. 
The study also involves a transition from EU-authorized Prolia to GP2411 for 
50% of the patients on EU-authorized Prolia at Week 52, with a subsequent 
evaluation of safety and immunogenicity for 26 weeks after the transition. 
Primary 
Objective(s)  
To demonstrate similar PK, PD and efficacy between GP2411 and EU-
authorized Prolia, the following sets of primary endpoints have been defined 
following scientific consultations with health authorities in Europe (EMA), US 
(FDA) and Japan (PMDA): 
• 
EMA requirement:  
(a) percent change from baseline (%CfB) at Week 52 in lumbar spine 
bone mineral density (LS-BMD) 
(b) area under the effect versus time curve (AUEC) after the first dose 
of %CfB in serum collagen C-telopeptide (CTX) 
• 
FDA and PMDA requirements: %CfB in LS-BMD at Week 52 
• 
PMDA requirement: PK similarity AUCinf and Cmax between GP2411 
and Prolia after the first dose 
Secondary 
Objective(s) 
Key Secondary Objective: 
To demonstrate PD similarity in terms of serum CTX response between 
GP2411 and EU-authorized Prolia: 
• 
FDA and PMDA requirements: AUEC after the first dose of %CfB in 
serum CTX 
Secondary Objectives: 
Treatment Period 1 (Day 1 - Week 52) 
To further compare GP2411 and EU-authorized Prolia in terms of PK, PD, 
efficacy, safety, and immunogenicity with respect to the following criteria: 
• 
BMD: %CfB in lumbar spine, femoral neck and total hip BMD (LS-BMD, 
FN-BMD, TH-BMD) at Week 26 

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• 
BMD: %CfB in femoral neck and total hip BMD (FN-BMD, TH-BMD) at 
Week 52 
• 
PD markers: CTX and procollagen I N-terminal propeptide (PINP) serum 
concentrations until Week 52 
• 
Safety: Fractures, vital signs, laboratory safety assessments, injection 
site reactions, ECG, occurrence of adverse events and serious adverse 
events, up to Week 52 
• 
Immunogenicity: Development of binding and neutralizing anti-drug 
antibodies (ADAs) until Week 52 
• 
Serum PK parameters AUCinf and Cmax after the first dose (EMA only) 
• 
Denosumab serum concentrations until Week 52 
Treatment Period 2 (Week 52 - Week 78):  
To further evaluate and compare GP2411 and EU-authorized Prolia in terms 
of PK, PD, efficacy, safety and immunogenicity with respect to the following 
criteria, after transitioning 50% patients from EU-authorized Prolia to GP2411: 
• 
BMD: %CfB in lumbar spine, femoral neck and total hip BMD (LS-BMD, 
FN-BMD, TH-BMD) at Week 78 
• 
PD markers: CTX and PINP serum 
concentrations from Week 52 to Week 78 
• 
Safety: Fractures, vital signs, laboratory safety assessments, injection 
site reactions, occurrence of adverse events and serious adverse 
events, from Week 52 up to Week 78 
• 
Immunogenicity: Development of binding and neutralizing 
ADAs from Week 52 to Week 78 
• 
Denosumab serum concentrations from Week 52 to Week 78 
Study design 
This is a multicenter, randomized, parallel arm, double-blind study with a 
total duration up to 82 weeks. Approximately 492 postmenopausal patients 
with osteoporosis will be randomized. Randomization will be stratified by 
region (US, Rest of World, Japan), age group (<65 years/ ≥65 years) and 
prior bisphosphonates use (yes/ no) and body weight group (<70 kg/ 
≥70 kg). 
The Screening Period of up to 5 weeks will assess patient’s eligibility. 
At the beginning of Treatment Period 1, eligible patients will be randomized 
using a 1:1 ratio to one of the two treatment groups: GP2411 or EU-authorized 
Prolia. All randomized patients will receive either 60 mg GP2411 or 60 mg 
EU-authorized Prolia on Day 1 and at Week 26. 
At the beginning of Treatment Period 2, which starts from Week 52, all 
patients still in the study will be allocated the treatment for Treatment Period 
2 through the IRT in a blinded manner. Patients in Treatment Period 1 Prolia 
group will be re-randomized 1:1 to either continue with a third dose of EU-
authorized Prolia, or transition to GP2411. All patients in the GP2411 group 
will continue the treatment with a third dose of GP2411. Thus, effectively in 
Treatment Period 2, the three groups "GP2411", "Prolia" and "Transition from 
Prolia to GP2411" are distributed in an approximate 2:1:1 ratio.   
PK, PD, efficacy, safety and immunogenicity will be evaluated until the end of 
study at Week 78.  
Population 
Postmenopausal women diagnosed with osteoporosis, aged ≥55 and ≤80 
years, with a body weight ≥50 and ≤90 kg 

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Key Inclusion 
criteria 
• 
Postmenopausal women, diagnosed with osteoporosis. 
Postmenopausal status is defined as at least 12 consecutive months of 
amenorrhea prior to date of screening, for which there is no other 
obvious pathological or physiological cause.  
[For CZ only: Postmenopausal status is defined as at least 12 
consecutive months of amenorrhea prior to date of screening for which 
there is no other obvious pathological or physiological cause and by 
elevated serum follicle-stimulating hormone (FSH) level assessed by 
central laboratory at screening] 
• 
Aged ≥55 and ≤80 years at screening 
• 
Body weight ≥50 kg and ≤90 kg at screening 
• 
Absolute bone mineral density consistent with T-score ≤-2.5 and ≥-4.0 at 
the lumbar spine as measured by DXA during the Screening Period 
• 
At least two vertebrae in the L1-L4 region (vertebrae to be assessed by 
central reading of lateral spine X-ray during the Screening Period) and 
at least one hip joint are evaluable by DXA  
Key Exclusion 
criteria 
• 
Previous exposure to denosumab (Prolia/ Pralia in Japan, Xgeva/ 
Ranmark in Japan, or biosimilar denosumab) 
• 
History of hypersensitivity to any recombinant protein drugs or any 
of the excipients used in GP2411 or Prolia 
• 
History and/or presence of one severe or more than two moderate 
vertebral fractures (as determined by central reading of lateral 
spine X-ray during the Screening Period) 
• 
History and/or presence of hip fracture 
• 
Presence of active healing fracture according to assessment of 
investigators 
• 
History and/or presence of bone metastases (see also exclusion 
criterion #25), bone disease or metabolic disease (except 
osteoporosis) that may interfere with the interpretation of the 
results, e.g. Paget's disease,  rheumatoid arthritis, ankylosing 
spondylitis, osteomalacia, osteogenesis imperfecta, 
osteopetrosis, Cushing's disease, hyperprolactinemia or 
malabsorption syndrome 
• 
Ongoing use of any osteoporosis treatment (other than calcium and 
vitamin D supplements). Following rules for wash-out periods for 
osteoporosis treatments have to be adhered to:  
• 
Drugs being investigated for osteoporosis: dose received at any 
time 
• 
Romosozumab: dose received at any time 
• 
Strontium or fluoride (for osteoporosis): dose received at any time 
• 
Intravenous bisphosphonates: dose received within 5 years prior to 
screening 
• 
Oral bisphosphonates  
• 
>3 years of cumulative use prior to screening 
• 
any dose received within 12 months prior to screening 
• 
Teriparatide or any PTH analogs: dose received within 12 months 
prior to screening 
• 
Tibolone, oral or transdermal estrogen, selective estrogen receptor 
modulators: dose received within 12 months prior to screening 

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• 
Calcitonin: dose received within 6 months prior to screening 
• 
Cinacalcet: dose received within 3 months prior to screening 
• 
Systemic glucocorticosteroids (≥5 mg prednisone equivalent per 
day for ≥10 days or a total cumulative dose of ≥50 
mg) within the past 3 months before screening 
• 
Other bone active drugs, including anti-convulsives (with 
the exception of benzodiazepines), heparin, systemic 
ketoconazole, adrenocorticotropic hormone, lithium,  gonadotropin 
releasing hormone agonists, anabolic steroids, within the past 3 
months before screening 
• 
Oral or dental conditions:  
• 
osteomyelitis or history and/or presence of osteonecrosis of 
the jaw (ONJ) 
• 
presence of risk factors for ONJ (e.g. periodontal disease, 
poorly fitting dentures, invasive dental procedures such as 
tooth extractions in 6 months before screening) 
• 
active dental or jaw condition which requires oral surgery 
• 
planned invasive dental procedure  
• 
Current uncontrolled status of hypothyroidism or hyperthyroidism 
• 
History and/or current hypoparathyroidism or hyperparathyroidism, 
irrespective of current controlled or uncontrolled status 
• 
Vitamin D deficiency (25 [OH] vitamin D serum level <50 nmol/L 
[<20 ng/mL]). Appropriate vitamin D dose in addition to vitamin D 
supplementation is permitted at the investigator’s discretion and 
patients will be retested during the screening period or may be 
rescreened (refer to Section 8.1) 
• 
Current hypocalcemia, defined as calcium <2.10 mmol/L [<8.42 
mg/dL]) or hypercalcemia, defined as calcium >2.62 mmol/L 
[>10.50 mg/dL]; patients must have normal albumin values (32 – 55 
g/L [3.2-5.5 g/dL]) according to central laboratory normal range. 
(Refer to Section 8.5.2 for specifications on repletion of calcium 
during the screening period). 
Study medication 
EU-authorized Prolia® pre-filled syringe (PFS) or GP2411 PFS 
Efficacy 
assessments 
LS-BMD, FN-BMD, TH-BMD as assessed by DXA will be measured at 
baseline, Week 26, 52, and 78. 
Pharmacodynamic 
assessments  
Serum CTX and PINP concentrations will be measured at time points 
specified in the assessment schedule. 
Pharmacokinetic 
assessments  
Serum denosumab concentrations will be measured at time points specified 
in the assessment schedule. 
Key safety 
assessments 
• 
Occurrence of fractures 
• 
Incidence of adverse events 
• 
Laboratory assessments 
• 
Vital signs 
• 
ECG 
• 
Anti-drug antibodies (ADA) 
Data analysis 
To evaluate the primary objectives 

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• 
For LS-BMD a mixed model repeated measures (MMRM) will be fitted 
using the %CfB measurements at Week 26 and Week 52. The MMRM 
model will include treatment (GP2411, Prolia), prior bisphosphonate use 
(yes/ no), DXA machine type (Lunar/ Hologic machine), time (visits 
Week 26, Week 52) and the interaction between time (visits Week 26, 
Week 52) and treatment (GP2411, Prolia) as fixed factors. Baseline LS-
BMD value will be included as a continuous covariate. 
• 
For the log-transformed AUEC (i.e. log(AUEC)) of the %CfB in CTX  
after first dose an analysis of covariance (ANCOVA) will be performed. 
The ANCOVA model will include treatment as fixed effect and baseline 
CTX as a continuous covariate.  
CIs for the least-squares mean differences in %CfB LS-BMD and in 
log(AUEC) of %CfB in serum CTX will be estimated from their 
respective models. CI for the ratio of the geometric mean AUEC 
of %CfB in serum CTX will then be calculated by anti-log transformation 
of the CI of the difference in log(AUEC).  
• 
For each of the log PK parameters (AUCinf and Cmax) an ANCOVA will 
be fitted which will include treatment as fixed factor and weight as 
continuous covariate. CI for the ratio of the geometric mean of the PK 
parameters will be calculated by anti-log transformation of the CI of the 
difference in the log PK parameters. 
The primary objective is considered met if: 
1. For EMA requirement: the 95% CI for the difference in %CfB for LS-BMD 
has to be completely contained within the equivalence interval of [-2.00%, 
2.00%] and the 95% CI for the ratio of the geometric mean AUEC of %CfB 
in serum CTX has to be completely contained within the equivalence 
interval of [0.80, 1.25]. 
2. For FDA requirement: the 95% CI for the difference in %CfB for LS-BMD 
has to be completely contained within the equivalence interval of [-1.45%, 
1.45%]. 
3. For PMDA requirement: the 95% CI for the difference in %CfB for LS-
BMD has to be completely contained within the equivalence interval of 
[-2.00%, 2.00%] and the 90% CI for the ratio of the geometric means of 
denosumab serum Cmax and AUCinf have to be completely contained 
within the equivalence interval of [0.80, 1.25]. 
The type I error rate will be controlled on health authority requirement level, 
i.e. a separate hierarchical testing strategy will be implemented per health 
authority. 
Summary statistics for continuous variables will include the number of non-
missing observations, mean, standard deviation (SD), minimum, median, and 
maximum. Summary statistics for discrete variables will be presented in 
contingency tables and will include absolute (n) and relative frequencies (%). 
For AUEC of %CfB in serum CTX, geometric means and CVs will be provided. 
The key secondary objectives are considered met if: 
1. For FDA and PMDA requirement: CI for the ratio of the geometric mean 
AUEC for %CfB in serum CTX has to be completely contained within the 
interval [0.80, 1.25] (FDA requirement is 90% CI and PMDA requirement 
is 95% CI). 

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To evaluate the other secondary objectives, the following data will be 
summarized using descriptive statistics: 
• 
BMD: %CfB of LS-BMD, FN-BMD, and TH-BMD at Weeks 26, 52, and 78 
• 
Safety: fractures, AEs, serious AEs, related AE, AEs leading to 
discontinuation up to Week 78 
• 
PD: serum CTX and PINP concentrations as per visit schedule 
• 
Serum PK parameters AUCinf and Cmax after the first dose (EMA  
requirement) 
• 
Denosumab serum concentrations as per visit schedule 
• 
Immunogenicity: binding and neutralizing ADAs measured up to 
Week 78   
Key words 
Denosumab, biosimilar, osteoporosis 

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1 
Introduction 
1.1 
Background 
Osteoporosis is defined as a progressive, systemic skeletal disorder characterized by low bone 
mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone 
fragility and susceptibility to fracture. Common sites for osteoporotic fractures are the spine, 
hip, distal forearm and proximal humerus (Kanis and Glüer 2000). Osteoporosis is estimated to 
affect 200 million women worldwide, approximately one-tenth of women aged 60, one-fifth of 
women aged 70, and two-fifths of women aged 80 (Johnell and Kanis 2006). It is widely 
recognized that osteoporosis and the consequent fractures are associated with increased 
morbidity and mortality. 
Denosumab is a fully human monoclonal antibody that targets and binds with high affinity and 
specificity to Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL), preventing 
activation of its receptor, RANK, on the surface of osteoclast precursors and osteoclasts. 
Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function and 
survival, thereby decreasing bone resorption in cortical and trabecular bone (Prolia EU SmPC, 
Prolia US PI). 
GP2411 is a proposed biosimilar that is being developed by Sandoz to Amgen's denosumab 
(marketed as Prolia®/ marketed as Pralia® in Japan [hereafter referred to as Prolia/ Pralia] and 
Xgeva®/ marketed as Ranmark® in Japan [hereafter referred to as Xgeva/ Ranmark]). The 
development of GP2411 aims for the treatment of all indications currently approved for Prolia/ 
Pralia in Japan and Xgeva/ Ranmark in Japan. Biosimilarity will be supported by the totality of 
evidence from analytical, nonclinical, clinical pharmacokinetics (PK), pharmacodynamics 
(PD), efficacy, safety and immunogenicity data. 
Development of biosimilar 
A biosimilar is a biological medicinal product that contains a version of the active substance of 
an already authorized biological medicinal product with demonstrated similarity in physico-
chemical characteristics, biological activity, efficacy and safety, based on a comprehensive 
comparability exercise (Weise et al 2011; Schneider et al 2012). It is intended to be used at the 
same dose(s) and dosing regimen(s) to treat the same disease(s) as the reference product. The 
development and commercialization of biosimilars can help address unmet medical needs by 
improving access to well-established therapeutic interventions while improving healthcare 
affordability (McCamish and Woollett 2012). 
Biological medicinal products are derived from living cells or organisms and consist of 
relatively large and complex molecular entities. Due to the inherent variability of the biological 
system as well as potential manufacturing process changes introduced over time, any resulting 
biological will display a certain range of variability, even between different batches of the same 
originator product (Weise et al 2011). Manufacturers and health authorities are managing this 
variability based on the principle that changes in quality attributes can be accepted as long as 
they do not alter the safety and efficacy of the biologic product (Schiestl 2011). 

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Development of GP2411 
GP2411 (proposed biosimilar denosumab) is a genetically engineered human immunoglobulin 
IgG2 type monoclonal antibody directed against the transmembrane or soluble protein RANKL. 
The antibody has a molecular weight of 147 kDa and is composed of two heavy chains and two 
light chains of the kappa subclass. 
Study CGP24112301 is part of the clinical development program of GP2411, and has been set 
up to support worldwide registration of GP2411 as a proposed biosimilar product to Amgen's 
denosumab (marketed as Prolia/ Pralia in Japan and Xgeva/ Ranmark in Japan). It is the first 
trial in which GP2411 is being administered in humans. 
The study aims at using a sensitive indication and sensitive endpoints to detect any clinically 
meaningful differences in comparison to the comparator (EU-authorized Prolia). Accordingly, 
postmenopausal osteoporosis (PMO) has been selected as the indication for the study for 
following reasons: 
• the pivotal studies on Prolia have been conducted in this indication 
• patients with PMO are relatively healthy and fully immunocompetent women, thus 
appropriate towards detecting potential differences in the safety profile between a 
biosimilar denosumab and the comparator 
• PMO has been recognized by the Health Authorities as representative of all indications of  
the originator product for conducting a biosimilar study 
1.2 
Purpose 
The purpose of the study is to demonstrate similar PK, PD, efficacy, safety and immunogenicity 
of GP2411 and EU-authorized Prolia in women with postmenopausal osteoporosis. The 
efficacy assessment is primarily based on percent change from baseline (%CfB) in lumbar spine 
bone mineral density (LS-BMD) at Week 52. PD similarity will be assessed in terms of the 
bone resorption marker collagen C-telopeptide (CTX) after the first dose at Week 26, while PK 
will also be evaluated after the first dose, based on AUCinf and Cmax parameters from the PK 
profiles. 
The study also aims at comparing the safety and immunogenicity profiles after the transition 
from EU-authorized Prolia to GP2411. 
2 
Objectives and endpoints 
The study design has been discussed and agreed with FDA, EMA and PMDA. Summarized 
below are the various endpoints (primary, key secondary and secondary) that have been agreed 
with the different agencies (Table 2-1). 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To demonstrate similar efficacy 
between GP2411 and EU-
• 
Percent change from baseline (%CfB) in lumbar spine 
BMD (LS-BMD) at Week 52 (FDA, EMA, PMDA) 

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Objective(s) 
Endpoint(s) 
authorized Prolia, in terms of 
BMD 
• 
To demonstrate similar PD 
between GP2411 and EU-
authorized Prolia, in terms of the 
bone resorption marker CTX 
• 
AUEC after first dose, of %CfB in serum CTX (only 
EMA) 
• 
To demonstrate similar 
PK between GP2411 and EU-
authorized Prolia 
• 
Serum PK parameters AUCinf and Cmax after first dose 
(only PMDA) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Key secondary objective:  
To demonstrate similar PD 
between GP2411 and EU-
authorized Prolia, in terms of the 
bone resorption marker CTX 
• 
AUEC after first dose, of %CfB in serum CTX (FDA, 
PMDA) 
• 
Treatment Period 1 (Day 1 − 
Week 52) 
To compare GP2411 and EU-
authorized Prolia in terms of PK, 
PD, efficacy, safety, and 
immunogenicity  
• 
%CfB in BMD at lumbar spine, femoral neck, and total 
hip (LS-BMD, FN-BMD, TH-BMD) at Week 26  
• 
%CfB in BMD: FN-BMD and TH-BMD at Week 52 
• 
PD markers: CTX and procollagen I N-terminal 
propeptide (PINP) serum concentrations as per visit 
schedule up to Week 52 
• 
Safety: fractures, vital signs, laboratory safety 
assessments, injection site reactions, electrocardiogram 
(ECG), occurrence of adverse events (AEs) and serious 
AEs up to Week 52 
• 
Immunogenicity: Development of binding and 
neutralizing anti-drug antibodies (ADAs) up to Week 52  
• 
Serum PK parameters AUCinf and Cmax after first 
dose (only EMA) 
• 
Denosumab serum concentrations as per visit schedule 
up to Week 52 
• 
Treatment Period 2 (Week 52 - 
Week 78) 
To further evaluate and compare 
GP2411 and EU-authorized 
Prolia in terms of PK, PD, 
efficacy, safety and 
immunogenicity, after 
transitioning 50% of patients on 
Prolia to GP2411 
• 
%CfB in LS-BMD, FN-BMD, TH-BMD at Week 78 
• 
PD markers: CTX and PINP serum 
concentrations as per visit schedule from Week 52 up to 
Week 78 
• 
Safety: fractures, vital signs, laboratory safety 
assessments, injection site reactions, ECG, occurrence 
of AEs and serious AEs from Week 52 up to Week 78 
• 
Immunogenicity: Development of binding and 
neutralizing anti-drug antibodies (ADAs) from Week 52 
up to Week 78 
• 
Denosumab serum 
concentrations as per visit schedule from Week 52 up to 
Week 78 

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3 
Study design 
This is an international, multicenter, randomized, double-blind, two-arm, parallel-group study 
with a total duration up to 83 weeks. A total of approximately 492 women with postmenopausal 
osteoporosis will be randomized on Day 1 of Treatment Period 1 in a 1:1 ratio into two treatment 
groups. Randomization in Treatment Period 1 will be stratified by region, age group, prior 
bisphosphonate use and body weight group. Re-randomization in Treatment Period 2 will not 
be stratified. 
The study consists of 3 periods: a Screening Period of up to 5 weeks to assess a patient's 
eligibility, a Treatment Period 1 (Day 1 to Week 52) and a Treatment Period 2 (Week 52 to 
Week 78). 
An outline of the study periods is presented in Figure 3-1 while a detailed visit and assessment 
schedule can be found in Table 8-1. 
Figure 3-1 
Study design 
 
1 Number of patients could vary due to drop-outs 
Screening Period (screening to randomization, Day -35 to Day 1) 
The Screening Period begins once the patient has provided written informed consent to 
participate in the study (Visit 1) and ends at randomization visit (Visit 2) of the study. The 
Screening Period will be no longer than 5 weeks and will be used to assess eligibility of the 
patients. 
Treatment Period 1 (Day 1 to Week 52) 
The Treatment Period 1 begins with randomization (Day 1, Visit 2) and ends with the 
completion of Week 52 (Visit 15) assessments. Eligible patients will be randomized in a 1:1 
ratio into one of two treatment groups, either GP2411 or EU-authorized Prolia. During the 
Treatment Period 1, patients should attend visits at the study site at Day 1, Day 2, Day 4, Day 
8, Day 15, Weeks 8, 14, 18, 22, 26, 28, 39, 50 and 52. 
The visits designated as Week 26 (Visit 11) and Week 52 (Visit 15) involve activities that 
belong to the end of one week and the beginning of the succeeding week. For instance, the visit 

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at Week 52 works as the transition between the Treatment Period 1 and the Treatment Period 
2, and the assessments at this visit will serve the dual purpose of assessments for the end of 
Treatment Period 1, and pre-dose assessments for the Treatment Period 2 dose administration. 
During the Treatment Period 1, patients will receive two doses of either GP2411 or Prolia, 
administered at a dose of 60 mg s.c. at Day 1 and Week 26. 
Analysis of primary endpoints and secondary endpoints will be performed after all patients have 
completed the Treatment Period 1 (Week 52). All safety data collected for patients who have 
progressed beyond Week 52 will also be included in this analysis.  
Treatment Period 2 (Week 52 to Week 78) 
After completion of study assessments to mark the end of the Treatment Period 1, the Treatment 
Period 2 begins with blinded allocation of study medication through the IRT system and 
administration of the third dose of the study medication at the end of Week 52 (Visit 15). During 
this process, all patients in the Prolia group will be re-randomized 1:1 to either continue with a 
third dose of Prolia, or transition to GP2411. All patients in the GP2411 group will continue 
with a third dose of GP2411. 
Analysis of Treatment Period 2 secondary endpoints will be done after all patients have 
completed Week 78. 
4 
Rationale 
4.1 
Rationale for study design 
The study is part of the clinical development program for GP2411 and aims to support 
worldwide registration of GP2411 as a proposed biosimilar product to Amgen's denosumab 
(marketed as Prolia/ Pralia in Japan and Xgeva/ Ranmark in Japan). The concept study design 
has been discussed and agreed with FDA, EMA and PMDA. 
The main indications of Amgen’s denosumab are the treatment of postmenopausal women at 
increased risk of fractures, the therapy of bone loss associated with hormone ablation in men 
with prostate cancer (Prolia) and the prevention of skeletal related events in adults with bone 
metastases from solid tumors (Xgeva). Patients with cancer treatment induced bone loss, or 
patients with metastatic bone disease are expected to have a larger background noise in terms 
of safety, due to the severity of the underlying condition, potential co-morbidities and 
concomitant medications. Cancer patients are also more likely not to be fully 
immunocompetent. The healthier and immunocompetent PMO patients are considered more 
sensitive to detect potential differences of adverse reactions and immunogenicity. Therefore, as 
also discussed in Section 1.1, Sandoz has decided to conduct this study in the appropriate and 
sensitive indication PMO to compare the proposed biosimilar denosumab to EU-authorized 
Prolia. 
The study has a parallel-group design, with a total duration of 82 weeks. The primary endpoint 
analyses are based on data collected up to 52 weeks. As discussed in Section 3 and 
Section 6.1.3, the study also involves a transition from Prolia to GP2411 for 50% of the patients 
on Prolia, with a subsequent evaluation of PK, PD, efficacy, and particularly safety and 
immunogenicity up to Week 78 (26 weeks after the transition). 

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4.2 
Rationale for dose/regimen and duration of treatment 
Dose, frequency and route of administration of the study medication are chosen according to 
the current Prolia/ Pralia in Japan label for the therapy of postmenopausal women with 
osteoporosis. After the initial s.c. injection of 60 mg GP2411/Prolia on Day 1, patients will 
receive a subsequent 60 mg s.c. dose after 6 months (Week 26), followed by the third 60 mg 
s.c. dose at Week 52, at the start of the Treatment Period 2. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
GP2411 is being developed as a similar biological medicinal product to Prolia/ Pralia in Japan. 
EU-authorized Prolia has been chosen as the comparator in this study to confirm similarity in 
terms of PK, PD, efficacy, safety and immunogenicity. 
4.4 
Purpose and timing of interim analyses 
Data analyses will be performed at two points:  
• Interim analysis at Week 52: This will be carried out after all patients have completed 
Week 52 or discontinued prior to Week 52. In addition, the interim analysis will also 
include all available safety data from Treatment Period 2 which has been collected up 
until the partial database lock.  
• Final analysis at Week 78: This will be carried out after all patients have completed the 
study.  
The interim analysis will allow for an early read-out of primary endpoint analyses. Additional 
information is presented in the interim analysis Section 12.7. 
4.5 
Risks and benefits 
Prolia has been licensed and commercialized world-wide since 2010 and Pralia in Japan since 
2013. Clinical studies have provided evidence of efficacy and safety in all approved indications, 
including osteoporosis. In osteoporosis, it is proven to increase bone mineral density and protect 
bones from fracture. Since approval of Prolia/ Pralia an extensive post-marketing experience 
has been gathered, which confirms Prolia's/ Pralia’s established safety and efficacy profile and 
demonstrates its favorable risk-benefit ratio (Prolia EU SmPC, Prolia US PI). 
In terms of safety profile, the most common side effects for Prolia/ Pralia are back pain, pain in 
the arms and legs, joint and/or muscle pain and bladder infection. Uncommon or rare cases of 
cellulitis, hypocalcemia, hypersensitivity, osteonecrosis of the jaw and fractures of the thigh 
bone have been observed. 
Based on the currently available analytical data, it is concluded that GP2411 and US-licensed 
and EU-authorized Prolia are similar at the physicochemical and functional level. 
Consequently, the PK, PD, efficacy, safety and immunogenicity of GP2411 in patients with 
postmenopausal osteoporosis are expected to be comparable to that of Prolia/ Pralia. All patients 
in the study will therefore be receiving active therapy with a similar expectation of benefit. The 
contraindications, precautions and warnings, as summarized in the Prolia EU SmPC and the 
Prolia US PI, will also apply to GP2411. 

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So far, the pandemic has not shown significant impact on trial conduct and patient compliance 
in terms of site visits and study procedures. As per Sandoz medical assessment, the treatment 
with study medication does not pose additional safety risks to the study patients in the context 
of the Covid-19 pandemic. Sandoz continues to carefully monitor Covid-19 related risks and 
implements risk mitigations as applicable according to Health Authority guidelines and internal 
procedures. It is the investigator’s responsibility to assess local circumstances of the pandemic 
which might lead to a local change in the risk/benefit assessment by the investigator. In this 
case, this investigator driven assessment should be documented in the investigator site file and 
communicated to the sponsor. 
4.5.1 
Blood sample volume 
Timings of blood sample collection are outlined in the assessment schedule Table 8-1. 
Additional samples may be required for safety monitoring. 
A summary blood log including volume as well as instructions for all sample collection, 
processing, storage and shipment information is available in the Laboratory Manual. 
5 
Population 
The study will enroll postmenopausal women with osteoporosis, with a BMD T-score ≤-2.5 and 
≥-4.0 at lumbar spine measured by dual energy X-ray absorptiometry (DXA). These criteria are 
in accordance with the current guidelines for PMO treatment (Kanis et al 2013, 
Camacho et al 2016).  
A total of approximately 492 patients will be randomized. Patients that drop out after they have 
been randomized will not be replaced. 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Postmenopausal women, diagnosed with osteoporosis.  
Postmenopausal status is defined as at least 12 consecutive months of amenorrhea prior to 
date of screening, for which there is no other obvious pathological or physiological cause. 
[For CZ only: Postmenopausal status is defined as at least 12 consecutive months of 
amenorrhea prior to date of screening for which there is no other obvious pathological or 
physiological cause and by elevated serum follicle-stimulating hormone (FSH) level 
assessed by central laboratory at screening] 
3. Aged ≥55 and ≤80 years at screening  
4. Body weight ≥50 kg and ≤90 kg at screening 
5. Absolute bone mineral density consistent with T-score ≤-2.5 and ≥-4.0 at the lumbar spine 
as measured by DXA during the Screening Period  
6. At least two vertebrae in the L1-L4 region (vertebrae to be assessed by central reading of 
lateral spine X-ray during the Screening Period) and at least one hip joint are evaluable by 
DXA  

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5.2 
Exclusion criteria 
Patients meeting any of the following criteria are not eligible for inclusion in this study. 
1. Use of other investigational drugs within 5 half-lives of the drug or until the expected 
pharmacodynamic effect of the drug has returned to baseline, whichever is longer, or 
longer if required by local regulations 
2. Previous exposure to denosumab (Prolia/ Pralia in Japan, Xgeva/ Ranmark in Japan, or 
biosimilar denosumab) 
3. History of hypersensitivity to any recombinant protein drugs or any of the excipients used 
in GP2411 or Prolia (excipients detailed in Table 6-1) 
4. History and/or presence of one severe or more than two moderate vertebral fractures (as 
determined by central reading of lateral spine X-ray during the Screening Period) 
5. History and/or presence of hip fracture 
6. Presence of active healing fracture according to assessment of investigators 
7. History and/or presence of bone metastases (see also exclusion criterion #25), bone 
disease,  metabolic disease (except osteoporosis)that may interfere with the interpretation 
of the results, e.g. Paget's disease, rheumatoid arthritis, ankylosing 
spondylitis, osteomalacia, osteogenesis imperfecta, 
osteopetrosis, Cushing's disease, hyperprolactinemia or malabsorption syndrome 
8. Ongoing use of any osteoporosis treatment (other than calcium and vitamin D 
supplements). Following rules for wash-out periods for osteoporosis treatments have to be 
adhered to: 
• Drugs being investigated for osteoporosis 
• Romosozumab: dose received at any time 
• Strontium or fluoride (for osteoporosis): dose received at any time 
• Intravenous bisphosphonates: dose received within 5 years prior to screening 
• Oral bisphosphonates  
• >3 years of cumulative use prior to screening 
• any dose received within 12 months prior to screening 
• Teriparatide or any PTH analogs: dose received within 12 months prior to screening 
• Tibolone, oral or transdermal estrogen, selective estrogen receptor modulators: dose 
received within 12 months prior to screening 
• Calcitonin: dose received within 6 months prior to screening 
• Cinacalcet: dose received within 3 months prior to screening 
9. Systemic glucocorticosteroids (≥5 mg prednisone equivalent per day for ≥10 days or a 
total cumulative dose of ≥50 mg) within the past 3 months before screening 
10. Other bone active drugs including heparin, anti-convulsives (with the exception 
of benzodiazepines), systemic ketoconazole, adrenocorticotropic hormone, lithium, 
gonadotropin releasing hormone agonists, anabolic steroids, within the past 3 months 
before screening 
11. Oral or dental conditions: 
• osteomyelitis or history and/or presence of osteonecrosis of the jaw (ONJ) 

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• presence of risk factors for ONJ (e.g. periodontal disease, poorly fitting dentures, 
invasive dental procedures such as tooth extractions in 6 months before screening) 
• active dental or jaw condition which requires oral surgery 
• planned invasive dental procedure  
12. Current uncontrolled status of hypothyroidism or hyperthyroidism 
13. History and/or current hypoparathyroidism or hyperparathyroidism, irrespective of current 
controlled or uncontrolled status 
14. Vitamin D deficiency (25 [OH] vitamin D serum level <50 nmol/L [<20 ng/mL]). An 
Appropriate vitamin D dose in addition to vitamin D supplementation is permitted at the 
investigator’s discretion and patients will be retested during the screening period or may be 
rescreened (refer to Section 8.1) 
15. Current hypocalcemia, defined as calcium <2.10 mmol/L [<8.42mg/dL] or hypercalcemia, 
defined as calcium >2.62 mmol/L [>10.50 mg/dL]; patients must have normal albumin 
values (32-55 g/L [3.2-5.5 g/dL]) according to central laboratory normal range. (Refer to 
Section 8.5.2 for specifications on repletion of calcium during the screening period). 
16. Known intolerance to, or malabsorption of calcium or vitamin D supplements 
17. History and / or presence of a severe allergic reaction (e.g. anaphylaxis) 
18. History and/or presence of significant cardiac disease as per investigator's discretion, 
including but not restricted to: 
• ECG abnormalities at screening indicating significant risk of safety for patients 
participating in the study 
• history and/or presence of myocardial infarction within 6 months before screening 
• history and/or presence of NYHA class III or IV heart failure 
19. Patients having at screening any of the following hematology values: 
• Hemoglobin <10.0 g/dL [<100 g/L] 
• White blood cell (WBC) count <3,500/µL [< 3.5 x 109 /L], or neutrophil count 
<2,000/µL [< 2.0 x 109 /L], or platelet count <125,000/µL [< 125 x 109 /L] 
20. Renal impairment manifesting with an estimated glomerular filtration rate (eGFR) <45 
ml/min 
21. Cirrhosis of the liver, unstable liver disease, or elevated liver function tests to the order of 
ALT or AST or ALP >2 times upper limit of normal 
22. Presence of clinically significant active infections (as per investigator' discretion) that may 
increase the risk associated with study participation  
23. Positive serology indicating Hepatitis B or Hepatitis C infections 
24. Positive serology for human immunodeficiency virus (HIV) infection or known diagnosis 
of AIDS 
25. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases 
26. Any medical or psychiatric condition which, in the investigator's opinion, would preclude 
the participant from adhering to the protocol or completing the study per protocol. Other 
severe acute or chronic medical or psychiatric condition or laboratory abnormality that 

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may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this  study 
27. Known alcohol, drug or substance abuse within 12 months prior to screening 
28. Patients who are legally institutionalized, or patients under judicial protection 
29. Patients with an immediate family member (i.e., spouse, parent/legal guardian, sibling or a 
child) being a member of study site staff or being a member of the sponsor’s study team 
6 
Treatment 
6.1 
Study treatment 
The study medications GP2411 (proposed biosimilar denosumab) and EU-authorized Prolia 
will both be supplied as 1 mL pre-filled syringes containing 60 mg of denosumab (60 mg/mL). 
6.1.1 
Investigational and comparator drugs 
Table 6-1 
Investigational/ comparator drug 
Name and Strength 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
GP2411 (60 mg/mL) 
Solution for injection 
Subcutaneous use 
Single use pre-filled 
syringe* 
EU-authorized 
Prolia (60 mg/mL) 
Solution for injection 
Subcutaneous use 
Single use pre-filled 
syringe 
 
 
GP2411 
Prolia 
Active ingredient (INN) 
Denosumab 
Denosumab 
Concentration 
60 mg/mL 
60 mg/mL 
Extractable volume 
1 mL 
1 mL 
Sorbitol 
4.7 % 
4.7 % 
Acetate 
17 mM 
17 mM 
Polysorbate 20 
0.01 % 
0.01 % 
* Single use pre-filled syringes are not certified (approved) in Japan 
6.1.2 
Additional study treatments 
According to the Prolia/ Pralia label, it is important that all patients receiving denosumab must 
have an adequate intake of calcium and vitamin D (Prolia EU SmPC, Prolia US PI). Therefore, 
from screening (Visit 1) until the end of study, all patients must receive at least 1000 mg of 
elemental calcium and 800 IU vitamin D daily throughout the study. Compliance with calcium 
and vitamin D supplementation throughout the study will be monitored and assessed.  
For JP only, Patients who received activated vitamin D before study start (Visit 1) have to 
switch to natural vitamin D. 

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If a patient develops hypercalcemia (calcium >2.62 mmol/L [>10.50 mg/dL]) over the course 
of the study, the investigator may use his/her medical judgement and reduce the calcium and/or 
vitamin D supplementation to maintain serum calcium concentration within the normal range. 
If a patient develops hypocalcemia (calcium <2.10 mmol/L [<8.42 mg/dL]) during the 
screening as well as over the course of the study, appropriate additional supplementation should 
be instituted as deemed acceptable by local guidelines, to maintain serum calcium concentration 
within the normal range.  
The supplementation given to the patients has to be based on the regular evaluation of     calcium 
test and serum 25-hydroxyvitamin D (25 (OH) vitamin D) levels; refer to central laboratory 
assessment for these two parameters in Table 8-1. 
Vitamin D and calcium supplements are commercially available and are to be provided locally 
at the sites. The sponsor will not provide these supplies but they will be reimbursed. 
For patients unable to tolerate a particular calcium or vitamin D dose or formulation, the patient 
should be instructed to try a different calcium or vitamin D formulation. If this approach fails 
and the patient remains unable to tolerate the specified dose of calcium and/or vitamin D, the 
investigator may document that only a lower dose is tolerated by the patient, and reduction of 
the supplementation dose will be allowed. 
6.1.3 
Treatment arms/group 
At randomization (Day 1, Visit 2) patients will be randomized in a 1:1 ratio to receive either 
GP2411 or EU-authorized Prolia with approximately 246 patients in each arm. Randomization 
on Day 1 will be stratified by region, age group, prior bisphosphonate use and body weight 
group (see also Section 6.3.2). 
Treatment Period 1 (Day 1 to Week 52) 
• GP2411: s.c. administration of 60 mg of GP2411 on Day 1 and at Week 26 
• Prolia: s.c. administration of 60 mg of Prolia on Day 1 and at Week 26 
Treatment Period 2 (Week 52 to Week 78) 
The Treatment Period 2 will begin with blinded allocation of treatment for Treatment Period 2 
through the IRT system at the end of Week 52. Patients in the Treatment Period 1 Prolia arm 
will be randomized in a 1:1 ratio to either continue with Prolia or transition into GP2411. All 
patients in the GP2411 group will continue treatment with GP2411. In order to maintain the 
blind, the process of allocating treatment in Treatment Period 2 will be carried out for all 
patients in a blinded fashion through a new interaction with the IRT system. Re-randomization 
will not be stratified. 
• GP2411: s.c. administration of 60 mg of GP2411 at Week 52 
• Prolia: s.c. administration of 60 mg of Prolia at Week 52 
6.1.4 
Treatment duration 
The planned duration of treatment is 18 months (12 months of Treatment Period 1 and 6 months 
of Treatment Period 2). During this period (as discussed above in Section 3) each patient will 
receive 3 doses of study medication at intervals of 6 months. 

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6.2 
Other treatment(s) 
No other treatments for osteoporosis other than study medication, calcium and vitamin D 
supplements are permitted throughout the course of the study. 
6.2.1 
Concomitant therapy 
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary except for those listed as prohibited medications in Section 6.2.2. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the sponsor/delegated Contract Research 
Organization (CRO) before randomizing a patient or allowing a new medication to be started. 
If the patient is already enrolled the sponsor/delegated CRO should be contacted to determine 
if the patient should continue participation in the study. 
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions), administered after the patient was enrolled into the study, must be recorded 
in the appropriate electronic Case Report/Record Form (CRF). Additionally, the eCRF will also 
capture data on medications and procedures administered prior to study start as below: 
• treatment for osteoporosis: all past treatment 
• treatment not related to osteoporosis: last 3 months prior to screening 
6.2.2 
Prohibited medication 
Use of the treatments mentioned below are prohibited during study participation (from 
screening up to end-of-study for an individual patient) as they are known or suspected to affect 
bone metabolism. In addition, as also discussed in the exclusion criteria in Section 5.2, an 
adequate washout period will be required for these medications prior to screening. 
• Denosumab (Prolia/ Pralia in Japan, Xgeva/ Ranmark in Japan, or biosimilar denosumab) 
• Investigational drugs for osteoporosis 
• Romosozumab 
• Strontium, fluoride (for osteoporosis) 
• Intravenous bisphosphonates 
• Oral bisphosphonates 
• Teriparatide or any PTH analogs 
• Calcitonin, oral or transdermal estrogen, selective estrogen receptor modulators 
• Tibolone, cinacalcet  
• Systemic glucocorticosteroids; inhaled and topical corticosteroids are acceptable 
• Other bone active drugs including but not limited to heparin, anticonvulsives (with 
the exception of benzodiazepines), systemic ketoconazole, adrenocorticotropic hormone, 
lithium, gonadotropin releasing hormone agonists, anabolic steroids and vitamin K 
6.2.3 
Restriction for study patients 
For the duration of the study, patients should be informed and reminded of the restrictions 
outlined in this section. 

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6.2.3.1 
Dietary restrictions 
All patients must be in fasting state prior to PD sampling. Fasting state is defined as overnight 
fasting; if overnight fasting is not feasible, a minimum of 8 hours fasting is required. 
6.2.3.2 
Other restrictions 
During screening/informed consent process and scheduled visits, the patients will be informed 
and reminded of the following restrictions: 
• avoid strenuous physical exercise the day before PD sampling 
• PD samples should be taken in the morning between 7:30 and 10:00 am. 
6.3 
Patient numbering, treatment assignment, randomization 
6.3.1 
Patient numbering 
Each patient is identified in the study by a unique Patient Number (Patient No.). The Patient 
No. consists of the Center Number (Center No.) (as assigned by the sponsor to the investigative 
site) and a sequential number suffixed to it, that is assigned from the Electronic Data Capture 
(EDC) system to the investigator when the patient is first enrolled for screening. This Patient 
No. is retained as the primary identifier for the patient throughout the entire participation in the 
trial, and with this each patient is numbered uniquely across the entire database. 
In case a patient is rescreened (refer Section 8.1), the patient will need to sign a new informed 
consent form and a new Patient No. will be assigned by the EDC system. The date of the new 
informed consent signature must be entered on the appropriate eCRF under the new Patient No. 
Informed Consent for a rescreened patient must be obtained prior to performing any study-
related assessments. 
6.3.2 
Treatment assignment, randomization 
At the randomization (Day 1, Visit 2) all eligible patients will be randomized 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 patient fulfills all the inclusion/exclusion criteria. 
The IRT will assign a randomization number to the patient, which will be used to link the patient 
to a treatment group and will specify a unique medication number for the first package of study 
medication to be dispensed to the patient. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. In effect there will be a 
separate randomization list for each stratum (combination of region, age group, prior 
bisphosphonate use and weight group). These randomization numbers are linked to the different 
treatment groups, which in turn are linked to medication numbers. A separate medication list 
will be produced by or under the responsibility of Novartis Global Clinical Supply (GCS) using 
a validated system that automates the random assignment of medication numbers to packs 
containing the study medication.  

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All patients who complete Treatment Period 1 will be allocated treatment for Treatment Period 
2 at the beginning of Treatment Period 2 via IRT in a blinded fashion. Those patients in the 
Treatment Period 1 Prolia treatment group will be re-randomized in a 1:1 ratio to either 
transition to receive GP2411 in the Treatment Period 2 or continue on Prolia. Patients originally 
randomized to GP2411 in the Treatment Period 1 will automatically continue on GP2411 in 
Treatment Period 2 but this will also be performed via the IRT system to maintain the blind of 
treatment assignment (i.e. all patients in the GP2411 group will be re-randomized to continue 
on GP2411 during the Treatment Period 2). 
Randomization on Day 1 for the Treatment Period 1 will be stratified by region (US, Rest of 
World and Japan), age group (<65 years/ ≥65 years) and prior bisphosphonates use (yes/ no) 
and body weight group (<70 kg/ ≥70 kg). It should be noted, however, that only a subset of the 
stratification factors are relevant for each of the co-primary analyses, and only the relevant 
factors will be included in the statistical model for each co-primary endpoint. Region is included 
as an administrative stratification factor in order to ensure a balanced allocation of patients in 
each region for relevant region-specific subgroup analyses. Prior bisphosphonates use was 
identified as a potential source of heterogeneity for the primary endpoint of LS-BMD and 
fracture incidence rates that cannot be assured to be completely controlled through the use of 
inclusion/exclusion criteria, and hence a prior treatment with bisphosphonates (yes/ no) is 
included as a stratification factor to balance prior treatment heterogeneity within the selected 
population in the study. Age was added as stratification factor as fracture incidence rate 
increases significantly after the age of 65 years with primary endpoint LS-BMD not being a 
sensitive predictor of fracture rates below the age of 65 years (CHMP 2005, Ettinger et al 2010). 
Weight is considered a major influencing factor on the PK endpoints. 
Re-randomization at the beginning of Treatment Period 2 will not be stratified.  
The randomization scheme for patients will be reviewed and approved by a member of the 
Novartis Randomization Office. 
6.4 
Treatment blinding 
Patients, investigators, and the sponsor will remain blinded to study medication throughout the 
study, except where indicated below. 
The identity of the study medications could not be concealed as the appearances of the syringes 
differ. To maintain the double-blind design of the study it is necessary to involve unblinded 
staff at the study site for handling the study medication. Unblinded site staff must not perform 
any clinical assessments. Prolia and GP2411 open label supply will be provided at sites to the 
unblinded site pharmacist. To ensure that the treatment will be blinded to the patient and the 
investigator, receipt, handling and administration of the s.c injection will be performed by 
unblinded study site personnel not involved in study assessments. All unblinded study 
documentation will be kept strictly confidential and will not be accessible by the blinded site 
staff. On a patient level, either a screen would be used to maintain blinding, or the patients will 
be asked to wear a blindfold during the three s.c. injections. 
Unblinding will only occur in case of patient emergencies, at the time of the primary endpoint 
readout (only for specific sponsor personnel involved in this analysis), and at the conclusion of 
the study. 

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Site staff 
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study medication throughout the study. 
Sponsor staff or delegate 
The following unblinded sponsor or delegate (CRO) roles are required for this study: 
• Unblinded field monitor(s) 
• Unblinded clinical staff managing drug supply to site or interacting with unblinded field 
monitor(s) 
• Unblinded designated study team members for primary endpoint readout (Week 52) 
• Unblinded quality assurance and compliance clinical operation staff 
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded field monitors are not provided with a randomization list directly but will be 
unblinded through review of source documentation compiled by the unblinded pharmacist, and 
verification of used/ unused syringes. 
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with randomization lists directly, but may be 
unblinded through communication of drug re-supply needs via the unblinded site pharmacists. 
After all patients have completed Week 52 assessment and after the database has been partially 
locked for the Primary Endpoint Readout, designated study team members will be unblinded to 
the initial study medication assignment. Patients, investigators and the rest of the study team 
will remain blinded until after the final database lock. Details will be explained in 
a Blinding Charter. 
The auditor(s) and/or sponsor quality assurance/compliance clinical operation staff, will review 
unblinded information during audits, compliance visits or other activities conducted by quality 
assurance or compliance clinical operation. 
All other sponsor staff will stay blinded to treatment assignments (except in the case of a safety 
event necessitating unblinding) until final database lock. 
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure until final database lock. 
Following final database lock all roles may be considered unblinded. See the blinding/ 
unblinding table for an overview of the blinding/ unblinding plan. 
Table 6-2 
Blinding and unblinding plan 
  
Time or Event 
Role 
Randomization 
list generated 
Treatment 
allocation & 
dosing 
Safety event 
(single patient 
unblinded) 
Primary 
Readout 
Analysis 
Patients 
B 
B 
UI 
B 
Site staff 
B 
B 
UI 
B 

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Time or Event 
Role 
Randomization 
list generated 
Treatment 
allocation & 
dosing 
Safety event 
(single patient 
unblinded) 
Primary 
Readout 
Analysis 
Unblinded site staff e.g. 
pharmacy staff, study 
medication administrating staff  
NA 
U 
NA 
NA 
Global Clinical Supply and 
Randomization Office 
U 
U 
NA 
NA 
Sponsor staff involved in 
handling of study medication, 
unblinded field monitoring, 
auditing/compliance clinical 
operation 
NA 
U 
NA 
NA 
Sponsor staff involved in primary 
endpoint analysis  
B 
B 
B 
U 
Pharmacovigilance sponsor staff 
NA 
NA 
UI 
NA 
All other sponsor staff not 
identified above (trial team, 
project team, management & 
decision boards, support 
functions) 
B 
B 
B 
B 
U: Unblinded 
UI: Allowed to be unblinded on individual patient level 
B: Remains blinded 
NA: Not applicable to this study 
6.5 
Dose escalation and dose modification 
Not applicable. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The information on study medication administration including any deviations will be captured 
in the source documents and recorded to the eCRF and will be verified by the blinded field 
monitor. Compliance will also be assessed by an unblinded field monitor using drug 
accountability information collected by IRT and counts of the pre-filled syringes.  
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all patients 
as detailed in the pharmacokinetic section (Section 8.5.2). 
6.6.2 
Recommended treatment of adverse events 
The safety profile for Prolia/ Pralia is well established. GP2411 is a proposed biosimilar to 
Prolia, and hence is expected to exhibit a comparable safety profile. According to 
Prolia EU SmPC, the most common adverse drug reactions with Prolia are musculoskeletal pain 
and pain in the extremity. Uncommon cases of cellulitis, rare cases of hypocalcaemia, 

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hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures have also been 
observed. 
The investigators will follow local guidelines and their best medical practice and judgement to 
treat adverse events (AEs) accordingly. Medications used to treat AEs must be recorded on the 
appropriate eCRF. 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required in order to treat the patient 
safely. Emergency treatment code breaks are performed using the IRT. When the investigator 
contacts the system to break a treatment code for a patient, he/ she must provide the requested 
patient identifying information and confirm the necessity to break the treatment code for the 
patient. The investigator will then receive details of the study medication treatment for the 
specified patient and a fax or email confirming this information. The system will automatically 
inform the sponsor/ delegated CRO and the study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide the 
following data to the IRT: 
• protocol number 
• patient number 
In addition, oral and written information to the patient must be provided on how to contact the 
investigator's backup in cases of emergency, or when the investigator is unavailable, to ensure 
that un-blinding can be performed at any time. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study medication in packaging as described under 
investigational and control drugs section. 
A unique medication number is printed on the study medication label. 
Unblinded site staff will identify the study medication kits to dispense to the patient by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label). Immediately before dispensing the medication kit to the patient, 
site personnel will detach the outer part of the label from the packaging and affix it to the source 
document. In addition, the medication number will be entered into the eCRF. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study medication must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only designated site personnel have 
access. Upon receipt, all study medication must be stored according to the instructions specified 
on the labels and in the Investigational Product Handling Manual. Clinical supplies are to be 
dispensed only in accordance with the protocol. Technical complaints are to be reported to the 
sponsor. Further details will be provided in the Investigational Product Handling Manual. 

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Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study medication but no information about 
the patient except for the medication number. 
The unblinded pharmacist must maintain an accurate record of the shipment and dispensing of 
study medication in a drug accountability log. Monitoring of drug accountability will be 
performed by unblinded field monitors during site visits or remotely and at the completion of 
the study. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study medication, packaging, drug labels, and a copy of the completed 
drug accountability log to the address provided. 
6.7.1.2 
Handling of additional treatment 
Calcium and vitamin D supplements are to be taken by patients as described in Section 6.1.2. 
6.7.2 
Instruction for prescribing and taking study treatment 
During the 18 months of study participation (Treatment Period 1 and Treatment Period 2), 
patients will receive 3 s.c. doses of study medication. Each dose is one pre-filled syringe of 
either 60 mg GP2411 or 60 mg EU-authorized Prolia.  
To reduce variability in the PK analysis, the s.c. injection will be administered only in the 
abdomen, by an unblinded healthcare professional at the site. 
7 
Informed consent procedures 
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation) IRB/IEC-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents. 
The sponsor will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by the sponsor before submission to the IRB/IEC. 
Information about common side effects already known about the study medication can be found 
in the Investigator's Brochure (IB). This information will be included in the informed consent 
form and should be discussed with the patient during the study as needed. Any new information 
regarding the safety profile of the investigational drug that is identified between IB updates will 
be communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the patient. 
A copy of the approved version of all consent forms must be provided to the sponsor after 
IRB/IEC approval. 

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8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all assessments when they are performed. All data 
obtained from these assessments must be supported in the patient's source documentation. 
Patients should be seen for all visits/ assessments as outlined in the assessment schedule or as 
close to the designated day/ time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Patients who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the Early Termination Visit will be performed. Early Termination Visit is not expected to 
be performed for patients not randomized or not treated. 
If patients refuse to return for these assessments or are unable to do so, every effort should be 
made to contact them by telephone or by sending appropriate correspondence. At this contact, 
the safety (e.g. potential occurrence of AEs or SAEs) and the efficacy outcome as well as the 
primary reason for a patient's premature withdrawal should be determined.  

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Table 8-1 
Assessment schedule 
Period 
Screening 
 
Treatment Period 1 
Treatment P1/ P2 Treatment Period 2 Treatment Withdrawal 
Visit Name 
Visit 1 
(Screening) 
Visit 2 
(Rando-
mization) 
Visit 
3 
Visit  
4 
Visit 
5 
Visit 
6 
Visit  
7 
Visit  
8 
Visit  
9 
Visit  
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Visit  
15 
Visit 
16 
Visit 
17 
End of 
Study 
Visit 
Early Termination 
Visit 
Days 
-35 to -2 
1 
2 
+1 
4 
8 
±1 
15 
±1 
57 
±3 
99 
±3 
127 
±3 
155 
±3 
184 
±3 
198 
±5 
275 
±5 
351 
±3 
366 
±3 
394 
±7 
457 
±7 
549 
±7 
- 
Weeks 
-5 to -1 
0 
0 
0 
1 
2 
8 
14 
18 
22 
26 
28 
39 
50 
52 
56 
65 
78 
0 
Study drug 
administration1 
  
X 
 
  
  
  
  
  
  
  
X 
  
  
  
X 
  
  
  
  
Informed consent 
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/ 
Exclusion criteria 
X 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomization 
  
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Re-randomization 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
Medical history 
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DXA scan 
X 
  
 
  
  
  
  
  
  
  
X 
  
  
  
X 
  
  
X 
  
Lateral spine X-
ray 
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
X 
  
Physical 
Examination8 
X2 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X2 
X 
X 
X2 
X2 
Height and weight 
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Vital Signs 
X 
X 
 
X 
  
  
  
  
  
  
X 
X 
  
  
X 
  
  
X 
X 
Electrocardiogram 
(ECG) 
X 
X 
 
  
X 
  
  
  
  
  
X 
  
  
  
X 
  
  
X 
X 
Serum FSH (CZ 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety laboratory 
X 
X 
 
  
  
  
  
  
  
X 
  
  
  
  
X 
  
  
X 
X 
Urinalysis3 
X 
X 
 
  
  
  
  
  
  
X 
  
  
  
  
X 
  
  
X 
X 
 Urine Sediment 
test3  (CZ only) 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Calcium test4 
X5 
X 
 
  
X 
X 
  
  
  
X 
  
X 
  
X 
X 
X 
  
X 
X 

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Period 
Screening 
 
Treatment Period 1 
Treatment P1/ P2 Treatment Period 2 Treatment Withdrawal 
Visit Name 
Visit 1 
(Screening) 
Visit 2 
(Rando-
mization) 
Visit 
3 
Visit  
4 
Visit 
5 
Visit 
6 
Visit  
7 
Visit  
8 
Visit  
9 
Visit  
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Visit  
15 
Visit 
16 
Visit 
17 
End of 
Study 
Visit 
Early Termination 
Visit 
Days 
-35 to -2 
1 
2 
+1 
4 
8 
±1 
15 
±1 
57 
±3 
99 
±3 
127 
±3 
155 
±3 
184 
±3 
198 
±5 
275 
±5 
351 
±3 
366 
±3 
394 
±7 
457 
±7 
549 
±7 
- 
Weeks 
-5 to -1 
0 
0 
0 
1 
2 
8 
14 
18 
22 
26 
28 
39 
50 
52 
56 
65 
78 
0 
25 (OH) vitamin D 
X 
X 
 
  
  
  
  
  
  
X 
  
  
  
X  
 
  
X  
 
 
Hepatitis and HIV 
Screen 
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PK 
blood6collection 
  
X 
 
X 
X 
X 
X 
X 
X 
 X 
X 
  
X 
  
X 
X 
X 
X 
X 
ADA 
blood6collection 
  
X 
 
  
  
X 
X 
X 
X 
X  
X 
  
X 
  
X 
X 
X 
X 
X 
PD blood 
collection6, 7 
  
X 
X 
X 
  
  
X 
  
X 
X 
X 
  
X 
  
X 
X 
X 
X 
  
Injection site 
reaction 
  
X 
X 
X 
X 
  
  
  
  
  
X 
X 
  
  
X 
X 
  
  
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
information 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor. 
1 After all assessments have been performed. 
2 Complete physical examination 
3 Urine sediment test at central lab and local dipstick urinalysis at site 
4 Calcium test refers to  calcium and albumin adjusted calcium measurements.  
5 Calcium test has to be repeated at Day -4 (-3) in patients switching from activated vitamin D to natural vitamin D at Visit. 
6 Serum samples may be used for anti-SARS-CoV-2 antibody testing 
7 A minimum of 8 hours fasting is required prior to blood collection and samples have to be collected at the same day time between 7:30 and 10 am. 
8 A Physical Examination will be performed at all visits marked above, however, actual results of the examinations will only be recorded in the eCRF if any clinically significant. medical 
history or adverse events are identified. Physical Examination was performed or not will only be recorded in the source documents. 

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8.1 
Screening 
Screening 
The Screening Period starts on the date the ICF is signed. Screening procedures may be 
performed on multiple days but must be completed within 35 days (5 weeks) prior 
randomization. The screening procedures are  
• Informed consent 
• Medical history and prior/ concomitant medication (including fracture history, active 
healing fracture assessment by investigators, and collecting information on bone-specific 
medications) 
• Assessment of and instructions for calcium and vitamin D supplementation 
• Physical examination 
• Vital signs: blood pressure, temperature and pulse rate 
• ECG 
• Height and weight 
• Blood samples for serum chemistry including calcium test, hematology, coagulation, and 
serum 25 (OH) vitamin D level as well as hepatitis and HIV screen.  
For CZ only: blood samples for serum FSH. 
For JP only: Calcium test has to be repeated at Day -4 (-3) in patients switching from 
activated vitamin D to natural vitamin D at Visit 1) 
• Local dipstick urinalysis 
• For CZ only: Urine sediment test by microscopy (conducted by the central laboratory) 
• AE reporting 
• Lateral spine X-ray (thoraco-lumbar) submitted to central imaging vendor as soon as 
possible following the visit 
• DXA scan of the lumbar spine, total hip, and femoral neck to be submitted to the central 
imaging vendor as soon as possible following the visit 
Rescreening 
Rescreening will be allowed for a patient who fails to meet the serum 25 (OH) vitamin D 
exclusion criterion. In order to be eligible for study participation, the patient must have a serum 
25 (OH) vitamin D level ≥20 ng/mL assessed by the central laboratory at rescreening. 
It may be permissible to rescreen a patient if she fails the initial screening for any other reason; 
however, each case must be discussed and agreed with the sponsor/ delegated CRO on a case-
by-case basis. 
In case a patient is rescreened, the following conditions will apply: 
• A new informed consent will require patient signature. 
• Patient will be logged as a screen failure into the IRT and entered as a rescreen. Patient 
not entered into IRT as a rescreen will not be eligible for randomization. 
• A new 35 day screening window will commence at this time. 

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• All screening procedures will be repeated; DXA not to be repeated if it is within 5 weeks 
of the initial scan; lateral spine X-ray not to be repeated if it is within 3 months of the 
initial scan. 
• Patient can only be rescreened once. 
8.1.1 
Information to be collected on screening failures 
Patients who sign an informed consent form and are subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate eCRF as well as on the screening and enrolment log. The 
demographic information, informed consent, and Inclusion/ Exclusion must also be completed 
for screen failure patients. No other data will be entered into the clinical database for patients 
who are screen failures, unless the patient experienced a serious adverse event (SAE) during 
the screening phase (see SAE section for reporting details). 
If the patient fails to be randomized, the IRT will be notified. 
Patients who are randomized and fail to start treatment, e.g. patient randomized in error, will be 
considered an early terminator. The reason for early termination should be recorded on the 
appropriate eCRF as well as on the screening and enrolment log. 
8.2 
Patient demographics/ other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: age 
at screening, sex, race, ethnicity, body height, body weight, relevant medical history/ current 
medical condition present before signing informed consent (where possible diagnoses and not 
symptoms will be recorded), prior/ current medications especially prior medications related to 
osteoporosis. 
8.3 
Efficacy/ Pharmacodynamics 
The following parameters will be assessed to demonstrate similar efficacy and 
pharmacodynamics of GP2411 and Prolia: 
• Change in BMD measured by DXA scan 
• Change in serum bone metabolism biomarkers CTX and PINP 
8.3.1 
DXA scan collection, processing and analytical methods 
Bone density measurements will be performed by dual-energy X-ray absorptiometry (DXA). 
Only bone densitometers from the manufacturers GE Healthcare (Lunar product series) and 
Hologic will be allowed for the study. The same DXA scanner should be used for all study 
procedures for a particular patient at each site. All DXA scans will be submitted to and analyzed 
by the central imaging vendor. 
For all patients bone density will be measured at the lumbar spine, total hip and femoral neck. 
Lumbar spine scan must include L1 through L4 vertebrae. To be eligible for the study, patient 
must have at least two evaluable lumbar vertebrae (to be assessed by central reading of lateral 
spine X-ray during the Screening Period) and at least one evaluable hip joint. 

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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 used consistently throughout the study.  
Detailed instruction for DXA scan acquisition can be found in the separate Imaging Manual. 
BMD Assessments 
DXA scan will be used to determine changes in BMD. DXA scan data will be submitted 
electronically to the central imaging vendor for analysis. Sites unable to submit data 
electronically can submit on CD as specified in the Imaging Manual, but electronic submission 
is preferred. The results from the central imaging vendor will be used as the final data for 
statistical analysis. 
After analysis by the central imaging vendor, a study site may be asked to re-acquire a scan due 
to malpositioning or other technical reasons. The study sites should comply with the requests 
from the central imaging vendor. 
8.3.2 
Bone metabolism biomarkers 
The effect of GP2411 and Prolia on the bone metabolism markers CTX (bone resorption) and 
PINP (bone formation) will be assessed in serum. CTX is a break-down product and PINP a 
by-product in the deposition of collagen I, the principal constituent of bone. PINP and 
CTX have been recommended by the International Osteoporosis Foundation and the 
International Federation of Clinical Chemistry Bone Marker Standards Working Group as 
reference markers of bone turnover for fracture risk prediction and monitoring of osteoporosis 
treatment (Eastell and Szulc 2017). 
8.3.2.1 
Biomarker blood sample collection and processing 
PD samples will be collected at the visits defined in the assessment schedule Table 8-1. All 
blood samples for the CTX and PINP assessment should be collected at the same time of day, 
between 7:30 am and 10 am and must be obtained from patients in the fasting state as indicated 
in Section 6.2.3.1 and Section 6.2.3.2. The actual sample collection date and time must 
be recorded on the appropriate eCRF. Blood samples of approximately 5 mL will be collected 
at each sampling time point by either direct venipuncture or an indwelling cannula inserted in 
a forearm. A total of 12 blood samples will be collected per patient for PD assessment. The 
instruction regarding sample collection, numbering, processing, storage and shipment are 
outlined in the Laboratory Manual. 
The study serum samples will be stored in freezers (-70°C) in an access controlled area for up 
to 15 years. 
8.3.2.2 
Analytical methods for quantification of bone metabolism biomarkers 
CTX and PINP serum concentrations will be determined by a validated ligand-binding 
immunoassay. Concentrations will be expressed in mass per volume units. Measurements will 
be performed at the Sponsor's bioanalytical laboratory. 

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8.3.3 
Appropriateness of efficacy assessments 
Published literature shows that efficacy based on fracture prevention alone is not sensitive 
enough to detect small but potentially clinically meaningful differences (Kanis et al 2003). FDA 
has recognized that in certain cases, PD markers may be more appropriate than clinical efficacy 
parameters, to demonstrate that there are no clinically meaningful differences between a 
proposed biosimilar and the reference product (CDER 2015). BMD has been demonstrated to 
correlate with vertebral fracture risk reduction with denosumab treatment and its applicability 
as surrogate marker of risk for fractures has been demonstrated for a multitude of treatments 
for osteoporosis with long duration of follow-up. However, CTX, although it lacks large 
evidence as surrogate marker of fracture risk reduction, has the highest dynamic range of bone 
metabolism biomarkers and seems to be the most sensitive PD endpoint to detect potential 
differences between GP2411 and the comparator. BMD has a very low dynamic range and very 
high inter-patient variability making it a less sensitive marker. Thus, CTX (better dynamic 
response) and BMD (greater clinical relevance) are both considered of importance and should 
meet clearly justified and pre-specified equivalence criteria, based both on clinical and 
statistical arguments. Assessment of the bone formation marker PINP in the study allows for 
further evaluation of similarity of efficacy of the biosimilar compared to the comparator. 
8.4 
Pharmacokinetics 
The following pharmacokinetic parameters will be determined from the serum concentration-
time data using the actual recorded sampling times and non-compartmental method(s) with 
Phoenix WinNonlin (Version 6.4 or higher): Cmax and AUCinf after the first dose. 
8.4.1 
Pharmacokinetics blood sample collection and handling 
Denosumab serum concentrations will be measured throughout the trial as indicated in the 
Assessment schedule in Table 8-1.  In case a patient will not be able to attend the site at the 
scheduled time and date, allowed time windows are also described in the assessment schedule. 
The actual sample collection date and time will be recorded in the eCRF. For each sample 
approximately 5 mL blood will be drawn at each sampling time point by either direct 
venipuncture or an indwelling cannula inserted in a forearm. A total of 14 blood samples will 
be collected per patient for PK assessment. Blood samples will be taken, numbered, processed 
to serum and shipped and stored according to instructions provided in the Laboratory Manual.  
The study serum samples will be stored in freezers (-70°C) in an access controlled area for up 
to 15 years. 
8.4.2 
Analytical methods for pharmacokinetics 
The analytical method to be used for PK analysis related to this study will be a ligand binding 
assay. Briefly, the concentration of free denosumab will be determined by binding to coated 
ligand molecules. Concentrations will be expressed in ng/mL. All PK assessments will be 
performed at the Sponsor’s bioanalytical laboratory. 

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8.4.3 
Appropriateness of pharmacokinetic measurements 
The PK assessments in all patients randomized in this trial are recognized as appropriate tools 
to assess pharmacokinetics between the drugs tested in the study. PMO women are fully 
immunocompetent, which allows a reliable assessment of PK parameters. The PK sampling 
time points are set to characterize and to capture potential differences in PK between GP2411 
and EU-Prolia. 
8.5 
Safety 
Safety assessment will consist of monitoring and recording all AEs and SAEs, the regular 
monitoring of hematology, blood chemistry, regular measurement of vital signs and physical 
examinations. The randomization and first administration of study medication will be 
performed on the basis of safety assessments obtained from the screening period. Safety 
laboratory assessments taken on Day1, Day 155 (±3), Day 366 (±3) and end of study visit will 
help safeguard patients throughout trial conduct. Safety laboratory assessments on Day 1 are 
taken to determine patients’ status quo prior to the start of study treatment. For calcium 
assessment, refer to hypocalcemia section below for the detail of calcium evaluation before 
each drug administration.   
Safety assessments are specified below with the assessment schedule (Table 8-1) detailing when 
each assessment is to be performed. 
For details on AE collection and reporting, refer to Section 10.1.1. 
8.5.1 
Physical examination and vital signs 
Physical examination 
A complete physical examination, including general appearance, 
skin (presence of rash), neck (including thyroid), eyes, ears, nose, 
throat , lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular and neurological examination will be performed at 
Screening, Week 52 and End of Study Visits. At all other visits, a 
short physical examination including the examination of general 
appearance will be done, unless a complete physical examination is 
required 
(at 
the 
investigator's 
discretion). If 
possible, assessments for an individual patient should be performed 
by the same member of the study site staff throughout the study. 
Information for all physical examinations will be recorded in the 
source documentation at the study site only. Actual results of the 
physical examination will only be recorded in the eCRF if any 
clinically relevant finding is observed. Clinically relevant findings 
that are present prior to signing informed consent must be included 
in the Medical History part of the eCRF. Significant findings made 
after first administration of study medication which meet the 
definition of an AE must be recorded on the AE section of the eCRF. 
Vital signs 
Vital signs (including body temperature, blood pressure and pulse 
rates) will be assessed as indicated in Table 8-1. 

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After the patient has been sitting for five minutes, with back 
supported and both feet placed on the floor, systolic and diastolic 
blood pressure will be measured twice using a validated device, with 
an appropriately sized cuff. The two measurements should be 
entered in the eCRF and the average of the two measurements will 
be used for analysis. 
When the timing of these measurements coincides with blood 
collection, the blood pressure and pulse rate should be obtained first. 
For visits with study dosing, vital signs should be taken prior to 
study medication administration. 
Height and weight 
Height and body weight will be measured as listed in Table 8-1. 
Height in centimeters (cm) and body weight (to the nearest 0.1 
kilogram (kg) in indoor clothing but without shoes). 
8.5.2 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimen [screening as well as on-study 
evaluations for serum chemistry including  calcium test, hematology, coagulation, serum 25 
(OH) vitamin D tests and serology test, for CZ: serum FSH] listed below in Table 8-2.
 
 
  
All blood samples will be obtained by venipuncture, at the time points outlined in the 
assessment schedule in Table 8-1. The date and time of blood collection will be recorded in the 
patient's medical record.  
Unscheduled laboratory assessments may be obtained at any time during the study to assess any 
perceived safety concerns.  
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. Values considered clinically relevant will be identified on the clinical laboratory 
report and an AE will be documented in the eCRF. 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 to repeat the test once in 
order to rule out laboratory error. 
Clinically significant abnormalities must be recorded as either medical history/ current medical 
condition or AEs as appropriate. 
Table 8-2 
Laboratory assessments 
Test category 
Test Name 
Hematology 
Hemoglobin, Platelets, White blood cells, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
Chemistry 
Albumin, Total protein, Alkaline phosphatase, ALT, AST, Lactate 
dehydrogenase (LDH), Calcium (equals Total calcium), Albumin adjusted 
serum calcium, Magnesium, Phosphorus, Sodium, Potassium, Creatinine, 
Total Bilirubin, Blood Urea Nitrogen (BUN), Glucose 

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Test category 
Test Name 
Coagulation 
Prothrombin time (PT)/ International normalized ratio (INR), Activated 
partial thromboplastin time (APTT) 
Hepatitis serology 
Hepatitis B (HBsAg, anti-HBs and anti-HBc), Hepatitis C (anti-HCV) 
HIV serology 
HIV-1 and HIV-2 antibodies 
Additional tests 
Serum 25 (OH) vitamin D level 
COVID-19 related 
testing 
serological test for antibodies against SARS-CoV-2 
For CZ only: FSH 
Serum FSH level 
Hypocalcemia 
Hypocalcemia (calcium <2.10 mmol/L [<8.42 mg/dL]) must be corrected by adequate 
supplementation of calcium and vitamin D before initiating treatment and each administration 
of study medication.  
During the screening period, if patient calcium level is >2.0 mmol/ [>8.02 mg/dL] and <2.10 
mmol/L [<8.42 mg/dL], calcium repletion is permitted only for the patients who had no calcium 
supplementation at all or a previous calcium supplementation of <1000 mg. In these patients, 
calcium re-test during the screening can be performed or patient may be re-screened. Patients 
with a calcium supplementation of ≥ 1000 mg per day before the screening visit and/or with 
calcium values <2.0 mmol/L [<8.02 mg/dL] are not allowed to enter into the study. Repletion 
should be conducted according to the local guideline or standard of care. 
Clinical monitoring of calcium level and vitamin D will be performed as indicated in  
Table 8-1. Since the calcium level needs to be known prior to the administration of study 
medication, the measurement from the following time points would be used: 
• 1st dose at Day 1:   calcium level from screening  
• 2nd dose at Week 26: calcium level from Week 22 
• 3rd dose at Week 52:  calcium from Week 50  
Local dipstick urinalysis 
Dipsticks will be provided by the central laboratory to the sites for local urinalysis assessments. 
The sites will record the results in the appropriate eCRF page for each patient. Dipstick 
measurements for ketones, pH, protein, glucose, and blood will be done at scheduled visits as 
indicated in Table 8-1. 
Urine sediment test (for CZ only) 
In addition to the urine dipstick, a microscopic urine sediment test will be performed at the 
central laboratory, and will be done at scheduled visits as indicated in Table 8-1 for the analysis 
of potentially existing red blood cells, white blood cells, epithelial cells, bacteria, casts and 
crystals in the urine. The sites will record the results in the appropriate eCRF page for each 
patient. Any abnormal finding that is deemed clinically significant must have a corresponding 
adverse event reported in the applicable page in eCRF.  

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8.5.3 
Immunogenicity 
As with all therapeutic proteins, there is a potential for immunogenicity and the emergence of 
antibodies to human recombinant proteins is well documented. Antibodies directed against a 
therapeutic agent may have neutralizing activity and interfere with the efficacy of the treatment. 
For safety reasons, evaluation for anti-drug antibodies (ADA) has been included in this study. 
Data specific to denosumab from Amgen revealed a low incidence of immunogenicity, with 
less than 1% of patients exposed to the medication in clinical studies developing ADAs. The 
immunogenicity risk of the product is considered low.  
8.5.3.1 
Immunogenicity blood sample collection and handling 
Immunogenicity will be assessed by measuring anti-drug antibody (ADA) levels in serum of 
all patients. Blood samples will be collected at the time points indicated in the assessment 
schedule Table 8-1 from all patients randomized and treated, in order to detect antibody 
formation against denosumab. 
Blood samples of approximately 8 mL will be collected at each sample time point by either 
direct venipuncture or an indwelling cannula inserted in a forearm. A total of 12 blood samples 
will be collected per patient for immunogenicity assessment. 
Serum will be prepared from blood and each sample will be labeled at the investigator’s site as 
per the instructions in the Laboratory Manual. The actual sample collection date and time will 
be entered on the appropriate eCRF. 
Complete instructions for sampling, processing, handling, shipment and storage will be 
provided in the Laboratory Manual.  
The study serum samples will be stored in freezers (-70°C) in an access controlled area for up 
to 15 years. 
Communication of immunogenicity results to investigators occurs after data base lock and 
finalization of the Clinical Study Report. 
8.5.3.2 
Analytical methods for immunogenicity determination 
Immunogenicity of denosumab will be determined by the formation of antibodies against the 
drug and will be evaluated by using validated immunoassays. 
All samples will first be analyzed in a screening assay. Study samples with a result below the 
validated screening cut-point are negative for binding anti-drug antibodies and will be reported 
accordingly. In the event of a positive result (result above or equal to the screening cut-point), 
the sample will additionally be analyzed in a secondary confirmatory assay (specificity assay). 
In case the assay signal can be reduced after addition of excess of denosumab beyond or equal 
to the validated confirmatory cut-point, a sample will be reported as confirmed positive for 
binding anti-drug antibodies. In contrast, samples with a result above the screening cut-point in 
the screening assay but which are negative in the confirmatory assay will be reported as 
negative. 
The titer of confirmed positive results will be determined. In addition, samples which were 
confirmed to be positive for binding anti-denosumab antibodies may be analyzed for their 

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neutralization potential in a neutralizing antibody (NAb) assay. All immunogenicity assays will 
be performed at the sponsor's bioanalytical laboratory. 
8.5.4 
Fractures 
As a safety measure, fracture rates (incidence of vertebral fractures and nonvertebral 
fractures) will be captured throughout the period of the study. 
Vertebral fracture 
Information on vertebral fractures will be centrally evaluated through the scheduled lateral 
thoraco-lumbar spine X-ray as indicated in the assessment schedule Table 8-1. Procedural 
instructions on X-rays will be provided in the Imaging Manual. 
For central assessment of vertebral fractures by lateral spine X-ray, a visual semiquantitative 
grading scale will be used (Genant et al 1993). Details on the grading scale are provided in the 
Imaging Manual. 
Nonvertebral fractures 
Information about any nonvertebral fractures while on study will be recorded as AE. The 
diagnosis of nonvertebral fractures will not require central X-ray reading and will be based on 
local radiology reports. 
8.5.5 
Injection site reactions 
The injection site reaction assessment will be done by the investigator/ designee. It consists of 
grading the severity of each injection reaction based on criteria (CTCAE) mentioned below in 
Table 8-3. Injection site reactions with a grading ≥1 will also be recorded as AE. 
Table 8-3 
Injection site reaction grading 
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 
8.5.6 
Electrocardiogram (ECG) 
According to Prolia/ Pralia label, rarely, patients receiving Prolia/ Pralia may develop 
hypocalcemia, which may also lead to QT prolongation.  
A standard 12-lead ECG will be performed at time points as indicated in Table 8-1. 
ECGs should be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs and blood sampling. The Fridenricia QT correction formula (QTcF) 
should be used for clinical decisions. 

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If the ECG findings at screening are clinically significant and would prevent the patient from 
participating in the study (taking into account the patient’s overall status as well as the treatment 
profile), the patient should not be randomized into the study. 
Throughout the course of the study, in the event that a clinically significant ECG abnormality 
is identified (e.g. severe arrhythmia, conduction abnormality of QTcF >500 ms), two more 
ECGs will be repeated to confirm the diagnosis, with the diagnosis decision based on the 
presence of the abnormality in at least two of the three ECGs. 
Clinically significant abnormality must be recorded on the eCRF as either medical history/ 
current medical conditions or AEs as appropriate. 
8.5.7 
Pregnancy and assessments of fertility 
 For the post-menopausal women population in the study, pregnancy is not expected. However, 
for exceptional rare occurrence of pregnancy, the process must be followed as described in 
Section 10.1.4. 
8.5.8 
Appropriateness of safety measurements 
The safety assessments being used in this study are standard for osteoporosis indication, and 
also aligned with the safety assessments required as per the safety profiles for EU-authorized,  
US-licensed Prolia and JP-licensed Pralia (Prolia EU SmPC, Prolia US PI). 
8.6 
Additional assessments 
8.6.1 
Clinical outcome assessments (COAs) 
Trial feedback 
This trial will include a "Trial Feedback Questionnaire", an option for patients to complete an 
anonymized questionnaire to provide feedback to the sponsor on their clinical trial experience. 
Individual patient level responses will not be reviewed by investigators. Responses would be 
used by the sponsor to understand where improvements can be made in the clinical trial process. 
This questionnaire does not collect data about the patient's disease, symptoms, treatment effect 
or AEs and therefore would not be trial data.  
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study medication for a patient occurs when study medication is stopped 
earlier than the protocol planned duration, and can be initiated by either the patient or the 
investigator. 
Reasons for discontinuation from study medication may include, but will not be limited to: 
• Patient decision 
• Pregnancy 

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• AEs that in the judgment of the investigator, taking into account the patient’s overall 
status, prevent the patient from continuing the study medication or study (for example 
osteonecrosis of the jaw).  
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient’s overall status, prevent the patient from continuing participation 
in the study. 
• Unsatisfactory therapeutic effect 
• Any situation, in which study participation might result in a significant risk to the patient’s 
safety 
• Following emergency unblinding 
If discontinuation of study medication occurs, the investigator should make effort to understand 
the primary reason for the patient’s premature discontinuation of study medication and record 
this information. 
Patients who discontinue study medication should NOT be considered withdrawn from the 
study UNLESS they withdraw their consent (see withdrawal of informed consent 
Section 9.1.2). Where possible, they should return for the assessments indicated in the 
assessment schedule, up to the next scheduled study medication administration visit (this next 
dose would not be administered to such a patient). The last of such scheduled visits should act 
as the early termination visit for the patient. If they fail to return for these assessments (post 
discontinuation of study medication) for unknown reasons, every effort (e.g. telephone, e-mail, 
or letter) should be made to contact the patient/ pre-designated contact as specified in the lost 
to follow-up section. This contact should preferably be done according to the study visit 
schedule. 
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule. 
After study medication discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/ email contact: 
• new/ concomitant treatments 
• AEs/ SAEs 
The investigator is advised to provide appropriate follow-up antiresorptive osteoporosis 
treatment for all patients discontinued from the study, especially for those with high risk of 
fractures. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
medication. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. 
9.1.2 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient: 

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• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/ her consent and 
record this information. 
Study medication must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed, unless safety findings require 
communicating or follow-up and upon agreement of the patient, an early termination visit as 
per Table 8-1 will be conducted.  
The sponsor will continue to retain and use all research results (data) that have been collected 
for the study evaluation. 
9.1.3 
Early termination visit 
Patients who prematurely withdraw consent towards study participation for any reasons during 
the Treatment Period 1 or Treatment Period 2 should be asked to undergo the assessments as 
per Early Termination Visit in Table 8-1. For the definition of withdrawal of consent, please 
refer to Section 9.1.2. 
9.1.4 
Lost to follow-up 
For patients, whose status is unclear, because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, letters, etc. A patient should not be considered as lost to follow-up until due diligence has 
been completed. 
9.1.5 
Early study termination by the sponsor 
The study can be terminated by the sponsor under certain circumstances. 
Examples of reasons for early termination but not limited to: 
• unexpected, significant, or unacceptable safety risk to patients enrolled in the study 
• decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• discontinuation of investigational drug development 
In taking the decision to terminate, the sponsor will always consider the patient welfare and 
safety. Should early study termination be necessary, patients must be seen as soon as possible 
(instructions would be provided for contacting the patient, when the patient should stop taking 
drug, when the patient should come for a final visit) and treated as a prematurely withdrawn 
patient. The investigator may be informed of additional procedures to be followed in order to 
ensure, that adequate consideration is given to the protection of the patient’s interests. The 
investigator or sponsor, depending on the local regulation, will be responsible for informing 
IRBs/ IECs of the early termination of the trial. 

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9.2 
Study completion and post-study treatment 
Study completion is defined as the date when the last patient finishes the End of Study Visit/ 
Early Termination Visit, or the date at which the last data point from the last patient is received, 
whichever is later. 
The investigator is advised to provide appropriate follow-up antiresorptive osteoporosis 
treatment for all patients completed the study, especially for those with high risk of fractures. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient after 
providing written informed consent for participation in the study. Therefore, an AE may or may 
not be temporally or causally associated with the use of a medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual patient and 
identifying AEs. 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. AEs also may be detected when they are volunteered by the patient during or 
between visits or through physical examination findings, laboratory test findings or other 
assessments. 
AEs must be recorded in the Adverse Events eCRF under the signs, symptoms or diagnosis 
associated with them, accompanied by the following information (as far as possible) (if the 
event is serious refer to Section 10.1.2): 
1. The Common Terminology Criteria for Adverse Events (CTCAE) grade. AEs will be 
assessed and graded according to the CTCAE version 5.0 or higher. If CTCAE grading 
does not exist for an AE, the severity of such AE should be graded as follows:  
• Grade 1: asymptomatic or mild symptoms; clinical or diagnostic observations 
only  
• Grade 2: minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (e.g., preparing meals, shopping 
for groceries or clothes, using the telephone, managing money, etc.)  
• Grade 3: severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self care activities of daily living  
• Grade 4: Life-threatening consequences; urgent intervention indicated  
• Grade 5: Death related to AE 

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2. its relationship to the study medication. If the event is due to lack of efficacy or 
progression of underlying illness (i.e. progression of the study indication) the assessment 
of causality will usually be ‘Not suspected’. The rationale for this guidance is that the 
symptoms of a lack of efficacy or progression of underlying illness are not caused by the 
trial drug, they happen in spite of its administration and/ or both lack of efficacy and 
progression of underlying disease can only be evaluated meaningfully by an analysis of 
cohorts, not on a single patient. 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/ 
not resolved must be reported. 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study medication 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Drug withdrawn 
6. its outcome  
a. not recovered/ not resolved; 
b. recovered/ resolved; 
c. recovering/ resolving, 
d. recovered/ resolved with sequelae; 
e. fatal; or unknown 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient. 
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. 
AE monitoring should be continued until the End of Study Visit for a particular patient. For 
patients that have withdrawn consent or discontinued treatment, please refer to Section 9.1. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 

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baseline or the previous visit, or values, which are considered to be non-typical in patients with 
the underlying disease.  
10.1.2 
Serious adverse events 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (ICH E15A 1993). 
• results in persistent or significant disability/ incapacity 
• constitutes a congenital anomaly/ birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (bone fragility and increased risk of fractures) . 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study  and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (ICH E15A 1993). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.  
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious AE, 
irrespective if a clinical event has occurred.  

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10.1.3 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring from the time of 
informed consent until the patient's last study visit must be reported to sponsor safety within 24 
hours of learning of its occurrence. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study medication, a Chief Medical Office and 
Patient Safety (CMO & PS) Department associate may urgently require further information 
from the investigator for health authority reporting. Sponsor may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
medication that this SAE has been reported. 
All potential risks, including Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be collected and reported to the competent authorities and relevant ethics committees in 
accordance with expectations set forth in national regulatory requirements of participating 
countries (including, but not limited to EU Guidance 2011/C 172/01 (EUR-Lex 2011/C 172/01) 
and 15 CFR 312.32 (c) in the US)  
Any SAEs experienced after the last study visit for each patient should only be reported to the 
sponsor Safety if the investigator suspects a causal relationship to study medication. 
10.1.4 
Pregnancy reporting 
Pregnancies 
For the post-menopausal women population in the study, pregnancy is not expected. However, 
for exceptional rare occurrence, the following process must be followed. 
As a general rule, the study medication must be discontinued, though the patient may stay in 
the study and follow the assessments, if she wishes to do so. Each pregnancy occurring after 
signing the informed consent must be reported to the sponsor within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine 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. 
Pregnancy should be recorded and reported by the investigator to the sponsor CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study medication any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported. 

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10.1.5 
Reporting of study treatment errors including misuse/ abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study medication errors and uses outside of what is foreseen in the protocol will be recorded 
on appropriate eCRF, irrespective of whether or not associated with an AE/ SAE, and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/ SAE within 24 hours of 
investigator’s awareness. 
Table 10-1 
Guidance for capturing the study medication errors including misuse/ 
abuse 
Treatment error type 
Document in Dose 
Administration eCRF 
(Yes/ No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
medication error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/ Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional safety monitoring 
Not applicable. 
11 
Data collection and database management 
11.1 
Data collection 
All data captured for this study will have an external originating source (either written or 
electronic) with the eCRF not being considered as source. 
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements. Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/ or verification of the entered data by the investigator staff. 
The investigator/ designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
investigator must certify that the data entered are complete and accurate. 

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After final database lock, the investigator will receive copies of the patient data for archiving at 
the study site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.2 
Database management and quality control 
Sponsor personnel (or designated CRO) will review the data entered by site's staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
study site via the EDC system. Designated investigator site staff are required to respond 
promptly to queries and to make any necessary changes to the data. 
Concomitant and prior treatment, entered into the database, will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/ current medical conditions and AEs will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. 
Randomization codes and data about all study medication(s) dispensed to the patient and all 
dose changes will be tracked using an IRT. The system will be supplied by a vendor, who will 
also manage the database. The data will be sent electronically to the sponsor (or a designated 
CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and field monitor. 
The code break functionality will remain available until study shut down or upon request of the 
sponsor. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by the sponsor. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator meeting, a sponsor and/ or 
delegated CRO representative will review the protocol and data capture requirements (i.e. 
eSource or eCRFs) with the investigators and their staff. During the study, the sponsor employs 
several methods of ensuring protocol and GCP compliance and the quality/ integrity of the sites’ 
data. Blinded and unblinded field monitor will visit the site to check the completeness of patient 
records, the accuracy of data capture/ data entry, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study medication is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the blinded and unblinded field monitor, respectively, during these visits. Remote 
monitoring of each site’s data will be performed by the delegated CRO. Additionally, the 
delegated CRO will analyze data centrally and identify risks and trends for site operational 
parameters, and provide reports to the sponsor clinical teams to assist with trial 
oversight. Details on blinded and unblinded monitoring activities as well as on centralized 
monitoring are described in the study specific Monitoring Plan. The investigator must maintain 
source documents for each patient in the study, consisting of case and visit notes (hospital or 

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clinic medical records) containing demographic and medical information, laboratory data, 
electrocardiograms, and the results of any other tests or assessments. All information on eCRFs 
must be traceable to these source documents in the patient’s file. The investigator must also 
keep the original informed consent form signed by the patient (a signed copy is given to the 
patient). 
The investigator must give the field monitor access to all source documents to confirm their 
consistency with the data capture and/ or data entry. The sponsor monitoring standards require 
full verification for the presence of informed consent, adherence to the inclusion/ exclusion 
criteria, documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the eCRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the patients will be disclosed. 
To support the investigators and their staff with retention and the prevention of missing data, 
ongoing training will be provided by the field monitor during monitoring visits.  A Visit 
Reminder Messaging Service implemented as an option has also been made available for those 
sites that do not have a visit reminder procedure in place for their patients.  Investigators will 
additionally have the option to arrange transportation services or receive transportation 
reimbursement for patients who require assistance with travel to their study visits.    
12 
Data analysis and statistical methods 
Data analysis will be performed at two time points: an interim analysis after all patients 
completed Treatment Period 1 and a final analysis after all patients completed the study. 
The interim analysis will include the primary endpoint analysis and will compare GP2411 with 
Prolia for Treatment Period 1 with a 1:1 ratio. Final analysis will be completed including the 
data collected from Week 52 until the end of the study at Week 78 comparing the three groups 
“Continued GP2411”, “Continued Prolia” and “transition into GP2411” and will be descriptive 
only. The number of patients in the three groups in Treatment Period 2 are expected to be in the 
approximate ratio 2:1:1 respectively. 
Because of different health authority requirements there are three sets of primary endpoints in 
this study: 
Table 12-1 
List of primary endpoints 
Health Authority 
Endpoint 
Equivalence criteria 
Analysis set 
EMA 
%CfB in LS-BMD at Week 52 
95% CI for difference in means 
contained in [-2.00%, 2.00%] 
PPS 
 
AUEC of %CfB in serum CTX 
after first dose 
95% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PDS 
FDA 
%CfB in LS-BMD at Week 52 
95% CI for difference in means 
contained in [-1.45%, 1.45%] 
TP1 FAS 
PMDA 
%CfB in LS-BMD at Week 52 
95% CI for difference in means 
contained in [-2.00%, 2.00%] 
TP1 FAS 
 
Serum PK parameter AUCinf 
after first dose 
90% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PKS 

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Health Authority 
Endpoint 
Equivalence criteria 
Analysis set 
 
Serum PK parameter Cmax 
after first dose 
90% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PKS 
In addition, equivalence testing will also be performed for the following secondary endpoints: 
Table 12-2 
List of secondary endpoints with equivalence testing 
FDA 
AUEC of %CfB in serum CTX 
after first dose 
90% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PDS 
PMDA 
AUEC of %CfB in serum CTX 
after first dose 
95% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PDS 
Endpoints will be described in the primary endpoint section when the endpoint is primary for 
any health authority and will be referenced in the secondary endpoint sections as necessary. Of 
note, the testing requirement for LS-BMD is different for different HAs and therefore a situation 
may arise where criteria for some HA are met while for other HAs they are not. Testing strategy 
is detailed in Section 12.5.2. 
Data collected during the study conduct can be used for submission to health authorities, ethic 
committees or IRBs. Any data analysis carried out independently by the investigator should be 
submitted to Sandoz/Hexal before publication or presentation. 
Unless otherwise indicated, continuous variables will be summarized with the following 
descriptive statistics: n (number of observations), (arithmetic) mean, SD, minimum, median and 
maximum value. For continuous PK and PD parameters as well as serum drug, CTX and PINP 
concentrations, the CV% mean, geometric mean and geometric coefficient of variation (%) 
(CV% geometric mean) will also be presented. 
Categorical data will be summarized with frequencies and percentages. Percentages by 
categories will be based on the number of patients included in the analysis set under 
consideration unless otherwise specified. 
12.1 
Analysis sets 
The following data sets will be used for analysis of the study data: 
The Treatment Period 1 Randomized Analysis Set (TP1 RAS) consists of all patients who 
were randomized into TP1. The TP1 RAS will include any patients who were randomized into 
TP1 including those that were not treated. 
The Treatment Period 1 Full Analysis Set (TP1 FAS) is a subset of TP1 RAS and consists of 
all patients who were randomized into TP1, who received at least one dose of study medication 
and for whom at least one post-baseline LS-BMD value (either at Week 26 or at Week 52 or at 
both visits) is available. Patients will be analyzed according to the treatment randomized to. 
The Treatment Period 1 Safety Set (TP1 SAF) consists of all patients who received at least 
one dose of study medication. Patients will be analyzed according to the treatment received.  
The Per-Protocol Set (PPS) is a subset of TP1 RAS and is characterized by the following 
criteria:  
• The LS-BMD assessments at baseline and Week 52 are available  

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• The patients received treatment according to protocol at Day 1 and Week 26 
• They experienced no relevant protocol deviations which would affect LS-BMD up to 
Week 52 (the time of the primary analyses) 
The PD Analysis Set (PDS) is a subset of the TP1 RAS and is characterized by the following 
criteria:  
• CTX values are available in order to be able to calculate the AUEC value for the primary 
analysis (further details will be provided in the statistical analysis plan (SAP)) 
• The patients received treatment according to protocol at Day 1 
• They experienced no relevant protocol deviations which would affect CTX measurements 
up to Week 26 (the time of the primary analyses) 
The PK analysis set (PKS) is a subset of the TP1 RAS and is characterized by the following 
criteria: 
• At least one PK primary endpoint (Cmax or AUCinf) is evaluable 
• The patients received treatment according to protocol at Day 1 
• They experienced no relevant protocol deviations affecting the PK parameters up to 
Week 26 (the time of the primary analyses) 
Separate PK analysis subsets may be defined for different PK parameters if deemed necessary. 
This will be described in detail in the SAP. 
The criteria to qualify a protocol deviation as leading to exclusion from PPS, PDS or PKS will 
be documented in the SAP version finalized before database lock. 
The Treatment Period 2 Randomized Analysis Set (TP2 RAS) is a subset of TP1 RAS and 
consists of all patients who were re-randomized into TP2. The TP2 RAS will include any 
patients who were re-randomized into TP2 including those that were not treated in TP2. 
The Treatment Period 2 Full Analysis Set (TP2 FAS) is a subset of the TP2 RAS and consists 
of all patients who were re-randomized into TP2 and for whom at least one TP2 efficacy, PD 
or PK value is available. Patients will be analyzed according to the treatment randomized to. 
The Treatment Period 2 SAF (TP2 SAF) consists of all patients who received at least one 
dose of study medication in TP2. Patients will be analyzed according to the treatment received 
in Treatment Period 2.  
In case of stratification errors recorded within the IRT system, patients will be assigned to the 
strata as collected in the IRT system for the TP1 FAS and to the strata as derived from the values 
stored in the clinical database for the PPS. If analyses sets comprise the same patients only one 
may be used for analysis. 
12.2 
Patient demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will summarized 
descriptively in TP1 for the TP1 SAF, TP1 FAS, PPS, PDS and PKS and in TP2 for the TP2 
FAS and TP2 SAF. 

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Descriptive statistics will be produced for age as a continuous variable, but age will also be 
included as age group (<65 years/ ≥65 years), and body weight as a continuous variable and 
body weight group (<70 kg/ ≥70 kg) 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, for all patients in TP1 for the TP1 SAF 
and in TP2 for TP2 SAF.  
12.3 
Treatments 
Study medication administration will be summarized for the respective safety set.  
Number of doses will be summarized as frequency and percentage including duration of 
exposure. 
Concomitant medications and significant non-drug therapies after the start of the study 
treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system for both safety sets. In addition, osteoporosis treatment prior to the start 
of study treatment will be summarized similarly. 
12.4 
Pharmacokinetics and pharmacodynamics 
12.4.1 
Pharmacokinetics 
Serum samples will be analyzed for free denosumab serum concentrations. PK parameters 
following the first 60 mg s.c. dose of study medication will be estimated using non-
compartmental analysis (best-fit method) with Phoenix WinNonlin (Version 8.0 or above) by 
the pharmacokineticist of a CRO. The main PK parameters, together with the abbreviations and 
definitions are provided in Table 12-3. More details regarding additional PK parameters and 
how they are calculated will be outlined in the SAP.  
Table 12-3 
Pharmacokinetic parameters 
Parameter 
Description 
AUCinf 
The area under the serum concentration-time curve measured from the time 
of dosing and extrapolated to infinity  [ng x day/mL] 
Cmax 
The maximum observed serum concentration [ng/mL] 
12.4.2 
Pharmacodynamics 
Serum samples will be analyzed for CTX and PINP concentrations. PD parameters of CTX only 
following the first s.c. dose of 60 mg study medication will be estimated using the non-
compartmental drug effect model in Phoenix WinNonlin (Version 8.0 or above) by the 
Pharmacokineticist of a CRO. The area under the effect versus time curve (AUEC) of baseline 
corrected serum CTX concentrations (% change from baseline) will be the main parameter of 
interest. The AUEC will be calculated as the area under 0 after the first 60 mg s.c. dose until 
CTX values return and cross the baseline for the first time. For patients where CTX does not 
cross or even return to baseline, the AUEC up to 26 weeks will be calculated.  In addition, the 
rebound area, where applicable, will be calculated following the first 60 mg s.c. dose. The 
PD parameters together with the abbreviations and definitions are provided in Table 12-4. 

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More details regarding the definition of different CTX areas and how they are calculated will 
be outlined in the SAP. 
Table 12-4 
Pharmacodynamic parameters 
Parameter 
Description 
AUEC 
The area that is below 0 and above the response curve [% x day] 
Rebound area 
The area that is above 0 and below the response curve [% x day] 
12.5 
Analysis of the primary endpoint(s) 
The main objective of this study is to demonstrate similar efficacy, PD and PK of GP2411 and 
Prolia (EU-authorized) in postmenopausal women with osteoporosis. This will be done by 
comparing %CfB of LS-BMD at Week 52 as well as AUEC of %CfB in serum CTX and 
AUCinf and Cmax after the first dose, following injection of either treatment every six months.  
12.5.1 
Definition of primary endpoint(s) 
A list of primary endpoints with respective primary analysis sets applicable to different health 
authorities is provided in Table 12-1.  
For LS-BMD and CTX the %CfB is defined as  
%𝐶𝐶𝐶𝐶𝐶𝐶= 100 ∗𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃−𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵
𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵
 
where PostBaseline is the the post-baseline LS-BMD or CTX value and Baseline is the baseline 
LS-BMD or CTX value. 
Definitions of AUEC, Cmax and AUCinf and can be found in Section 12.4. 
12.5.2 
Statistical model, hypothesis, and method of analysis 
The type I error rate will be controlled on health authority requirement level, i.e. a separate 
hierarchical testing strategy will be implemented per health authority. Testing strategy for FDA 
can be found in Table 12-5, testing strategy for EMA in Table 12-6 and testing strategy for 
PMDA in Table 12-7 and results will be presented in one clinical study report. 
Table 12-5 
Hierarchical testing strategy for FDA 
Endpoint 
Equivalence criteria 
Analysis set 
Step 1 
%CfB in LS-BMD at Week 52 
95% CI for difference in means 
contained in [-1.45%, 1.45%] 
TP1 FAS 
Step 2 
AUEC of %CfB in serum CTX after 
first dose 
90% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PDS 
Table 12-6 
Hierarchical testing strategy for EMA 
Endpoint 
Equivalence criteria 
Analysis set 
Step 1 
%CfB in LS-BMD at Week 52 
95% CI for difference in means 
contained in [-2.00%, 2.00%] 
PPS 
Step 2 
AUEC of %CfB in serum CTX after 
first dose 
95% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PDS 

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Table 12-7 
Hierarchical testing strategy for PMDA 
Endpoint 
Equivalence criteria 
Analysis set 
Step 1 
%CfB in LS-BMD at Week 52 
95% CI for difference in means 
contained in [-2.00%, 2.00%] 
TP1 FAS 
Step 2 
Serum PK parameter AUCinf after 
first dose 
90% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PKS 
 
Serum PK parameter Cmax after 
first dose 
90% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PKS 
Step 3 
AUEC of %CfB in serum CTX after 
first dose 
95% CI for ratio of geometric 
means contained in [0.80, 1.25] 
PDS 
For all testing strategies, each subsequent step will only be performed if the previous step was 
deemed successful. 
12.5.2.1 %CfB in LS-BMD 
The following statistical hypotheses will be tested to assess equivalence between GP2411 and 
Prolia in terms of %CfB in LS-BMD at Week 52. 
𝐻𝐻0: |𝐺𝐺𝐺𝐺2411 −𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃| ≥∆ 
versus 
𝐻𝐻1: |𝐺𝐺𝐺𝐺2411 −𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃| < ∆ 
Therapeutic equivalence in terms of %CfB in LS-BMD for EMA and PMDA requirements will 
be concluded if the 95% CI for the difference in mean changes is contained within the interval 
[−2.00%, 2.00%], and for FDA requirement if the 95% CI of the difference is contained within 
the interval [-1.45%, 1.45%]. 
A mixed-model repeated measures (MMRM) analysis will be performed for %CfB as the 
endpoint including the following variables: 
• treatment (GP2411, Prolia)  
• Prior bisphosphonate use (yes/ no) as a categorical variable 
• DXA machine type (Lunar/ Hologic) as a categorical variable 
• time (visits Week 26, Week 52)  as a categorical variable 
• interaction between time (visits Week 26, Week 52) and treatment (GP2411, Prolia) 
• baseline LS-BMD value as a continous covariate 
The primary analysis will be based on the least-squares mean treatment differences at Week 52 
(and not on the overall treatment differences). Mean change from baseline at Week 52, standard 
errors and the two-sided 95% CIs for the mean difference between GP2411 and Prolia at Week 
52 will be estimated from the model and the respective CI compared to the pre-specified 
equivalence range of [-Δ; Δ].  
Stratification factor region (US, Rest of World, Japan) is considered an administrative 
stratification factor and therefore not included in the statistical model. 
Stratification factor age (<65 years/ ≥65 years) can best be assumed to have a linear effect on 
LS-BMD (van Schaik et al 2015) and therefore using the %CfB in LS-BMD as primary 

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endpoint and including LS-BMD Baseline value as covariate should already account for the 
change in LS-BMD with age. 
Stratification factor prior bisphosphonate use (yes/ no) was identified as a potential source of 
heterogeneity for the primary endpoint of LS-BMD that cannot be assured to be completely 
controlled though the use of inclusion/exclusion criteria and is therefore included in the model. 
Stratification factor body weight group (<70 kg/ ≥70 kg) is not expected to have a relevant 
impact on LS-BMD and is therefore not included in the model for LS-BMD. This stratification 
factor was set up to ensure interpretable PK analyses. 
For DXA machine type there is a concern, although the %CfB is used and should adjust for 
different DXA machine types, that if this adjustment is insufficient and that it would be prudent 
to include an adjustment for DXA machine type. 
The model includes data for each patient from both the Week 26 and Week 52 BMD 
measurements. This is done to increase the statistical power of the model as Week 26 LS-BMD 
values will be correlated with Week 52 values. This is differentiated in the model by the use of 
the time factor. However, it is highly likely that the treatment difference at Week 26 and Week 
52 are not identical and hence a treatment by visit interaction is included. 
The most flexible covariance matrix being unstructured will be assumed, that is, all variance 
and covariance parameters are estimated from the data. This will allow adjustment for 
correlation in LS-BMD values across visits within patients. In case some strata are not 
sufficiently large enough to ensure appropriate analysis inclusion of strata into the primary 
analysis model may be revised in the SAP.  
For EMA the primary analysis will be performed on the PPS which is considered the most 
sensitive analysis set to use when testing for equivalence. For FDA and PMDA the primary 
analysis will be performed on the TP1 FAS to reduce potential selectivity bias undermining the 
integrity of the randomization by including all available data (see Table 12-1). The respective 
analysis set will be used as supplementary analysis (see Section 12.5.5). For handling of missing 
data see Section 12.5.3.1. 
12.5.2.2 AUEC after the first dose for CTX 
The assessment of bioequivalence will be based upon the CIs (95% for EMA) of the ratio of the 
geometric means (test/ reference) for the AUEC of %CfB in serum CTX concentrations after 
first dose, which have to be contained entirely within the pre-specified acceptance interval of 
[0.80, 1.25]. 
If µCTX,T and µCTX,R denote the population means for test and reference of the AUEC, then the 
following null and alternative hypotheses are being tested: 
𝐻𝐻0: 𝜇𝜇𝐶𝐶𝐶𝐶𝐶𝐶,𝑇𝑇𝜇𝜇𝐶𝐶𝐶𝐶𝐶𝐶,𝑅𝑅
⁄
≤0.80 𝑜𝑜𝑜𝑜∶ 𝜇𝜇𝐶𝐶𝐶𝐶𝐶𝐶,𝑇𝑇𝜇𝜇𝐶𝐶𝐶𝐶𝐶𝐶,𝑅𝑅
⁄
≥1.25 
versus 
𝐻𝐻1: 0.80 < 𝜇𝜇𝐶𝐶𝐶𝐶𝐶𝐶,𝑇𝑇𝜇𝜇𝐶𝐶𝐶𝐶𝐶𝐶,𝑅𝑅< 1.25
⁄
 
ANCOVA will be performed on the log-transformed AUEC. 
The ANCOVA model will include the following variables 

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• treatment as fixed effect 
• baseline CTX value as a continuous covariate 
The ANCOVA will include calculation of least-squares means (LSM) for the treatments. The 
ratios of LSM will be calculated using the exponentiation of the LSM from the analyses on the 
corresponding log-transformed AUEC. Consistent with the two one-sided tests for 
bioequivalence at the 2.5% significance level (Schuirmann 1987), 95% CIs for the ratio will 
respectively be derived for AUEC.  
Stratification factors age, prior bisphosphonate use, weight and region were implemented for 
other reasons than impact on AUEC of %CfB in CTX (see Section 12.5.2.1) and therefore are 
not included in the model. 
The primary analysis will be based on the PDS. 
Descriptive statistics of AUEC of %CfB in serum CTX concentrations after the first dose will 
be presented by treatment group. 
12.5.2.3 PK parameters after the first dose 
The assessment of bioequivalence will be based upon the 90% CIs for the ratio of the geometric 
means (test/reference) for the AUCinf and Cmax which have to be contained entirely within the 
pre-specified PK acceptance interval of [0.80, 1.25]. 
If µPK,T and µPK,R denote the respective population means for test and reference of the PK 
parameter at Week 26, then the following null and alternative hypotheses are being tested for 
both parameters: 
𝐻𝐻0: 𝜇𝜇𝑃𝑃𝑃𝑃,𝑇𝑇𝜇𝜇𝑃𝑃𝑃𝑃,𝑅𝑅
⁄
≤0.80 𝑜𝑜𝑜𝑜∶ 𝜇𝜇𝑃𝑃𝑃𝑃,𝑇𝑇𝜇𝜇𝑃𝑃𝑃𝑃,𝑅𝑅
⁄
≥1.25 
versus 
𝐻𝐻1: 0.80 < 𝜇𝜇𝑃𝑃𝑃𝑃,𝑇𝑇𝜇𝜇𝑃𝑃𝑃𝑃,𝑅𝑅< 1.25
⁄
 
ANCOVA will be performed on the log-transformed PK parameters. The ANCOVA model will 
include the following variables 
• treatment as fixed factor  
• weight as a continuous covariate 
The ANCOVA will include calculation of LSM for the treatments. The ratios of LSM will be 
calculated using the exponentiation of the LSM from the analyses on the corresponding log-
transformed PK parameter. Consistent with the two one-sided tests for bioequivalence at the 
5% significance level (Schuirmann 1987), 90% CIs for the ratio will be derived for respective 
PK parameter.  
Stratification factors age, prior bisphosphonate use and region were implemented for other 
reasons than impact on PK parameters (see Section 12.5.2.1) and therefore are not included in 
the model. 
The primary analysis will be based on the PKS. 
Descriptive statistics of AUCinf and Cmax will be presented by treatment group and in addition 
by treatment group and weight group (<70 kg/ ≥70 kg).                   

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12.5.3 
Handling of missing values/discontinuations 
For the primary endpoints of %CfB in LS-BMD until Week 52 patterns of missing data will be 
observed and summarized by reason and treatment group. 
12.5.3.1 %CfB in LS-BMD 
For the %CfB in LS-BMD, if the baseline LS-BMD is missing then no %CfB can be calculated 
for any post-baseline visit, and the patient will not be included in the primary analysis. 
For the PPS and FAS primary analysis using the MMRM model as specified in Section 12.5.2.1 
if the Week 26 or Week 52 LS-BMD (if applicable) is missing then the corresponding value 
of %CfB is missing and will not be formerly imputed, but the missing value will be assumed 
missing at random (MAR, using the MMRM model). Of note, patients will not be included in 
the primary analysis using either FAS or PPS if both the Week 26 and Week 52 LS-BMD values 
are missing.  
With the primary efficacy analysis performed on the TP1 FAS the following missing data 
patterns are possible.  
Table 12-8 
Missing data patterns for %CfB in LS-BMD for TP1 FAS 
Pattern 
Baseline LS-BMD 
Week 26 LS-BMD 
Week 52 LS-BMD 
1 
Available 
Available 
 
2 
Available 
 
Available 
Pattern 1 is considered the most likely and most influential pattern in terms of missing data 
handling as the primary endpoint at Week 52 itself is missing. Scenario 2 is not expected to 
occur frequently as the LS-BMD measurement is taken at the same visit as the dosing is 
expected to be performed at site and missing a dose would lead to patient discontinuing study  
due to safety reasons. In addition, for pattern 2 the primary endpoint at Week 52 is available 
and only the Week 26 value (used in the model to increase comparison’s power) is missing. 
The primary analysis will be based on the MAR assumption. For patients in missing data pattern 
2 and patients with no missing data the primary efficacy endpoint of %CfB in LS-BMD is 
available. For patients with pattern 1, the development of the other patients observed in the 
study with non-missing Week 52 values given their own Week 26 value, is the best available 
estimate for the study. 
To confirm robustness of conclusions using the MAR assumption, a sensitivity analysis in form 
of a tipping point analysis will be performed using NMAR, see Section 12.5.4. 
In addition, missing data due to COVID-19 pandemic is not expected to be related to treatment 
effect or representative of treatment outside the context of a clinical study, further supporting 
the MAR assumption for missing data for the primary efficacy analysis. 
Any LS-BMD values measured outside of the visit window will still be considered in the 
analysis, however, the patient may be excluded from the PPS because of visit window 
violations. The visit windows leading to exclusion from the analysis sets will be documented in 
the SAP version finalized before database lock.  

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12.5.3.2 AUEC after the first dose for CTX 
The AUEC of %CfB in serum CTX will be calculated if the baseline (pre-treatment) CTX value 
and the CTX values at Visit 4, Visit 9 and Visit 11 are available. Otherwise, the AUEC will be 
missing and the patient will be excluded from this primary analysis. 
Serum CTX concentrations below LLOQ will be treated as LLOQ for the AUEC calculations. 
12.5.3.3 PK parameters after the first dose 
For PK parameter calculations below LLOQ values will be treated as missing, except for the 
pre-dose sample, which will be treated as zero. 
12.5.4 
Sensitivity analyses 
Sensitivity analysis to assess robustness of normality assumption for MMRM 
In case the %CfB LS-BMD the residuals of the MMRM for the %CfB LS-BMD analysis are 
not approximately normally distributed (i.e. fail a Shapiro-Wilks test at p=0.05 level) then a 
95% non-parametric Hodges-Lehmann CI for the difference between the treatment groups will 
also be calculated on the subset of patients with a Week 52 %CfB in LS-BMD value available. 
This will be done in order to assess the sensitivity of the results to a possible departure from the 
normality assumption underlying the MMRM. 
Sensitivity analysis to assess robustness of MAR assumption for MMRM 
performed on the TP1 FAS  
The primary analysis of %CfB in LS-BMD on the TP1 FAS will assume missing data is MAR 
and this data will be taken care of by the MMRM model (see Section 12.5.3.1). 
A sensitivity analysis in form of a tipping point analysis will be carried out using multiple 
imputation (MI) methods to impute missing %CfB in LS-BMD at Week 52 values not directly 
related to the COVID-19 pandemic by making estimated values worse up to a δ of -2.00%. 
Missing values directly related to COVID-19 pandemic will still be considered MAR. This 
analysis is to explore the potential impact of different assumptions about the missing data 
patterns. 
The MI method for missing data in this analysis will be based on the algorithm proposed by 
Carpenter et al 2013. To build the joint distribution of pre- (Week 26) and postdeviation (Week 
52) data, a proposal by Koch 2008 adapted to the biosimilar setting will be followed. In order 
to avoid bias in the direction of making arms more similar and thereby possibly increasing the 
likelihood of an incorrect demonstration of equivalence, as a second step all imputed values 
separately for the biosimilar arm and reference arm are made worse by the margin δ for LS-
BMD for which larger positive values represent better response. Hereby, the first step will 
remain the same, but there will be two different scenarios for the second step.  
• Step 1: get an estimate for the Week 52 missing data in both arms by deriving the patient’s 
pre-deviation distribution per the algorithm specified by Carpenter assuming MAR 
• Step 2 (derive the patient’s joint distribution of pre- and postdeviation data by reducing 
the mean Week 52 value by δ): 

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a. Reduce the mean Week 52 value for the biosimilar arm (but not the reference arm) by 
WKHPDUJLQįRI 
b. Reduce the mean Week 52 value for the reference arm (but not the biosimilar arm) by 
WKHPDUJLQįRI 
This analysis will also be performed for įUDQJLQJIURP-2.00% to 0% using 0.05% steps. This 
will thereby provide a tipping point analysis showing not only study conclusion robustness 
assuming missing data are worse by the clinically relevant margin, but potentially also the 
maximum difference in treatment effect for missing data that would not change study 
conclusions. 
More details of this sensitivity analysis will be provided in the SAP. 
 
 
 
 
 
12.5.5 
Supplementary analyses 
For LS-BMD primary analysis from both PPS and TP1 FAS the analysis set that is not 
considered primary will be used as supplementary analysis using the methodology as specified 
for the primary analysis for the respective other analysis set in Section 12.5.2.1. Supportive 
analyses 
Descriptive analysis of the rebound area will be conducted to demonstrate robustness of the co-
primary CTX AUEC endpoint. More details regarding the supportive analysis and the definition 
of the area will be outlined in the SAP.  
12.6 
Analysis of secondary endpoints 
12.6.1 
Efficacy endpoints 
For Treatment Period 1 (Day 1 to Week 52) LS-BMD, FN-BMD, TH-BMD values and 
associated %CfB will be summarized descriptively by treatment at the completion of Weeks 26 
and Week 52. This will be performed for the PPS and TP1 FAS. 
For Treatment Period 2 (Week 52 to Week 78) LS-BMD, FN-BMD, TH-BMD values (%CfB) 
will be summarized descriptively by treatment group. This will be performed for the TP2 FAS. 
12.6.2 
Safety endpoints 
For all safety analyses, the respective safety set will be used. All listings and tables will be 
presented by treatment group. Safety summary tables will include only data from the on-
treatment period (i.e. starting from the time point of first administration of the study 
medications) with the exception of baseline data which will also be summarized where 
appropriate (e.g. change from baseline summaries). 
Safety endpoints for Study Treatment Period 1: 
PI

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• Patient incidence of AEs by system organ class and preferred term 
• Fracture rates of any vertebral, nonvertebral, hip and all fractures will be summarized 
descriptively by treatment. Rates will be calculated for the number of fractures per patients 
and the number of patients with at least one fracture. 
• Number of patients and incidence of fractures 
• Number and grade of injection site reactions 
• Changes from baseline in laboratory assessments (serum chemistry and hematology) and 
the shift between baseline and the worst value between baseline and completion of Week 
52 
• Changes from baseline in vital signs 
• Summary of abnormal ECG values 
• Patient incidence of antibodies to the study medications 
Safety endpoints for Study Treatment Period 2:  
• Patient incidence of AEs by system organ class and preferred terms 
• Fracture rates of any vertebral, nonvertebral, hip and all fractures will be summarized 
descriptively by treatment. Rates will be calculated for the number of fractures per 
patients and the number of patients with at least one fracture. 
• Number of patients and incidence of fracture 
• Number and severity of injection site reactions 
• Changes from baseline in laboratory assessments (serum chemistry and hematology) and 
the shift between start of Week 52 to completion of Week 78 and the worst value within 
this period 
• Changes from baseline in vital signs 
• Summary of abnormal ECG values 
• Patient incidence of antibodies to the study medications within this period 
Adverse events 
All information obtained on AEs will be displayed by treatment group and patients. 
The number (and percentage) of patients with treatment emergent AEs (events started after the 
first dose of study medication or events present prior to start of double-blind treatment but 
increased in severity) based on preferred term will be summarized in the following ways: 
• by treatment group, primary system organ class and preferred term. 
• by treatment group, primary system organ class, preferred term and maximum severity 
Separate summaries will be provided for study medication related AEs, SAEs, and AEs leading 
to study discontinuation. 
A patient with multiple AEs within a primary system organ class is only counted once towards 
the total of the primary system organ class. 
There is no planned statistical testing in the safety analyses. 

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Listing of death, SAEs, AEs leading to study drug discontinuation, AEs leading to study 
discontinuation and study drug related AEs will be provided.  
Vital signs 
Summary statistics will be provided by treatment group and visit. 
Clinical laboratory evaluations 
All abnormal clinically relevant laboratory data will be listed by treatment group, patient, and 
visit. Summary statistics of relevant laboratory parameters will be provided by treatment group 
and visit either numerically or graphically. 
Shift tables using the low/ normal/ high (low and high) classification will be used to compare 
baseline to the worst on-treatment value for relevant laboratory parameters. 
12-lead ECG 
Summary statistics of number of patients with clinically significant ECG abnormalities will be 
provided by visit. 
Immunogenicity  
The incidence of patients who develop binding and neutralizing anti-drug antibodies (ADAs) 
by visit will be compared descriptively 
12.6.3 
Pharmacokinetics 
Descriptive summary statistics of drug serum concentrations will be provided by treatment 
group and visit/ sampling time point. 
Concentrations below LLOQ will be treated as zero in summary statistics. Geometric means 
will not be reported if there are values below the limit of quantification. Summary statistics will 
be presented at each visit, as well as a summary figure of mean concentrations over time by 
treatment group. 
The bioequivalence of the secondary PK endpoints AUCinf and Cmax (EMA) will be assessed 
descriptively by calculating ratios of the geometric means and 90% CIs. 
The analyses will be performed on the PKS.  
12.6.4 
Pharmacodynamics 
The bioequivalence of the secondary PD endpoint (FDA/ PMDA) will be assessed in the same 
way as the primary PD endpoint as described in Section 12.5.2.2. The assessment of 
bioequivalence will be based upon the CIs (90% for FDA and 95% for PMDA) of the ratio of 
the geometric means (test/reference) for the AUEC of %CfB in serum CTX concentrations after 
first dose, which have to be contained entirely within the pre-specified acceptance interval of 
[0.80, 1.25]. 
For Treatment Period 1 (Day 1 to Week 52) CTX and procollagen I N-terminal propeptide 
(PINP) serum concentrations values will be analyzed descriptively per scheduled visit until 
completion of Week 52. 
These analyses will be performed on the PDS. 

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For Treatment Period 2 (Week 52 to Week 78) CTX and PINP serum concentrations values will 
be analyzed descriptively per scheduled visit between the start of Week 52 and completion of 
Week 78. This will be performed for the TP2 FAS. 
Serum CTX concentrations below LLOQ will be treated as LLOQ in summary statistics. 
12.7 
Interim analyses 
Timing and purpose of data analyses is described in Section 4.4. 
The interim analysis at Week 52 will include all formal testing of the primary endpoints with 
full alpha level and will compare GP2411 with Prolia. The interim analysis will allow for an 
early read-out of primary endpoint analyses while maintaining the blind for study personnel 
involved in the active conduct of the study. 
The final analysis at Week 78 will include data collected from Week 52, after half of the patients 
in the Prolia arm transitioned to GP2411, until the end of the study at Week 78. The final 
analysis will compare the three groups “Continued GP2411”, “Continued Prolia” and 
“transition into GP2411” and will be descriptive only with no impact on primary analyses 
completed at Week 52. The number of patients in the three groups in Treatment Period 2 are 
expected to be in the approximate ratio 2:1:1 respectively. The CSR for the final analysis at 
Week 78 will be cumulative and also include the primary analysis from Week 52. 
12.8 
Sample size calculation 
The required sample size was calculated using SAS 9.4. 
12.8.1 
Assumptions of sample size calculation 
The calculations were based on the following assumptions. 
Table 12-9 
Assumptions for sample size calculation 
Endpoint 
%CfB in LS-BMD 
AUEC of %CfB CTX 
AUCinf 
Cmax 
Assumed distribution 
LS-BMD ~ 
Normal 
log(AUEC) ~ Normal 
log(AUCinf) 
~ Normal 
log(Cmax) ~ 
Normal 
Assumed variation 
SD = 4.08% 
CV = 21.4% 
CV = 33.5% 
CV= 33.1% 
Expected difference 
between treatments 
0% 
5% 
5% 
5% 
Correlation coefficient 
between the endpoints 
0.6* 
0.5** 
* Correlation between %CfB of LS-BMD and log(AUEC) 
** Correlation between log(AUCinf) and log(Cmax) 
The correlation between the PK parameters and the PD/ efficacy parameters is assumed to be 
zero. Most likely there is a correlation between PK and PD endpoints but it is difficult to 
estimate the value a-priori and setting it to zero leads to a conservative estimate of the power. 
The SD for %CfB in LS-BMD by the end of 52 weeks of treatment is estimated as pooled SD 
over 3 published clinical trials, see Table 12-10. 

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Table 12-10 
%CfB in LS-BMD at 12 months for denosumab 60 mg compared to 
placebo in three published clinical trials 
i 
Study 
Denosumab 
 
Placebo 
𝑛𝑛1𝑖𝑖 
Sample 
mean [𝑥𝑥1𝑖𝑖] 
Sample 
SD [𝑠𝑠1𝑖𝑖] 
 
𝑛𝑛2𝑖𝑖 
Sample 
mean [𝑥𝑥2𝑖𝑖] 
Sample 
SD [𝑠𝑠2𝑖𝑖] 
1 
FREEDOM (Cummings 
et al 2009) 
232 
5.5 
3.88 
 
209 
0 
3.69 
2 
McClung et al 2006 
41 
4.6 
3.01 
40 
-0.8 
3.04 
3 
DEFEND 
(Bone et al 2008) 
163 
4.5 
4.56 
163 
-0.6 
3.9 
 
Pooled 
 
 
4.08* 
 
 
 
 
* calculated as ඥ(∑(𝑛𝑛1𝑖𝑖−1)𝑠𝑠1𝑖𝑖
2
𝑖𝑖
) (∑𝑛𝑛1𝑖𝑖
𝑖𝑖
−3)
⁄
 
The CVs of the AUCinf, Cmax and AUEC of baseline corrected serum CTX (% change from 
baseline) were derived from simulations using a published denosumab population PK/ PD 
model by Amgen (Sutjandra et al 2011, Zheng et al 2015) generated from a simulation study 
based on Prolia data. The correlation between Cmax and AUCinf is an assumption and the true 
value of the correlation is likely to be higher. However, again this leads to a conservative 
estimate of the power.  
The sample size was calculated for both the FDA, and combined EMA/ PMDA requirement in 
a joint calculation, i.e. the statistical power of meeting all co-primary endpoints was considered. 
12.8.2 
Margin derivation for %CfB in LS-BMD 
Margin derivation is based on the same 3 published clinical trials as for the estimate of SD 
of %CfB in LS-BMD (see Table 12-10) and has been agreed with FDA, EMA and PMDA as 
appropriate. Information used in the meta-analysis to derive the margins are presented in 
Table 12-11. 
Table 12-11 
Meta-analysis of treatment effects of denosumab - placebo 
i 
Study 
Mean difference 
[𝑥𝑥𝑑𝑑𝑑𝑑] 
Variance of mean difference 
[𝑣𝑣𝑑𝑑𝑑𝑑]^ 
Weight 
[𝑤𝑤𝑖𝑖= 1 𝑣𝑣𝑑𝑑𝑑𝑑
⁄
] 
1 
FREEDOM trial 
(Cummings et al 2009) 
5.5 
0.1308 
7.6479 
2 
McClung et al 2006 
5.35 
0.4519 
2.2131 
3 
DEFEND trial 
(Bone et al 2008) 
5.1 
0.2209 
4.5269 
 
Overall weighted 
average 
5.35* 
0.0695** 
  
^ calculated as 
(𝑛𝑛1𝑖𝑖−1)𝑠𝑠1𝑖𝑖
2 +(𝑛𝑛2𝑖𝑖−1)𝑠𝑠2𝑖𝑖
2  
𝑛𝑛1𝑖𝑖+𝑛𝑛2𝑖𝑖−2
× ቀ
1
𝑛𝑛1𝑖𝑖+
1
𝑛𝑛2𝑖𝑖ቁ with 𝑛𝑛1𝑖𝑖, 𝑛𝑛2𝑖𝑖, 𝑠𝑠1𝑖𝑖, 𝑠𝑠2𝑖𝑖 as defined in Table 12-10 
* calculated as ∑
𝑤𝑤𝑖𝑖𝑥𝑥𝑑𝑑𝑑𝑑
3
𝑖𝑖=1
∑
𝑤𝑤𝑖𝑖
3
𝑖𝑖=1
⁄
 applying inverse variance weighting 
** calculated as ∑
𝑤𝑤𝑖𝑖
2𝑣𝑣𝑑𝑑𝑑𝑑
3
𝑖𝑖=1
(∑
𝑤𝑤𝑖𝑖
3
𝑖𝑖=1
)2
⁄
= 1 ∑
𝑤𝑤𝑖𝑖
3
𝑖𝑖=1
⁄
 
Therefore, the point estimate of the difference in treatment effects is 5.35% with 95% CI 
(4.83%, 5.87%). 

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The lower bound of the 95% CI is used to justify an appropriate margin: 
• A margin of 1.45% retains at least 70% of the minimum treatment effect (FDA approach) 
• A margin of 2.00% retains more than 50% of the minimum treatment effect (EMA and 
PMDA approach) 
12.8.3 
Combined sample size calculation 
Table 12-12 shows the requirements for the combined testing of all co-primary endpoints for 
FDA, EMA and PMDA. Estimation of variability for each endpoint is shown in Table 12-9. 
Table 12-12 
Testing specifications for combined requirements 
Requirement 
FDA %CfB in LS-
BMD1 
EMA AUEC 
of %CfB CTX 
PMDA AUCinf 
PMDA Cmax 
Equivalence margin 
(-1.45%, +1.45%) 
(80%, 125%) 
(80%, 125%) 
(80%, 125%) 
Expected difference 
between treatments 
0% 
5% 
5% 
5% 
 
Power for each 
endpoint 
90.4% 
> 99.9% 
>99.9% 
>99.9% 
Two-sided alpha 
level 
5% 
5% 
10% 
10% 
Drop-out rate 
15% for FAS 
1. The FDA for %CfB in LS-BMD requirement is more stringent and hence EMA and PMDA 
requirement are not shown. 
100,000 samples of sample size of 418 evaluable patients (209 evaluable patients per arm) were 
generated from a multivariate normal distribution as defined in Table 12-9 leading to a sample 
size of 492 patients (246 per arm). Using the testing requirements defined in Table 12-12 each 
co-primary endpoint was tested for each random sample. If all four tests were passed then the 
sample was a success. The overall power was estimated as the percentage of successes out of 
the 100,000 random samples.  Using the above simulation a power of 90.4% for simultaneously 
passing all the equivalence tests for the co-primary endpoints was obtained. 
Treatment Period 2 
The analysis of the Treatment Period 2 is only descriptive and therefore no formal sample size 
calculation is conducted for the Treatment Period 2. 
12.8.4 
Supplementary analysis of primary endpoint 
With a sample size of 492, assuming a drop-out rate of 25%, the power of the supplementary 
analysis for %CfB in LS-BMD for PPS using a (-1.45%, 1.45%) margin can be estimated to be 
85.0%. However, with the expectation to observe a lower SD for PPS the power might be higher 
than 85.0%. 

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13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/ institution must obtain approval/ favorable opinion 
from the Institutional Review Board/ Independent Ethics Committee (IRB/ IEC) for the trial 
protocol, written informed consent form, consent form updates, patient recruitment procedures 
(e.g., advertisements) and any other written information to be provided to patients. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/ her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
sponsor monitors, auditors, sponsor Quality Assurance representatives, designated agents of the 
sponsor, IRBs/ IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform the sponsor immediately 
that this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT (European Union Drug Regulating Authorities Clinical Trials database). 
In addition, after study completion (defined as last patient last visit) and finalization of the study 
report the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.). 
For details on the sponsor publication policy including authorship criteria, please refer to the 
sponsor publication policy training materials that were provided to you at the trial investigator 
meetings. 
Any data analysis carried out independently by the investigator should be submitted to the 
sponsor before publication or presentation. 
13.4 
Quality control and quality assurance 
Sponsor maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures (SOP) as well as applicable global/ local GCP regulations and ICH 
Guidelines. 
Audits of investigator sites, vendors, and sponsor systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/ risk based approach. 

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Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written sponsor processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to the 
sponsor and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by the sponsor 
and approved by the IRB/ IEC and health authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the sponsor, health authorities where required, and the IRB/ IEC prior to 
implementation. 
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/ IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the sponsor 
should be notified of this action and the IRB/ IEC at the study site should be informed according 
to local regulations. 

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15 
References 
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Appendices 
Not applicable.