A Randomized, Double-blind, Parallel-group, Active-controlled Study to Compare the Efficacy, Safety, Pharmacodynamics, Pharmacokinetics, and Immunogenicity of Enzene Denosumab (ENZ215) and Prolia® in Postmenopausal Women With Osteoporosis
Phase: PHASE3
Conditions: Postmenopausal Osteoporosis
Sponsor: Enzene Biosciences Ltd.

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Title Page 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Parallel-group, 
Active-controlled Study to Compare the Efficacy, Safety, 
Pharmacodynamics, Pharmacokinetics, and Immunogenicity of Enzene 
Denosumab (ENZ215) and Prolia® in Postmenopausal Women with 
Osteoporosis 
Brief Title:  
A Phase 3 Study to Compare Enzene Denosumab (ENZ215) and 
Prolia® in Postmenopausal Women with Osteoporosis 
Compound: 
Enzene Denosumab (ENZ215) 
Indication: 
Postmenopausal Osteoporosis 
Study Sponsor: 
Alkem Laboratories Ltd. 
ALKEM HOUSE, “Devashish”, 
Adjacent to Matulya centre,  
Senapati Bapat Marg,  
Lower Parel, Mumbai, India–400 013 
Telephone: +91-22-39829999 
Co-Sponsor 
Enzene Biosciences Ltd.  
Plot No. A-22/A/1/2, 
MIDC Chakan Industrial Area, 
Phase II, Vill-Khalumbre, Taluka Khed,  
Pune-410 501, Maharashtra, India 
Phone: +91-20-30674622 
Protocol Number: 
ALK22/ENZ215-DEN2 
Study Phase: 
Phase 3 
EUDRACT Number: 2021-004811-26 
Version: 
3.0 
Approval Date: 
Final: 16 February 2023 
 
 

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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Amendment Scope 
Protocol Version 
Date 
Amendment 3 
Global 
Version 3.0  
16 February 2023 
Amendment 2 
Global 
Version 2.0 
08 April 2022 
Amendment 1 
Global 
Version 1.1 
16 December 2021 
Original Protocol 
Not Applicable 
1.0 
22 October 2021 
 
Amendment 3.0 (16 February 2023) 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study. 
Overall Rationale for the Amendment: 
The Global clinical study protocol (CSP) Amendment 3.0 was prepared  to add clarifications and 
update typo errors noted in earlier version of the document. 
Other improvements, such as updates to summary of protocol amendment are not presented in 
this summary. 
Section 
Description of Change 
 
Brief Rationale 
Section 1 Protocol Summary 
- Synopsis 
Section 3: Objectives and 
Endpoints 
Secondary Pharmacokinetics 
Endpoint updated as:  Serum 
Concentrations PK 
Parameters (Cmax, Tmax, 
partial AUC(0-28 days 0-1 month), 
and AUC(0-6 month)) and 
AUC(0-inf))of denosumab 
measured at baseline 
(Day 1), Day 8, Day 15, 
Month 1, Month 3, Month 6 
Typographic error: Replaced 
Serum Concentrations with 
PK parameters as these are 
PK parameters, not Serum 
concentrations.  
The AUC(0-inf)) is removed 
from analysis as there are 
limited PK sample points in 

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(prior to second dose), and 
Month 12. 
Terminal phase and it is not 
possible to derive AUC(0-inf)). 
AUC(0-28 days) is made AUC(0–
1 month) to make it consistent 
with Protocol Schedule of 
assessment. 
Table 1.1 Schedule of 
Activities,  
Section 8 Study Assessments 
and Procedures: Visit 2, Visit 
7 and Visit 9 
Section 8.2.3 Injection site 
reaction 
Corrected Injection site 
reaction monitoring after IP 
administration as at least for 
up to one hour 
Injection site reaction 
monitoring is required at 
least for one hour post 
dosing, the wording up to 
one hour was misleading 
thus the same was updated 
Table 1.1 Schedule of 
Activities,  
Section 8: Study 
Assessments and Procedures 
Added DXA at Early 
Termination visit if done 
after Month 6 and prior to 
Month 12  
To have DXA assessments 
for subjects who have 
discontinued post Month 6 
and prior to Month 12 
Table 1.1 Schedule of 
Activities,  
Section 8 – Study 
Assessments and Procedures  
Screening (day -35 to day -1) 
Month 12 (±7 days)  
Month 18//EOS / Early 
Discontinuation Withdrawal 
(±7 days) 
Lateral lumbar spine X-ray 
replaced with Lateral thoracic 
and lumbar spine X-ray 
X-ray imaging site 
mentioned is corrected and 
made consistent with image 
acquisition guideline by 
Calyx. 
Table 1.1 Schedule of 
Activities 
 
Updated Instruction # 4 in 
footer as 
“ A written, signed and dated 
re-consent form should be 
obtained from patients who 
volunteer to participant in the 
open-label, switch-over study 
until Month 18.  
To clarify requirement of 
reconsenting at Month 12 for 
participation in Extension 
study. 

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A written, signed and dated 
consent should also be 
obtained from those 
subjects who previously at 
visit 1 did not consent but 
now at visit 9 have shown 
interest to continue their 
participation in to the 
open-label, switch-over 
study.” 
Table 1.1 Schedule of 
Activities 
Deleted below instructions 
for “Blood sample collection 
for testing of TSH and iPTH 
should be done at early 
morning.” 
As there is no specific 
requirement or instruction 
for testing TSH and iPTH 
from the central lab. 
Table 1.1 Schedule of 
Activities 
Updated instruction # 21 as 
“Only Serum calcium levels 
will be tested on Day 15 for 
all patients”. 
Updated Instruction # 24 as 
‘Serum calcium levels can 
will be tested locally prior to 
dosing at Month 6 and 
Month 12. This can either be 
done on the same day as the 
dosing visit or at a separate 
unscheduled visit if required 
per local standard of care. If 
hypocalcemia is identified, 
the patient should not be 
dosed until calcium levels 
are corrected. In case the 
serum Calcium assessments 
are performed via the 
Central Lab, all lab 
samples required for the 
impending visit can be 
collected on the same day 
of Calcium assessment, 
provided the sample 
collection date is within the 
window period for the visit. 
To clarify the Lab Sample 
collection at Month 6 and 
Month 12  
 
 
 
 
Section 5.1 Inclusion Criteria 
7 
Inclusion Criteria 7 updated 
as ‘No other clinically 
significant medical history, 
To add clarification 

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vital signs, physical 
examination, laboratory 
profiles as deemed by the 
Investigator or designee that 
would pose a risk to 
participant safety or 
interfere with the study 
evaluation, procedures or 
completion’ 
Section 5.2 Exclusion 
Criteria 5 
Exclusion Criteria 5 updated 
as: Use of intravenous 
bisphosphonates within the 
past 5 years prior to 
screening. Added note If 
used more than 5 years 
prior, patients will be 
excluded if cumulative use 
was > 3 years. 
To clarify subjects with 
cumulative use of 
bisphosphonates for more 
than 3 years to be excluded. 
Section 5.2 Exclusion 
Criteria 6 
Exclusion Criteria #6 
updated as ‘Use of 
parathyroid hormone or its 
derivatives, systemic 
hormone replacement 
therapy, romosozumab, 
selective estrogen-receptor 
modulators, or tibolone or 
calcitonin within 12 months 
prior to enrollment’ 
Added Note: occasional use 
of intravaginal estrogen 
treatment is not 
exclusionary 
Added romosozumab history 
as exclusion considering 
impact of its use on bone 
metabolism, 
To clarify continuous non 
systemic use of Hormone 
replacement therapy is also 
exclusion and occasional use 
of intravaginal estrogen 
treatment is not exclusion 
Section 5.2 Exclusion 
Criteria 9 
Exclusion Criteria updated as 
‘Other bone active drugs (i.e. 
drugs affecting bone 
metabolism) including 
heparin, anti-epileptics 
(except for benzodiazepines 
and pregabalin), 
antidepressants such as 
SSRIs, SNRIs, 
antipsychotics, systemic 
ketoconazole, 
adrenocorticotrophic 
The 
criteria 
have 
been 
updated in order to make it 
consistent with section 6.11 – 
Prohibited Medications of the 
protocol. 

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hormone (ACTH), lithium, 
protease inhibitors, 
gonadotropin releasing 
hormone (GnRH) agonists, 
or anabolic steroids within 
the past 3 months prior to 
screening or requiring 
treatment with these agents 
during the study. 
Added Note: Please refer to 
Section 6.11 for a 
comprehensive list of 
prohibited medications 
Section 5.2 Exclusion 
Criteria 20 
Significantly impaired renal 
function (determined by 
glomerular filtration rate of 
≤ 45 mL/min/1.73m2 < 45 
mL/min/1.73 m2 by the 
Modification of Diet in 
Renal Disease (MDRD) 
formula, as calculated by the 
central laboratory) or 
receiving dialysis 
corrected as it was typo error 
Section 5.2 Exclusion 
Criteria 24 
Updated exclusion criteria 
#24 as 
 Patient with an active 
infection or history of 
infection as follows: 
a. 
Any active infection 
for which systemic 
anti-infectives were 
used within 4 weeks 
prior to screening 
randomization 
b. A serious infection 
defined as requiring 
hospitalization or 
intravenous 
anti-infectives 
Updated as it was typo error 

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within 8 weeks 
prior to screening 
randomization 
c. 
Recurrent or 
chronic infections 
or other active 
infection that, in the 
opinion of the 
Investigator, might 
compromise the 
safety of the patient 
Section 6: Study 
Interventions and 
Concomitant Therapy 
Updated Calcium as 
elementary Calcium 
updated 
for 
better 
understanding 
Section 6.11 Prohibited 
Medications  
Deleted Raloxifen and 
Bazedoxifen 
Added Romosozumab to 
prohibited medications list 
Updated Antidepressants as 
selective serotonin reuptake 
inhibitors (SSRIs) as well as 
Serotonin and 
norepinephrine reuptake 
inhibitors (SNRIs) 
Antipsychotics made as a 
separate bullet, which was 
earlier specified under anti-
depressants  
As those are covered under 
class 
selective 
estrogen-
receptor modulators listed as 
prohibited medication 
To Specify SNRIs are also 
prohibited along with SSRIs 
To specify antipsychotics as it 
is a different class of drug 
from antidepressants 
Section 8.2.1 Physical 
Examinations 
Updated Brief Physical 
Examination with below 
line: Weight will also be 
measured and recorded at 
least 3 monthly i.e. at Visit 
6, 7, 8, 9, 10, and 11. 
Added body weight under 
brief physical examination 
that was missed to mention 
earlier. 
Section 8.2.2 Vital Signs 
The following text: “Oral 
temperature, heart rate, 
respiratory rate, and blood 
pressure will be assessed” 
This change is performed to 
allow other sites for body 
temperature measurement 
i.e., axillary, tympanic, 

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has been updated to “Body 
temperature, heart rate, 
respiratory rate, and blood 
pressure will be assessed.” 
temporal artery, rectal etc 
inorder to avoid any potential 
risk of infection such as 
COVID-19 infection 
Section 9.3.2 Primary 
Pharmacodynamic Analysis 
The CI for Primary 
Pharmacodynamic analysis is 
updated as 90% instead of 
95%. 
The assessment of 
equivalence for the co-
primary endpoint will be 
assessed based upon the 
90% CI of the ratio of the 
geometric mean 
(test/reference) for the 
percentage change from 
baseline in AUEC sCTX 
over the initial 6 Months 
contained within the pre-
specified acceptance limits 
of 80% to 125%.  
 
 sCTX is a highly variable 
parameter with a high inter 
subject variability hence 
90% CI limits considered for 
assessment of equivalence 
instead of 95% CI   
Section 10.2 Appendix  
Deleted Instructions ‘Local 
urine testing will be standard 
for the protocol unless serum 
testing is required by local 
regulation or IRB/IEC.’ 
 
Deleted this point as it is a 
typo error 
 

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Table of Contents 
Title Page ........................................................................................................................................ 1 
Table of Contents .......................................................................................................................... 10 
List of Tables ................................................................................................................................. 13 
List of Figures ............................................................................................................................... 14 
1 
Protocol Summary .................................................................................................................. 15 
1.1 
Synopsis .............................................................................................................................. 15 
1.2 
Schema ............................................................................................................................... 19 
1.3 
Schedule of Activities ......................................................................................................... 20 
2 
Introduction............................................................................................................................. 26 
2.1 
Study Rationale .................................................................................................................. 26 
2.2 
Background......................................................................................................................... 26 
2.2.1 
Non-clinical Data of Innovator Denosumab ................................................................... 27 
2.2.2 
Clinical Data of Prolia® .................................................................................................. 27 
2.2.2.1 
Effect on Vertebral Fractures ...................................................................................... 28 
2.2.2.2 
Effect on Hip Fractures ............................................................................................... 28 
2.2.2.3 
Effect on Nonvertebral Fractures ................................................................................ 29 
2.2.2.4 
Effect on Bone Mineral Density ................................................................................. 29 
2.2.2.5 
Bone Histology and Histomorphometry ..................................................................... 29 
2.2.3 
SARS-CoV-2 .................................................................................................................. 30 
2.3 
Benefit/Risk Assessment .................................................................................................... 30 
2.3.1 
Risk Assessment ............................................................................................................. 30 
2.3.2 
Benefit Assessment ......................................................................................................... 33 
2.3.3 
Risk Assessment for COVID-19 Pandemic .................................................................... 33 
2.3.4 
Overall Benefit/Risk Conclusion .................................................................................... 34 
3 
Objectives and Endpoints ....................................................................................................... 34 
4 
Study Design ........................................................................................................................... 36 
4.1 
Overall Design .................................................................................................................... 36 
4.2 
Scientific Rationale for Study Design ................................................................................ 38 
4.3 
Justification for Dose .......................................................................................................... 38 
4.4 
End of Study Definition...................................................................................................... 38 
5 
Study Population ..................................................................................................................... 39 
5.1 
Inclusion Criteria ................................................................................................................ 39 

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5.2 
Exclusion Criteria ............................................................................................................... 39 
5.3 
Lifestyle Considerations ..................................................................................................... 43 
5.3.1 
Activity ........................................................................................................................... 43 
5.4 
Screen Failures ................................................................................................................... 43 
5.4.1 
Screening and Enrollment Log and Patient Identification Numbers .............................. 43 
5.5 
Criteria for Temporarily Delaying Enrollment/Randomization/Administration of Study 
Intervention......................................................................................................................... 44 
6 
Study Interventions and Concomitant Therapy ...................................................................... 44 
6.1 
Study Interventions Administered ...................................................................................... 44 
6.1.1 
Calcium and Vitamin D supplementation ....................................................................... 46 
6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 46 
6.3 
Retrieval of Study Interventions ......................................................................................... 47 
6.4 
Unused Study Interventions ............................................................................................... 48 
6.5 
Measures to Minimize Bias: Randomization and Blinding ................................................ 48 
6.5.1 
Randomization ................................................................................................................ 48 
6.5.2 
Blinding .......................................................................................................................... 48 
6.6 
Study Intervention Compliance .......................................................................................... 49 
6.7 
Dose Modification .............................................................................................................. 49 
6.8 
Continued Access to Study Intervention After the End of the Study ................................. 50 
6.9 
Treatment of Overdose ....................................................................................................... 50 
6.10 Concomitant Therapy ......................................................................................................... 50 
6.11 Prohibited Medications ....................................................................................................... 51 
7 
Discontinuation of Study Intervention and Patient Discontinuation ...................................... 52 
7.1 
Discontinuation of Study Intervention ............................................................................... 52 
7.2 
Patient Discontinuation/Withdrawal from the Study .......................................................... 52 
7.3 
Loss to Follow-up ............................................................................................................... 54 
8 
Study Assessments and Procedures ........................................................................................ 54 
8.1 
Efficacy Assessments ......................................................................................................... 63 
8.2 
Safety Assessments ............................................................................................................. 63 
8.2.1 
Physical Examinations .................................................................................................... 63 
8.2.2 
Vital Signs ...................................................................................................................... 64 
8.2.3 
Injection site reaction ..................................................................................................... 64 
8.2.4 
Electrocardiograms ......................................................................................................... 64 

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8.2.5 
Clinical Safety Laboratory Tests .................................................................................... 64 
8.3 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting ..... 66 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 66 
8.3.2 
Method of Detecting AEs and SAEs .............................................................................. 67 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 67 
8.3.4 
Regulatory Reporting Requirements for SAE ................................................................ 67 
8.3.5 
AEs of Special Interest ................................................................................................... 68 
8.4 
Pharmacokinetics ................................................................................................................ 68 
8.5 
Pharmacodynamics ............................................................................................................. 68 
8.6 
Genetics .............................................................................................................................. 69 
8.7 
Biomarkers ......................................................................................................................... 69 
8.8 
Immunogenicity Assessments ............................................................................................ 69 
9 
Statistical Considerations........................................................................................................ 70 
9.1 
Statistical Hypotheses ......................................................................................................... 70 
9.1.1 
Multiplicity Adjustment .................................................................................................. 70 
9.2 
Analysis Sets ...................................................................................................................... 70 
9.3 
Statistical Analyses ............................................................................................................. 71 
9.3.1 
General Considerations .................................................................................................. 71 
9.3.2 
Primary Endpoint Analysis ............................................................................................. 71 
9.3.3 
Secondary Endpoint(s) Analysis ..................................................................................... 72 
9.3.3.1 
Efficacy Endpoints ...................................................................................................... 72 
9.3.3.2 
Safety Endpoints ......................................................................................................... 73 
9.3.3.3 
Pharmacokinetics Endpoints ....................................................................................... 73 
9.3.4 
Safety Analyses .............................................................................................................. 73 
9.3.5 
Other Analyses ................................................................................................................ 73 
9.4 
Interim Analyses ................................................................................................................. 73 
9.5 
Sample Size Determination ................................................................................................ 74 
10 Supporting Documentation and Operational Considerations ................................................. 75 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 75 
10.1.1 
Regulatory and Ethical Considerations .......................................................................... 75 
10.1.2 
Financial Disclosure ....................................................................................................... 75 
10.1.3 
Responsibilities of Investigators ..................................................................................... 76 
10.1.4 
Responsibilities of Sponsor and Study Management ..................................................... 76 
10.1.5 
Informed Consent Process .............................................................................................. 77 
10.1.6 
Patient and Data Confidentiality .................................................................................... 78 

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10.1.7 
Committees Structure ..................................................................................................... 78 
10.1.7.1 
Data Monitoring Committee ....................................................................................... 78 
10.1.8 
Dissemination of Clinical Study Data ............................................................................ 78 
10.1.9 
Auditing and Inspection ................................................................................................. 79 
10.1.10 Data Quality Assurance .................................................................................................. 79 
10.1.11 Record Retention ............................................................................................................ 81 
10.1.12 Source Documents .......................................................................................................... 81 
10.1.13 Study and Site Start and Closure .................................................................................... 81 
10.1.14 Publication Policy ........................................................................................................... 82 
10.1.15 Protocol Approval and Amendment ............................................................................... 83 
10.1.16 Protocol Deviations and Violations ................................................................................ 83 
10.1.17 Liability and Insurance ................................................................................................... 84 
10.1.18 Property Rights and Data Protection .............................................................................. 84 
10.2 Appendix 2: Clinical Laboratory Tests ............................................................................... 85 
10.3 Appendix 3: Total blood loss .............................................................................................. 87 
10.4 Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................... 88 
10.4.1 
Definition of AE ............................................................................................................. 88 
10.4.2 
Definition of SAE ........................................................................................................... 89 
10.4.3 
Recording and Follow-up of AE and SAE ..................................................................... 90 
10.4.4 
Reporting of SAE ........................................................................................................... 92 
10.5 Appendix 7: Abbreviations ................................................................................................. 94 
10.6 Appendix 8: Protocol Amendment History ........................................................................ 96 
11 References............................................................................................................................... 97 
Investigator Agreement Page ........................................................................................................ 98 
 
List of Tables 
Table 1-1 
Schedule of Activities ........................................................................................... 21 
Table 2-1 
Effect of Prolia® on the Incidence of New Vertebral Fractures in Postmenopausal 
Women .................................................................................................................. 28 
Table 2-2 
The Effect of Prolia® on the Incidence of Nonvertebral Fractures at Year 3 in 
Postmenopausal Women ....................................................................................... 29 
Table 2-3 
Risk Assessment.................................................................................................... 31 
Table 3-1 
Objectives and Endpoints ..................................................................................... 34 

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Table 6-1 
Study Interventions Administered......................................................................... 45 
Table 10-1 
Protocol-required Safety Laboratory Tests ........................................................... 85 
 
List of Figures 
Figure 1–1 
Study Design ......................................................................................................... 19 
 
 
 

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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A Phase 3, Randomized, Double-blind, Parallel-group, Active-controlled Study 
to Compare the Efficacy, Safety, Pharmacodynamics, Pharmacokinetics and Immunogenicity of 
Enzene Denosumab (ENZ215) and Prolia® in Postmenopausal Women with Osteoporosis 
Brief Title: A Phase 3 Study to Compare Enzene Denosumab (ENZ215) and Prolia® in 
Postmenopausal Women with Osteoporosis 
Sponsor Protocol No.: ALK22/ENZ215-DEN2 
Study Phase: Phase 3 
Sponsor: Alkem Laboratories Ltd. 
Co-Sponsor: Enzene Biosciences Ltd. 
Rationale: 
Biologics are relatively new and expensive drugs. Even though the use of biologics has enabled 
great advances in the treatment of numerous diseases, their high cost has a direct impact on their 
access and on healthcare budget around the world. Biosimilar medicines are similar to original 
biologics and are available at lower costs. 
Denosumab (ENZ215), the proposed biosimilar to Prolia®, is a monoclonal antibody which is 
structurally and functionally similar to Prolia®. This study plans to compare equivalence of 
ENZ215 (test product) to Prolia® (reference product) in terms of efficacy, safety, and 
immunogenicity in postmenopausal women with osteoporosis. 
Development of ENZ215 will involve extensive structural and functional characterization 
followed by non-clinical testing, human pharmacokinetics (PK), and pharmacodynamics (PD) 
studies, and clinical immunogenicity assessment. If there is residual uncertainty, additional 
comparative clinical studies will be required to support demonstration of biosimilarity. 

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Objectives and Endpoints: 
Co-primary Efficacy Objectives 
Co-Primary Efficacy Endpoints 
• To evaluate the efficacy of ENZ215 when 
compared to Prolia® in patients with 
postmenopausal osteoporosis, in terms of 
change in bone mineral density (BMD) at 
lumbar spine from baseline to Month 12 
• Percentage change in BMD at lumbar 
spine (L1-L4 region) measured by 
dual-energy X-ray absorptiometry (DXA) 
from baseline to Month 12 
• To compare the area under the effect 
curve (AUEC) of serum C-telopeptide of 
Type-1 collagen (sCTX) levels from 
baseline to Month 6 
• AUEC of sCTX over the initial 6 months 
(from Day 1 pre-dose to Month 6 
pre-dose) 
Secondary Efficacy Objectives 
Secondary Efficacy Endpoints 
• To compare the change in serum 
procollagen type 1 N-terminal propeptide 
(sP1NP) levels from baseline to Month 6 
• Percentage change in sP1NP 
concentrations from baseline to Month 1, 
Month 3, and Month 6 
• To compare the change in BMD at the 
lumbar spine from baseline to Month 6 
• Percentage change in BMD at lumbar 
spine measured by DXA from baseline to 
Month 6 
• To compare the change in BMD at total 
hip and femoral neck from baseline to 
Month 6 and Month 12 
• Percentage change in BMD at total hip 
and femoral neck measured by DXA from 
baseline to Month 6 and 12 
Secondary Safety Objectives 
Secondary Safety Endpoints 
• To compare the immunogenicity potential 
of ENZ215 and Prolia® 
• ADAs incidence at baseline (Day 1) and 
Months 1, 3, 6, 9, and 12 and during 
open-label switch over period i.e. 
Months 15 and 18 
• To compare the safety and tolerability of 
ENZ215 and Prolia® 
• Treatment-emergent serious and 
non-serious adverse events (TEAEs) 
during main treatment period and 
open-label switch-over period 
• Alteration in clinical laboratory 
parameters during main treatment period 
and open-label switch-over period 
Secondary Pharmacokinetics Objective 
Secondary Pharmacokinetics Endpoint 
• To compare the pharmacokinetics of 
ENZ215 and Prolia® 
• PK Parameters (Cmax, Tmax, partial AUC(-0-
1 month), and AUC(0-6 month)) of denosumab 
measured at baseline (Day 1), Day 8, 
Day 15, Month 1, Month 3, Month 6 
(prior to second dose), and Month 12 

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Overall Design: 
This is a Phase 3, randomized, double-blind, parallel-group, active-controlled study in 
postmenopausal women with osteoporosis. The double-blind treatment period will be for 12 
months followed by the open-label, switch-over study until Month 18. 
Five hundred four (504) patients (252 patients in each treatment arm) will be enrolled in this 
study. All eligible patients will be randomized in the double-blind treatment period in a 1:1 ratio 
to receive either ENZ215 or Prolia® (60 mg) subcutaneously (SC) on Day 1 and Month 6. Patient 
allocation will be stratified by age (≥ 55 to < 70 years and ≥ 70 to ≤ 85 years) and based on prior 
use of bisphosphonate. 
All patients randomized to the double-blind treatment period (except for a subset of 120 patients, 
as described hereafter) will complete the study at Month 12. A subset of 120 patients initially 
randomized to Prolia® arm will be re-randomized in a 1:1 ratio (i.e. 60 patients in each arm) in 
order to have 100 evaluable patients (i.e. 50 patients in each arm) in an open-label switch-over 
period to receive either ENZ215 or Prolia® (60 mg) SC at Month 12 in order to assess the impact 
on immunogenicity and safety of switching patients from Prolia® to ENZ215. Re-randomization 
will not be stratified. The subset of patients selected for re-randomization to the open-label, 
switch-over study will be patients who complete 12 months of the double-blind treatment period 
without any significant safety concerns as per the Investigator’s discretion and who have 
re-consented for the open-label extension period. These patients will complete the study at 
Month 18. 
For patients receiving ENZ215 or Prolia® and not continuing to the switch-over study, the study 
duration will be approximately 25 months, with a recruitment period of 12 months and a study 
period of 13 months (up to 5 weeks of screening period, 12 months of treatment period). For 
patients receiving Prolia® and who re-consent to continue to participate in the switch-over study, 
the study duration will be approximately 31 months (additional 6 months of open-label 
switch-over study, i.e. until Month 18). 

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Brief Summary: 
Patients will be required to visit the site for the following visits: Visit 1/screening period 
(Day -35 to Day -1), Visit 2/Day 1, Visit 4/Month 1 (Day 15), Visit 5/Month 1 (Day 30), 
Visit 6/Month 3 (Day 90), Visit 7/Month 6 (Day 180), Visit 8/Month 9 (Day 270) and 
Visit 9/Month 12 (Day 360). 
Visit 10/Month 15 (Day 450) and Visit 11/Month 18 (Day 540) will be additional visits to the 
above-mentioned visits for patients initially randomized to receive Prolia® and re-randomized in 
the switch-over study (subset of 120 patients). 
Except on Visit 1 and Visit 2, a window period of ±3 days is allowed on Day 8, Day 15, Day 30 
(Month 1), and Day 90 (Month 3). A window period of ± 7 days is allowed from Month 6 until 
EOS. 
EOS assessment will be performed on Month 12 (±7 days) or Month 18 (±7 days) as applicable 
or at the time of early discontinuation or withdrawal of the patient. 
Note: There will be an additional visit (Visit 3/Day 8) for those patients who provide consent for 
participation in PK sampling. For PK sampling on Day 8 and Day 15, the visit window is ±3 
days but a window period of ± 2 hours is allowed in relation to the time of IP administration on 
Day 1. 
Number of Patients: 
Five hundred four (504) postmenopausal female patients with osteoporosis aged ≥ 55 years and 
≤ 85 years fulfilling the study selection criteria will be enrolled from approximately 60 to 70 
sites (centers) across the European Union. 
Intervention Groups: 
Based on the randomization schedule, the investigational product (IP, either ENZ215 or Prolia®) 
will be administered to the patients at a dose of 60 mg (multiple doses) SC at 6-month intervals 
into the upper thigh. 
In addition, all patients will receive daily supplementation with at least 1 g of calcium and at 
least 400 IU of vitamin D till Month 12 or Month 18, as applicable. Calcium and vitamin D 
supplements will be dispensed to patients starting on Day 1 and at each subsequent study visit to 
be consumed at home daily till Month 12. Vitamin D supplements will be dispensed during the 
screening period, if required, for replenishment of vitamin D deposits. For patients initially 

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randomized to the Prolia® arm and who re-consent to participate in the open-label, switch-over 
study, calcium and vitamin D supplements will be dispensed again at Month 12 for daily 
supplementation until EOS. If a patient becomes hypercalcemic over the course of the study, the 
calcium and/or vitamin D supplementation may be reduced or temporarily discontinued per 
Investigators’ medical judgment until the serum calcium concentration returns to the normal 
range. If a patient develops hypocalcemia over the course of the study, calcium and/or vitamin D 
supplementation may be adjusted per Investigators’ medical judgment until the serum calcium 
concentration returns to the normal range. 
Data monitoring committee 
A data monitoring committee (DMC) has been appointed for this study. The DMC is a group of 
independent scientists who are appointed to monitor the safety of a human research intervention. 
The composition of the committee is dependent upon the scientific skills and knowledge required 
for monitoring this particular study. 
1.2 Schema 
A complete study design is presented in Figure 1–1. 
Figure 1–1 
Study Design 
 
• Double-blind treatment period: The patients will be randomized in a 1:1 ratio to receive 
either ENZ215 or Prolia® (60 mg) administered as a SC injection (i.e. 252 patients in each 
treatment arm). All patients randomized to ENZ215 and all (except a subset of 120 patients) 
patients randomized to Prolia® will complete the study at Month 12. 

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• Open-label switch-over extension period: At Month 12, a subset of 120 patients initially 
randomized to Prolia® arm will be re-randomized to receive either ENZ215 or Prolia® 
(60 mg) in a 1:1 ratio (i.e. 60 patients in each arm) in order to have 100 evaluable patients 
(i.e. 50 patients in each arm) at Month 18. 
1.3 Schedule of Activities 
A complete study visit schedule (schedule of activities [SoA]) is presented in Table 1-1. 
 

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Table 1-1 
Schedule of Activities 
Assessments 
Screening 
Period  
(D -35 to 
D -1) 
Double-blind 
Randomized Main Study (Treatment) Period 
Open 
label 
Switch 
over/ 
Extension 
period 
EOS/ 
Early 
Discontinuation
/ 
Withdrawal1 
D1 
M1 
M3 
M6 
M9 
M12* 
M15 
M12/M18 
Days 
35 days 
1 
82 
15 
30 
90 
180 
270 
360 
450 
540 
Visit window 
N/A 
N/A 
±3 days 
± 7 days 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Informed consent  
PK consent, as applicable 
X3 
 
 
 
 
 
 
 
X4 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination (including 
oro-dental examination)5 
X6 
X6 
X 
X 
X 
X 
X6 
X 
X6 
X 
X 
Medical/surgical history7 
X 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
Current medical conditions  
X 
 
 
 
 
 
 
 
 
 
 
COVID-19 signs and 
symptoms8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
X10 
 
 
12-lead ECG 
X 
 
 
 
 
 
X 
 
X 
 
X 
Patient diary review 
 
X11 
X 
X 
X 
X 
X 
X 
X 
X 
X11 
Investigational product 
administration12 
 
X 
 
 
 
 
X 
 
X 
 
 

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Assessments 
Screening 
Period  
(D -35 to 
D -1) 
Double-blind 
Randomized Main Study (Treatment) Period 
Open 
label 
Switch 
over/ 
Extension 
period 
EOS/ 
Early 
Discontinuation
/ 
Withdrawal1 
D1 
M1 
M3 
M6 
M9 
M12* 
M15 
M12/M18 
Days 
35 days 
1 
82 
15 
30 
90 
180 
270 
360 
450 
540 
Visit window 
N/A 
N/A 
±3 days 
± 7 days 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Injection site reaction 
monitoring after IP 
administration (at least for one 
hour) 
 
X 
 
 
 
 
X 
 
X 
 
 
Calcium and vitamin D 
supplementation13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lateral thoracic and lumbar 
spine X-ray for 
fracture/vertebral abnormality 
assessment 
X 
 
 
 
 
 
 
 
X 
 
X 
25 (OH) vitamin D level14 
X 
 
 
 
 
 
X15 
 
 
 
 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
Thyroid function test (T3, T4, 
TSH) 
X 
 
 
 
 
 
X16 
 
 
 
 
iPTH 
X 
 
 
 
 
 
 
 
 
 
 
DXA lumbar spine, hip and 
femoral neck 
X17 
 
 
 
 
 
X 
 
X 
 
X18 
Hematology19 
X 
 
 
 
 
 
X 
 
X 
 
X 
HIV, HBsAg, HCV 
X 
 
 
 
 
 
 
 
 
 
 
Serum chemistry20 
X 
 
 
X21 
 
X 
X22 
X 
X22 
 
X 
Urinalysis23 
X 
 
 
 
 
X 
X 
X 
X 
 
X 

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Assessments 
Screening 
Period  
(D -35 to 
D -1) 
Double-blind 
Randomized Main Study (Treatment) Period 
Open 
label 
Switch 
over/ 
Extension 
period 
EOS/ 
Early 
Discontinuation
/ 
Withdrawal1 
D1 
M1 
M3 
M6 
M9 
M12* 
M15 
M12/M18 
Days 
35 days 
1 
82 
15 
30 
90 
180 
270 
360 
450 
540 
Visit window 
N/A 
N/A 
±3 days 
± 7 days 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
sCTX24 
 
X 
 
X 
X 
X 
X 
 
 
 
 
sP1NP24 
 
X 
 
X 
X 
X 
X 
 
 
 
 
ADAs 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
PK assessment25 
 
X 
X26 
X26 
X 
X 
X 
 
X 
 
 
AE/SAE recording27 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA = anti-denosumab antibodies, ALP = alkaline phosphatase, ALT = alanine aminotransferase ALT, AST = aspartate aminotransferase, BP = blood pressure, 
BMD = bone mineral density, BUN = blood urea nitrogen, D = day, DXA = dual-energy X-ray absorptiometry, eGFR = estimated glomerular filtration rate, 
ECG = electrocardiogram, EOS = End of Study, FSH = follicle stimulating hormone, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, 
HIV = human immunodeficiency virus, iPTH = intact parathyroid hormone, M = month, PA = posteroanterior, PK = pharmacokinetic, PR = pulse rate, 
RR = respiratory rate, RBC = red blood cells, sCTX = serum C-telopeptide of type 1 collagen, 25 (OH) vitamin D = 25-hydroxy vitamin D, WBC = white blood 
cells 
1. EOS assessment will be performed at Month 12 (±7 days) or Month 18 (±7 days) based on the treatment arm in which the patients will be initially randomized. 
Information related to further management of patient is provided in Section 7. 
2. Visit on Day 8 will only be applicable to patients participating in the PK sub-study. 
3. While patient consent is being recorded for the main study, consent should also be obtained for continued participation into the open-label, switch-over study 
until Month 18. For patients volunteering to participate in PK sub-study, an additional written signed and dated consent should be obtained prior to PK 
assessments. 
4. A written, signed and dated re-consent form should be obtained from patients who volunteer to participant in the open-label, switch-over study until Month 18. 
A written, signed and dated consent should also be obtained from those subjects who previously at visit 1 did not consent but now at visit 9 have shown 
interest to continue their participation in to the open-label, switch-over study.  
5. A complete physical examination should be performed at screening and a brief physical examination will be performed at all other visits. 

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6. Oro-dental examination should be performed on screening as well as before IP administration on Day 1, Day 180 (Month 6) and Day 360 (Month 12). In case 
of any dental abnormality, the patient should be referred to a dental surgeon for further dental examination. 
7. Includes fracture history and family history of premature cardiovascular disease. 
8. Patient may be contacted by phone one day prior to every visit for assessing COVID-19 symptoms and signs and will be asked not to attend the site in case of 
suspected reports. 
9. Vital signs will be recorded in supine position after 5 minutes of rest: HR (beats/minute), BP measurement (mmHg), RR (breaths/minute), and body 
temperature (°F/°C). 
10. A subset of 120 patients initially randomized to Prolia® arm will be re-randomized in a 1:1 ratio (i.e. 60 patients in each arm) in order to have 100 evaluable 
patients (i.e. 50 patients in each arm) at Month 18. 
11. Patient diary will be dispensed on Day 1, reviewed at each visit and will be collected at EOS assessment visit. 
12. IP administration as mentioned in Section 6.1. IP administration at Month 12 is only applicable for patients who will continue into the open-label, switch over 
study. 
13. Calcium and vitamin D supplements will be dispensed on Day 1 and at each subsequent visit to be consumed at home daily. Vitamin D supplements will be 
dispensed during the screening period, if required, for replenishment of vitamin D deposits. 
14. During screening, if the 25 (OH) vitamin D level of a patient is < 20 ng/mL (<50 mmol/L), replenishment of vitamin D deposits can be attempted following 
sites standard of care (e.g., loading dose of Vitamin D). After replenishment, vitamin D should be retested to confirm value is within the eligibility range. 
15. The 25 (OH) vitamin D level of all patients will be re-tested at Month 6. 
16. Patients with thyroid dysfunction on L-thyroxine therapy should have thyroid function test (TSH) done at least at Month 6 visit or earlier per discretion of the 
Investigator. 
17. DXA should be done and submitted as early as possible during the screening period to allow for enough time in case a repeat exam is requested by Medical 
Imaging.  
18. Applicable only for early terminated/withdrawal subjects discontinued post 6 months and before Month 12. Not required for EOS in patients participating in 
OLE or if ET occurs during OLE. 
19. Hematology includes total leukocyte count (WBC count), total erythrocyte count (RBC count), hemoglobin, platelet count, and absolute neutrophil count. 
20. Serum chemistry includes liver function tests (ALT, AST, ALP, total bilirubin, albumin and total proteins), kidney function tests (BUN, creatinine, and eGFR, 
electrolytes (sodium, potassium, and chloride), glucose, serum calcium, albumin-adjusted calcium, magnesium, and phosphorous. 
21. Only Serum calcium levels will be tested on Day 15 for all patients. 
22. Serum calcium levels can be tested locally in patients prior to dosing at Month 6 and Month 12. This can either be done on the same day as the dosing visit or 
at a separate unscheduled visit if required per local standard of care. If hypocalcemia is identified, the patient should not be dosed until calcium levels are 
corrected. In case the serum Calcium assessments are performed via the Central Lab, all lab samples required for the impending visit can be collected on the 
same day of Ca assessment, provided the sample collection date is within the window period for the visit.  
23. Urine analysis includes: Color, transparency, pH, specific gravity, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, leukocyte esterase, and microscopic 
examination including RBC, leukocytes, epithelial cells, bacteria, and crystals. 
24. For sCTX and sP1NP, blood samples should be collected prior to IP administration (if applicable for the visit) at the same time (in the morning between 07:30 
and 10:00 am) and after a minimum of 8 hours of fasting. Refer Section 8.5 for more details. 

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25. PK Parameters (Cmax, Tmax, AUC (0-1 month) and AUC(0-6 months) -) of denosumab will be measured at baseline (Day 1), Day 8, Day 15, Month 1, Months 3, and 
Month 6 (prior to second dose). PK parameters (Ctrough) will be measured at Month 12. Refer Section 8.4 for more details. 
26. For PK sampling on Day 8 and Day 15, the visit window is ±3 days but a window period of ± 2 hours is allowed in relation to the time of IP administration 
on Day 1. 
27. Recording of adverse events will start after signing of informed consent up to EOS assessment. 
*Month 12 visit will be the extension period baseline. 

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2 Introduction 
Denosumab is a fully human monoclonal immunoglobulin G2 (IgG2) antibody that binds and 
inhibits the receptor activator of nuclear factor kappa-B ligand (RANKL). 
The term “study intervention(s)” throughout the protocol refers to the test product, ENZ215 or 
reference product, Prolia®. 
2.1 Study Rationale 
Biologics are relatively new and expensive drugs. Even though the use of biologics has enabled 
great advances in the treatment of numerous diseases, their high cost has a direct impact on their 
access and on healthcare budgets around the world. Biosimilar medicines are similar to original 
biologics and are available at lower costs. 
Denosumab (ENZ215), the proposed biosimilar to Prolia®, is a monoclonal antibody which is 
structurally and functionally similar to Prolia®. This study plans to compare equivalence of the 
ENZ215 (test product) to Prolia® (reference product) in terms of efficacy, safety, and 
immunogenicity in postmenopausal women with osteoporosis. 
2.2 Background 
Osteoporosis is estimated to affect 200 million women worldwide, approximately one-tenth of 
women aged ≥ 60 years, one-fifth of women aged ≥ 70 years, and two-fifths of women aged 
≥ 80 years. It is characterized by low bone mineral density (BMD), micro-architectural 
deterioration, and degradation of other determinants of bone strength, resulting in an increased 
risk of fractures. The United States Food and Drug Administration (US FDA) first approved 
denosumab in 2010 for the treatment of osteoporosis in postmenopausal women at high risk for 
fracture, defined as having a history of osteoporotic fracture, multiple risk factors for fracture, or 
failure or intolerance to other available osteoporosis therapy. 
By binding to RANKL on the surface of osteoclasts and their precursors, denosumab inhibits 
development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. 
For the treatment of osteoporosis, denosumab is administered at a dose of 60 mg subcutaneously 
(SC) once every 6 months (Q6M) and is thus associated with greater compliance than 
medications requiring daily administration. Its efficacy in reducing the risk of vertebral, hip, and 
nonvertebral fractures has been demonstrated in a large prospective, randomized multicenter 
study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months 
[FREEDOM]) involving 7808 postmenopausal women with osteoporosis with Q6M 
administration of 60 mg denosumab for 36 months. 

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Another 2-year randomized, double-blind, placebo-controlled study involving 
332 postmenopausal women also showed that Q6M denosumab increased BMD and decreased 
bone turnover markers. 
Biosimilar medicines are similar to original biologics and are available at lower costs. The 
regulatory pathway uses a stepwise totality-of-evidence approach as the basis for approval of 
biosimilars, which is required to be similar to the reference product with respect to quality, 
safety, and efficacy. For demonstration of biosimilarity between the innovator product (Prolia®) 
and proposed biosimilar (ENZ215), the stepwise approach starts with an extensive structural and 
functional characterization followed by nonclinical testing, human pharmacokinetic (PK) and PD 
studies, and the clinical immunogenicity assessment. If there is residual uncertainty, additional 
comparative clinical studies will be required to support demonstration of biosimilarity.1 
2.2.1 Non-clinical Data of Innovator Denosumab 
The carcinogenic and genotoxic potential of denosumab has not been evaluated in long-term 
animal studies. Denosumab is an inhibitor of osteoclastic bone resorption via inhibition of 
RANKL. In ovariectomized monkeys, once-a-month treatment with denosumab suppressed bone 
turnover and increased BMD and strength of cancellous and cortical bone at doses 50-fold higher 
than the recommended human dose of 60 mg administered Q6M, based on body weight (mg/kg). 
Bone tissue was normal with no evidence of mineralization defects, accumulation of osteoid, or 
woven bone. As the biological activity of denosumab in animals is specific to nonhuman 
primates, evaluation of genetically engineered (“knockout”) mice or use of other biological 
inhibitors of the RANK/RANKL pathway, namely OPG-Fc, provided additional information on 
the PD properties of denosumab. RANK/RANKL knockout mice exhibited absence of lymph 
node formation, as well as an absence of lactation due to inhibition of mammary gland 
maturation (lobulo-alveolar gland development during pregnancy). Neonatal RANK/RANKL 
knockout mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study 
in 2-week-old rats that were administered the RANKL inhibitor OPG-Fc also showed reduced 
bone growth, altered growth plates, and impaired tooth eruption. These changes were partially 
reversible in this model upon discontinuation of dosing with the RANKL inhibitors.2,3 
2.2.2 Clinical Data of Prolia® 
The efficacy and safety of Prolia® in the treatment of postmenopausal osteoporosis was 
demonstrated in a 3-year, randomized, double-blind, placebo-controlled study. Enrolled women 
had a baseline BMD T-score between -2.5 and -4.0, either at the lumbar spine or total hip. 
Women with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget’s 
disease) or on therapies that affect bone were excluded from this study. The 7808 enrolled 

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women were aged between 60 and 91 years with a mean age of 72 years. Overall, the mean 
baseline lumbar spine BMD (LS-BMD) T-score was -2.8. Approximately 23% of women had a 
vertebral fracture at baseline. Women were randomized to receive SC injections of either placebo 
(N = 3906) or Prolia® 60 mg (N = 3902) Q6M. All women received at least 1 g calcium and 
400 IU vitamin D supplementation daily. 
The primary efficacy variable was the incidence of new morphometric (radiologically diagnosed) 
vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine 
radiographs (T4-L4) using a semiquantitative scoring method. Secondary efficacy variables 
included the incidence of hip fracture and nonvertebral fracture, assessed at 3 years.2,3 
2.2.2.1 
Effect on Vertebral Fractures 
Prolia® significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 
3 years (p < 0.0001), as shown in Table 2-1. The incidence of new vertebral fractures at Year 3 
was 7.2% in the placebo-treated women compared with 2.3% in the Prolia®-treated women. The 
absolute risk reduction was 4.8% and relative risk reduction was 68% for new morphometric 
vertebral fractures at Year 3 (Table 2-1). 
Table 2-1 
Effect of Prolia® on the Incidence of New Vertebral Fractures in 
Postmenopausal Women 
Years 
Proportion of Women with Fracture (%)+ 
Absolute Risk 
Reduction (%)* 
(95% CI) 
Relative Risk 
Reduction (%)* 
(95% CI) 
Placebo 
N = 3691 (%) 
Prolia®  
N = 3702 (%) 
0-1 Year 
2.2 
0.9 
1.4 (0.8, 1.9) 
61 (42, 74) 
0-2 Years 
5.0 
1.4 
3.5 (2.7, 4.3) 
71 (61, 79) 
0-3 Years 
7.2 
2.3 
4.8 (3.9, 5.8) 
68 (59, 74) 
CI = confidence interval 
+ 
Event rates based on crude rates in each interval. 
*Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusting for age group 
variable. 
Prolia® was effective in reducing the risk for new morphometric vertebral fractures regardless of 
age, baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a 
drug for osteoporosis.2,3 
2.2.2.2 
Effect on Hip Fractures 
The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for 
Prolia®-treated women at Year 3. The age-adjusted absolute risk reduction of hip fractures was 
0.3% with a relative risk reduction of 40% at 3 years (p-value = 0.04).2,3 

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2.2.2.3 
Effect on Nonvertebral Fractures 
Treatment with Prolia® resulted in a significant reduction in the incidence of nonvertebral 
fractures as seen in Table 2-2.2,3 
Table 2-2 
The Effect of Prolia® on the Incidence of Nonvertebral Fractures at 
Year 3 in Postmenopausal Women 
 
Proportion of Women with Fracture (%)+ 
Absolute Risk 
Reduction (%) 
Relative Risk 
Reduction (%) 
Placebo 
N = 3906 (%) 
Prolia® 
N = 3902 (%) 
(95% CI) 
(95% CI) 
Nonvertebral fracture1 
8.0 
6.5 
1.5 (0.3, 2.7) 
20 (5, 33)* 
+ Event rates based on Kaplan-Meier estimates at 3 years. 
1 Excluding those of the vertebrae (cervical, thoracic, and lumbar), skull, facial, mandible, metacarpus, and finger 
and toe phalanges. 
* p-value = 0.01. 
2.2.2.4 
Effect on Bone Mineral Density 
Treatment with Prolia® significantly increased BMD at all anatomic sites measured at 3 years. 
The treatment differences in BMD at 3 years were 8.8% at the lumbar spine, 6.4% at the total 
hip, and 5.2% at the femoral neck. Consistent effects on BMD were observed at the lumbar 
spine, regardless of baseline age, race, weight/body mass index, baseline BMD, and level of 
bone turnover. After Prolia® discontinuation, BMD returned to approximately baseline levels 
within 12 months.2,3 
2.2.2.5 
Bone Histology and Histomorphometry 
A total of 115 trans-iliac crest bone biopsy specimens were obtained from 92 postmenopausal 
women with osteoporosis at either Month 24 and/or Month 36 (53 specimens in the Prolia® 
group, 62 specimens in the placebo group). Of the biopsies obtained, 115 (100%) were adequate 
for qualitative histology and 7 (6%) were adequate for full quantitative histomorphometry 
assessment. 
Qualitative histology assessments showed normal architecture and quality with no evidence of 
mineralization defects, woven bone, or marrow fibrosis in patients treated with Prolia®. 
The presence of double tetracycline labeling in a biopsy specimen provides an indication of 
active bone remodeling while the absence of tetracycline label suggests suppressed bone 
formation. In patients treated with Prolia®, 35% had no tetracycline label present at the Month 24 
biopsy and 38% had no tetracycline label present at the Month 36 biopsy, while 100% of 
placebo-treated patients had double label present at both time points. When compared to placebo, 

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treatment with Prolia® resulted in virtually absent activation frequency and markedly reduced 
bone formation rates. However, the long-term consequences of this degree of suppression of 
bone remodeling are unknown.2,3 
2.2.3 SARS-CoV-2 
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2). This new virus has rapidly spread across the 
globe causing the World Health Organization to declare a pandemic situation on March 11, 2020. 
The countermeasures initiated by national and local governments worldwide and the 
recommendations issued by the health authorities have impacted current and new clinical studies. 
As the threat of pandemic burden including new outbreaks, locally or globally, will impact the 
further conduct of clinical studies, appropriate risk assessments and mitigation measures will 
need to be taken into consideration in all clinical studies to protect patients, site staff, and society 
as a whole. 
Both European Medicines Agency (EMA)4 and FDA5 as well as national health authorities in 
Europe have issued guidelines that aim to provide recommendations for actions for conduct of 
clinical studies of medical products during COVID-19 pandemic. Since the pandemic situation is 
evolving, guidelines, recommendations, national laws and local restrictions may change at high 
pace. Given the circumstances of potentially relapsing pandemic or epidemic situation with 
regards to the spread of COVID-19 in future, special attention will be paid to protect patients in 
the study and site staff involved in the investigations against infection with SARS-CoV-2 as 
requested by the newly issued EMA guideline. 
2.3 Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of denosumab may be found in the Summary of Product 
Characteristics.2 
2.3.1 Risk Assessment 
ENZ215 has been developed as a similar biological medicinal product to Prolia® (denosumab, 
Amgen Inc.). ENZ215 and Prolia® have identical primary, secondary ,and tertiary structures and 
the active substance for both products is denosumab (a novel antiresorptive agent that inhibits 
osteoclast-mediated bone resorption through a different pathway). Thus, the risk assessment of 
the ENZ215 is expected to be similar to the innovator denosumab (Prolia®). 

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Table 2-3 
Risk Assessment 
Potential Risk of 
Clinical Significance2 
Summary of Data/Rationale for Risk2 
Mitigation Strategy2 
Study Intervention (Innovator denosumab, Prolia®) 
Hypocalcemia 
• In two phase 3 placebo-controlled clinical studies in 
postmenopausal women with osteoporosis, approximately 
0.05% (2 out of 4050) of patients had decline in serum 
calcium levels (< 1.88 mmol/L) following Prolia® 
administration. 
• Rare cases of severe symptomatic hypocalcemia with most 
cases occurring in the first weeks of initiating therapy leading 
to symptoms such as QT interval prolongation, tetany, 
seizures, altered mental status, paresthesias or muscle 
stiffness, twitching, spasms and muscle cramps. 
• Patients with severe renal impairment (creatinine clearance 
< 30mL/min) or undergoing dialysis have an increased risk of 
hypocalcemia and increase in parathyroid hormone levels. 
• Adequate intake of calcium and 
vitamin D. 
• Monitoring of calcium and 
vitamin D levels for the duration 
of the study. 
Serious infections 
Patients receiving denosumab may develop serious infections 
including skin infections (predominantly cellulitis). 
Prompt medical attention if a patient 
develops signs or symptoms of 
cellulitis or other severe infections. 
Osteonecrosis of the 
jaw (ONJ) 
The risk of ONJ increased with duration of exposure to 
denosumab. Incidence of ONJ was 0.04% at 3 years, 0.06% at 
5 years and 0.44% at 10 years of denosumab treatment in a Phase 
3 study in postmenopausal women with osteoporosis.  
• Discontinuation of treatment 
should be considered after 
evaluation of individual 
benefit-risk assessment. 

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Potential Risk of 
Clinical Significance2 
Summary of Data/Rationale for Risk2 
Mitigation Strategy2 
Study Intervention (Innovator denosumab, Prolia®) 
• Mitigation of risk factors such as 
comorbid oral conditions or 
concomitant medications 
(corticosteroids, chemotherapy, 
head and neck radiotherapy, 
angiogenesis inhibitors) 
Atypical 
femur 
fractures 
Atypical femoral fractures have been reported in patients with 
certain co-morbid conditions (e.g., vitamin D deficiency, 
rheumatoid arthritis, hypophosphatasia) and with use of certain 
medicinal products (e.g., bisphosphonates, glucocorticoids, 
proton pump inhibitors) and also without antiresorptive therapy. 
Discontinuation of study intervention 
in patients suspected to have an 
atypical femur fracture after 
evaluation of individual benefit-risk 
assessment. 
Fertility, pregnancy and 
lactation 
Limited clinical data available about use of denosumab in 
pregnant women. However, animal studies have shown 
reproductive toxicity. 
Only postmenopausal women aged ≥ 
55 and ≤ 85 years will be enrolled in 
the study. 
Study Procedures 
Dry natural rubber of 
the needle cover of the 
pre-filled syringe 
The dry natural rubber may cause allergic reactions 
Site staff to monitor patient for 
allergic manifestation after 
administration of study intervention. 

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2.3.2 Benefit Assessment 
The study of biosimilars such as ENZ215 may help in contributing to the process of developing 
therapies that are as effective as their innovative drugs with access to a wider patient population. 
Appropriate medical measures have been implemented into this protocol to detect COVID-19 
disease to confirm eligibility of patients and to safely conduct the study. 
2.3.3 Risk Assessment for COVID-19 Pandemic 
As with Prolia®, ENZ215 is a RANKL inhibitor and can increase the risk of infection although 
there is no evidence to date that denosumab treatment can be associated with increased risk of 
severe COVID-19. Since risk of exposure to infected people cannot be completely excluded as 
the patients may need to expose themselves to public areas (e.g., commute to the site) and have 
additional human contact (e.g., with site staff and other patients of the clinical study), adequate 
precautionary measures should be taken by patients to prevent accidental exposure and patients 
should seek prompt medical attention in case of any signs and symptoms of COVID-19. 
Measures to mitigate the potential additional risks caused by COVID-19 are as follows: 
• Study enrollment will begin only when the Sponsor and Parexel in collaboration deem it is 
safe to start the study. In addition, the study will not start until the local confinement 
measures or other safety restrictions linked to the COVID-19 pandemic are lifted by the local 
authorities. 
• Current national laws and local recommendations for prevention of pandemic will be strictly 
adhered to. 
• Patients will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnea, sore throat, and fatigue throughout the study. Once clinical signs 
of infection are reported by patients, the Investigator needs to determine whether samples can 
be collected, and safety data can be recorded on site. If not, AEs and concomitant 
medications will be obtained via phone calls. Daily body temperature measurements during 
outpatient visits will be implemented. 
• The study intervention will not be administered to patients upon identification of any signs of 
COVID-19 infection. 
• The probability of virus transmission will be controlled as much as possible by: 
• 
Advice for patient to adhere to local requirements for reduction of the public exposure 
while ambulatory. 

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• 
All patients may be contacted by phone one day prior to every visit for assessing 
COVID-19 symptoms and signs and will be asked not to attend the site in case of 
suspected reports. In addition, patients will be asked for any contact with a person who 
has tested positive for SARS-CoV-2. If applicable, patients will be referred to the local 
healthcare system for further follow-up and treatment. 
• 
Physical distancing and person-to-person contact restrictions will be applied during site 
visits. 
• 
Where physical distancing is not possible, personal protective equipment will be used 
by patient (surgical face mask, gloves) and staff (e.g., but not limited to masks, gloves, 
protectors, medical suits) if deemed appropriate by the Investigators and site staff and 
guided by local requirements. 
• 
Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing. 
2.3.4 Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimize risk to patients participating in this study, 
the potential risks identified in association with ENZ215 are justified by the anticipated benefits 
that may be afforded to postmenopausal women with osteoporosis. 
3 Objectives and Endpoints 
The study objectives and endpoints are provided in Table 3-1. 
Table 3-1 
Objectives and Endpoints 
Co-primary Efficacy Objectives 
Co-primary Efficacy Endpoints 
• To evaluate the efficacy of ENZ215 when 
compared to Prolia® in patients with 
postmenopausal osteoporosis, in terms of 
change in BMD at the lumbar spine from 
baseline to Month 12 
• Percentage change in BMD at lumbar 
spine (L1-L4 region) measured by DXA 
from baseline to Month 12 
• To compare the AUEC of sCTX levels 
from baseline to Month 6 
• AUEC of sCTX over the initial 6 months 
(from Day 1 pre-dose to Month 6 
pre-dose) 

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Secondary Efficacy Objectives 
Secondary Efficacy Endpoints 
• To compare the change in sP1NP levels 
from baseline to Month 6 
• Percentage change in sP1NP 
concentrations from baseline to Month 1, 
Month 3, and Month 6 
• To compare the change in BMD at lumbar 
spine from baseline to Month 6 
• Percentage change in BMD at lumbar 
spine measured by DXA from baseline to 
Month 6 
• To compare the change in BMD at total 
hip and femoral neck from baseline to 
Month 6 and Month 12 
• Percentage change in BMD at total hip 
and femoral neck measured by DXA from 
baseline to Month 6 and Month 12 
Secondary Safety Objectives 
Secondary Safety Endpoints 
• To compare the immunogenicity potential 
of ENZ215 and Prolia® 
• ADAs incidence at baseline (Day 1) and 
Months 1, 3, 6, 9, and 12 and during 
open-label switch-over period, i.e. 
Months 15 and 18 
• To compare the safety and tolerability of 
ENZ215 and Prolia® 
• Treatment-emergent serious and 
non-serious adverse events (TEAEs) 
during main treatment period and 
open-label switch-over period 
• Alteration in clinical laboratory 
parameters during main treatment period 
and open-label switch-over period 
Secondary Pharmacokinetics Objective 
Secondary Pharmacokinetics Endpoint 
• To compare the pharmacokinetics of 
ENZ215 and Prolia® 
• PK Parameters (Cmax, Tmax, partial AUC-(0-
1 month), AUC(0-6 month)) of denosumab 
measured at baseline (Day 1), Day 8, 
Day 15, Month 1, Month 3, Month 6 
(prior to second dose), and Month 12 
 
 

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4 Study Design 
Environmental sanitization procedures will be implemented in the study site and where study 
procedures are conducted. The study design and associated safety measures are deemed 
appropriate for conduct during COVID-19 pandemic. 
4.1 Overall Design 
This is a Phase 3, randomized, double-blind, parallel-group, active-controlled study in 
postmenopausal women with osteoporosis. The double-blind treatment period will be for 
12 months followed by the open-label, switch-over study until Month 18. 
Five hundred four (504) patients (252 patients in each treatment arm) will be enrolled in this 
study. All eligible patients will be randomized in the double-blind treatment period in a 1:1 ratio 
to receive either ENZ215 or Prolia® (60 mg) SC on Day 1 and Month 6. Patient allocation will 
be stratified by age (≥ 55 to < 70 years and ≥ 70 to ≤ 85 years) and based on prior use of 
bisphosphonate. 
PK sub-study will be conducted in a subset of the patients, i.e. 60 patients in each arm in order to 
have 50 evaluable patients in each arm. For patients participating in PK sub-study, PK samples 
will be collected as mentioned in the PK sample collection (Section 8.4). 
In addition, all patients will receive daily supplementation with at least 1 g of calcium and at 
least 400 IU of vitamin D till Month 12 or Month 18 as applicable. Calcium and vitamin D 
supplements will be dispensed to patients starting on Day 1 and at each subsequent visit to be 
consumed at home daily till Month 12. Vitamin D supplements will be dispensed during the 
screening period, if required, for replenishment of vitamin D deposits. For patients initially 
randomized to the Prolia® arm and who re-consent to participate in the open-label, switch-over 
study, calcium and vitamin D supplements will be dispensed again at Month 12 for daily 
supplementation until EOS. If a patient becomes hypercalcemic over the course of the study, the 
calcium and/or vitamin D supplementation may be reduced or temporarily discontinued per 
Investigators’ medical judgment until the serum calcium concentration returns to the normal 
range. If a patient develops hypocalcemia over the course of the study, calcium and/or vitamin D 
supplementation may be adjusted per Investigators’ medical judgment until the serum calcium 
concentration returns to the normal range. 

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All patients randomized to the double-blind treatment period (except for a subset of 120 patients, 
as described hereafter) will complete the study at Month 12. A subset of 120 patients initially 
randomized to Prolia® arm will be re-randomized in a 1:1 ratio (i.e. 60 patients in each arm) in 
order to have 100 evaluable patients (i.e. 50 patients in each arm) in an open-label, switch-over 
period to receive either ENZ215 or Prolia® (60 mg) SC at Month 12. This open-label, 
switch-over study will assess the impact on immunogenicity and safety of switching patients 
from Prolia® to ENZ215. Re-randomization will not be stratified. The subset of patients selected 
for re-randomization to the open-label, switch-over study will be patients who complete 12 
months of the double-blind treatment period without any significant safety concerns as per the 
Investigator’s discretion and who have re-consented for the open-label extension period. These 
patients will complete the study at Month 18. 
For patients receiving ENZ215 or Prolia® and not continuing to the switch-over study, the study 
duration will be approximately 25 months with a recruitment period of 12 months and a study 
period of 13 months (up to 5 weeks of screening period, 12 months of treatment period). For 
patients receiving Prolia® and who re-consent to continue to participate in the switch-over study, 
the study duration will be approximately 31 months (additional 6 months of open-label 
switch-over study, i.e. until Month 18). 
Patients will be required to visit the site for the following visits: Visit 1/screening period 
(Day -35 to Day -1), Visit 2/Day 1, Visit 4/Month 1 (Day 15), Visit 5/Month 1 (Day 30), 
Visit 6/Month 3 (Day 90), Visit 7/Month 6 (Day 180), Visit 8/Month 9 (Day 270) and 
Visit 9/Month 12 (Day 360). 
Visit 10/Month 15 (Day 450) and Visit 11/Month 18 (Day 540) will be additional visits to the 
above-mentioned visits for patients initially randomized to receive Prolia® and re-randomized in 
the switch-over study (subset of 120 patients). 
Except on Visit 1 and Visit 2, a window period of ±3 days is allowed on Day 8, Day 15, Day 30 
(Month 1), and Day 90 (Month 3). A window period of ± 7 days is allowed from Month 6 until 
EOS. 
EOS assessment will be performed at Month 12 (±7 days) or Month 18 (±7 days) as applicable 
or at the time of early discontinuation or withdrawal of the patient. 
Note: There will be an additional visit (Visit 3/Day 8) for those patients who provide consent for 
participation in PK sampling. For PK sampling on Day 8 and Day 15, the visit window is ±3 
days but a window period of ± 2 hours is allowed in relation to the time of IP administration on 
Day 1. Details of the study visit schedule is provided in Section 1.3. 

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During the study, blood and urine samples will be collected for eligibility and safety assessments 
(hematology, serology, routine serum chemistry, urine analysis, PK analysis, PD assessments, 
and ADA). 
4.2 Scientific Rationale for Study Design 
This study forms part of the clinical development program and is aimed to assess the efficacy 
and safety of ENZ215 compared to Prolia® in women with postmenopausal osteoporosis as a 
randomized, double-blind, multicenter phase 3 study. The concept study design has been 
discussed and agreed with FDA and EMA. Of all therapeutic indications of Prolia®, 
postmenopausal osteoporosis is considered to be the most sensitive indication as postmenopausal 
osteoporotic females are exempt from underlying disease conditions and concomitant 
medications that might influence the efficacy and the safety of the study intervention. 
Consequently, they represent the most homogenous study population. The safety assessments for 
the study are accepted measures for ensuring safety of patients during a clinical study. The 
sample size is considered adequate and sufficient to allow for a meaningful comparison between 
ENZ215 and Prolia®. The rationale for dose selection is discussed in Section 4.3. The study 
design is deemed appropriate for conduct during the COVID-19 pandemic. 
4.3 Justification for Dose 
Dose, frequency, and route of administration of the study intervention are chosen according to 
the current Prolia® label for the treatment of postmenopausal women with osteoporosis. This is 
the dose approved in postmenopausal women. 
4.4 End of Study Definition 
The EOS is defined as the date of the last visit of the last patient in the study or last scheduled 
procedure shown in the schedule of activities (SoA) (Table 1-1) for the last patient in the study 
globally. 
A patient is considered to have completed the study if she has completed all periods of the study 
including the last visit or the last scheduled procedure shown in the SoA (Table 1-1). 

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5 Study Population 
Five hundred four (504) postmenopausal women with osteoporosis aged ≥ 55 and ≤ 85 years, 
fulfilling the study selection criteria will be enrolled in approximately 60 to 70 sites (centers) 
across the European Union. 
Patient selection will be established by reviewing all inclusion/exclusion criteria at screening and 
at baseline (Day 1). The Investigator must ensure that all patients being considered for the study 
meet the following eligibility criteria (all the inclusion and none of the exclusion): 
5.1 Inclusion Criteria 
The patients will be included in the study if they meet all the following criteria:  
 Willing to provide voluntary written informed consent and able to comply with the protocol 
requirements 
 Postmenopausal women aged ≥ 55 and ≤ 85 years globally, except for Spain. In Spain 
specifically refer to the below criteria: 
 
a. Postmenopausal women aged ≥ 75 and ≤ 85 years with LS T-score ≤ -2.5 or 
b. Postmenopausal women aged ≥ 65 and < 75 years with LS T-score is ≤ -2.5 and a prior 
fragility fracture (except for hip fracture), including non-exclusionary vertebral fractures 
c. In both cases (i.e. criteria a and b), it must also be that these are women who present a 
contraindication for the use of bisphosphonates or who do not tolerate the oral route. 
 Body weight ≥ 50 kg and ≤ 90 kg 
 Diagnosed with osteoporosis, with absolute BMD consistent with T-scores of ≤ -2.5 and 
≥ - 4.0 at the lumbar spine (L1-L4 region) as measured by dual-energy X ray absorptiometry 
(DXA) at screening 
 At least 5 years of postmenopausal status confirmed by follicle-stimulating hormone (FSH) 
levels at screening 
 At least one hip joint and two vertebrae in L1-L4 region evaluable by DXA 
 No other clinically significant medical history, vital signs, physical examination, laboratory 
profiles as deemed by the Investigator or designee that would pose a risk to participant safety 
or interfere with the study evaluation, procedures or completion 
5.2 Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 

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 Known hypersensitivity to denosumab or any of the excipients of the study drug  
 Known intolerance to, or malabsorption of calcium or vitamin D supplements 
 Previous exposure to Prolia® or any other denosumab biosimilar 
 Previous use of oral bisphosphonates: 
a. 
Used for 3 or more years cumulatively 
b. If used for < 3 years, use within the past 12 months prior to screening 
 Use of intravenous bisphosphonates within the past 5 years prior to screening. If used more 
than 5 years prior, patients will be excluded if cumulative use was > 3 years. 
 Use of parathyroid hormone or its derivatives, hormone replacement therapy, romosozumab, 
selective estrogen-receptor modulators, or tibolone or calcitonin within 12 months prior to 
enrollment 
Note: occasional use of intravaginal estrogen treatment is not exclusionary  
 Any prior use of fluoride or strontium 
 Systemic glucocorticoids (≥ 5 mg prednisone equivalent per day or cumulative dose 
≥ 50 mg) for more than 10 days within 3 months prior to enrollment (topical and inhaled 
corticosteroids are allowed) 
 Other bone active drugs (i.e. drugs affecting bone metabolism) including heparin, 
anti-epileptics (except for benzodiazepines and pregabalin), antidepressants such as SSRIs, 
SNRIs, antipsychotics, systemic ketoconazole, adrenocorticotrophic hormone (ACTH), 
lithium, protease inhibitors, gonadotropin-releasing hormone (GnRH) agonists, or anabolic 
steroids within the past 3 months prior to screening or requiring treatment with these agents 
during the study. 
Note: Please refer to Section 6.11 for a comprehensive list of prohibited medications 
 Known sensitivity to drug products derived from mammalian cell lines such as hormones, 
enzymes, cytokines, bone morphogenic proteins, clotting factors, antibodies, and fusion 
protein therapeutics. Patients with any known hypersensitivity to complex proteins such as 
monoclonal antibodies will be excluded. 
 History of one severe or more than two moderate vertebral fractures per Genant classification 
as determined by the central reading center 
 History of hip fracture or bilateral hip replacement 
 Total hip or femoral neck T-score <−4.0 
 History and/or presence of atypical femoral fracture 

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 Presence of any active healing fracture according to the Investigator’s assessment 
 History of any transplant or chronic immunosuppression (including patients on 
immunosuppressive therapy) 
 Severe liver dysfunction (alanine aminotransferase [ALT] or aspartate aminotransferase 
[AST] > 3 times upper limit of normal) 
 Positive testing for hepatitis B (hepatitis B virus surface antigen [HbsAg]) or hepatitis C 
(hepatitis C virus antibody [HCV Ab]) virology 
 Known history of human immunodeficiency virus (HIV) infection or positive serology for 
HIV at screening 
 Significantly impaired renal function (determined by glomerular filtration rate of < 
45 mL/min/1.73 m2 by the Modification of Diet in Renal Disease (MDRD) formula, as 
calculated by the central laboratory) or receiving dialysis 
 Oral or dental conditions: 
a. 
Osteomyelitis or history and/or presence of osteonecrosis of the jaw (ONJ) 
b. Presence of risk factors for ONJ (e.g., periodontal disease, poorly fitting dentures, poor 
oral hygiene, invasive dental procedures such as tooth extractions within 6 months prior 
to screening) 
c. 
Active dental or jaw condition which requires oral surgery 
d. Planned invasive dental procedure 
 Major surgery within 8 weeks prior to screening or anticipated major surgery during the 
study 
 Clinically significant leukopenia, neutropenia, or anemia as determined by the Investigator or 
any other clinically significant medical condition or laboratory abnormality that, in the 
opinion of the Investigator, would pose a risk to patient safety or interfere with adherence to 
study procedures, study completion, or the interpretation of study results 
Note: In case of an abnormal laboratory result which in the opinion of the investigator may 
be an error, is borderline, or indeterminate for inclusion in the study, the investigator may 
consider repeating the test once in order to rule out laboratory error. 
 Patient with an active infection or history of infection as follows: 
a. 
Any active infection for which systemic anti-infectives were used within 4 weeks prior 
to randomization 
b. A serious infection defined as requiring hospitalization or intravenous anti-infectives 
within 8 weeks prior to randomization 

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c. 
Recurrent or chronic infections or other active infection that, in the opinion of the 
Investigator, might compromise the safety of the patient 
 Evidence of any of the following conditions per laboratory test results, medical history, 
electrocardiogram (ECG), DXA, or X-ray review: 
a. 
Uncontrolled hyperthyroidism or hypothyroidism 
Note: Clinical significance of abnormal TSH values in patients on stable replacement 
therapy due to hypothyroidism or on anti-thyroid medication should be assessed and 
discussed with the Medical Monitor. 
b. History or current hyperparathyroidism or hypoparathyroidism (intact parathyroid 
hormone levels not within normal range) 
Note: Mild secondary hyperparathyroidism in the context of vitamin D deficiency may be 
acceptable upon discussion with the Medical Monitor. 
c. 
Vitamin D deficiency defined as 25 (OH) vitamin D level < 20 ng/mL (< 50 nmol/L) 
Note: Patients can be enrolled if a repeat test (post supplementation) prior to enrollment 
shows corrected 25 (OH) vitamin D level ≥ 20 ng/mL (≥ 50 nmol/L). 
d. Current hypocalcemia (albumin-adjusted serum calcium < 8.0 mg/dL [< 2.0 mmol/L]) 
or hypercalcemia (albumin-adjusted serum calcium > 10.6 mg/dL [> 2.62 mmol/L]) 
e. 
History of parathyroid surgery 
f. 
Any bone or metabolic disease which may affect BMD or interfere with the 
interpretation of the findings, e.g., osteomalacia, osteogenesis imperfecta, osteopetrosis, 
achondroplasia, Paget’s disease, rheumatoid arthritis, ankylosing spondylitis, Cushing’s 
disease, hyperprolactinemia, or malabsorption syndrome 
g. Any malignancy, including solid tumors, and hematologic malignancies (except basal 
cell carcinoma and squamous cell carcinomas of the skin, cervical, or breast ductal 
carcinoma in situ, that have been completely excised and are considered cured) within 
the last 5 years 
h. Known or suspected history of alcoholism (including heavy drinking defined as 
consuming more than 3 drinks on one day or more than 7 drinks per week) or substance 
abuse within the past 12 months prior to the first dosing that the Investigator believes 
would interfere with understanding or completing the study 
i. 
Current heavy smoking, defined as smoking 20 or more cigarettes per day. 
j. 
Participated in any other clinical study in last 30 days prior to screening 
k. History and/or presence of significant cardiac disease as per Investigator’s discretion, 
including but not restricted to: 

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i. 
History of cardiac arrhythmia or long QT syndrome or ECG abnormalities at 
screening indicating significant risk for safety (e.g., that required hospitalization, 
emergency cardioversion, or defibrillation)  
ii. 
History and/or presence of myocardial infarction within 6 months before 
screening 
iii. 
History and/or presence of New York Heart Association (NYHA) class III or IV 
heart failure 
 Suspected signs and symptoms of COVID-19/confirmed COVID-19 or with recent history of 
travel/contact (less than 2 weeks from screening) with any COVID-19 positive 
patient/isolation/quarantine 
5.3 Lifestyle Considerations 
5.3.1 Activity 
Patients will be allowed to do normal routine activity avoiding strenuous physical activity 
24 hours prior to all study visits. 
5.4 Screen Failures 
A screen failure occurs when a patient who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention/enrolled in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure patients to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
reason for screen failure (e.g., eligibility requirements failed), and documentation of any medical 
occurrences that qualify as serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, after discussion with the Medical Monitor. Patients that are screen-failed due to 
hypocalcemia are not eligible for rescreening. Rescreened patients will be assigned a new patient 
number. All screening procedures will be repeated except for: 
• DXA, if performed within 5 weeks from the date of rescreening 
• Spine X-ray, if performed within 3 months from the date of rescreening 
5.4.1 Screening and Enrollment Log and Patient Identification Numbers 
The patient’s enrollment will be recorded in the Screening and Enrollment Log. Upon 
enrollment, each patient will receive a unique patient identification number. Patient numbers 
must not be re-used for different patients. 

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5.5 Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
Not applicable. 
6 Study Interventions and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a patient according to the study 
protocol. An Investigator manual will be prepared to describe the procedure for handling of IPs. 
6.1 Study Interventions Administered 
Based on the randomization schedule, either ENZ215 or Prolia® will be administered to the 
patients at a dose of 60 mg (multiple-dose) SC in 6-month intervals into the upper thigh. 
In addition, all patients will receive daily supplementation with at least 1 g of elementary 
calcium and at least 400 IU of vitamin D till Month 12 or Month 18, as applicable. Calcium and 
vitamin D supplements will be dispensed to patients starting on Day 1 and at each subsequent 
visit to be consumed at home daily till Month 12. Vitamin D supplements will be dispensed 
during the screening period, if required, for replenishment of vitamin D deposits. For patients 
initially randomized to the Prolia® arm and who re-consent to participate in the open-label, 
switch-over study, calcium and vitamin D supplements will be dispensed again at Month 12 for 
daily supplementation until EOS. If a patient becomes hypercalcemic over the course of the 
study, the calcium and/or vitamin D supplementation may be adjusted or temporarily 
discontinued per Investigator’s medical judgement until the serum calcium concentration returns 
to the normal range. If a patient develops hypocalcemia over the course of the study, calcium 
and/or vitamin D supplementation may be adjusted per Investigator’s medical judgment until the 
serum calcium concentration returns to the normal range. For further details, refer to Section 
6.1.1. 
IP administration, disposal and other handling information will be included in the Investigator 
manual. Retention samples will be maintained as per local regulations. 
The study interventions are presented in Table 6-1. 

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Table 6-1 
Study Interventions Administered 
Intervention Label 
ENZ215 
Prolia® 
Vitamin D 
Calcium 
Intervention Name 
ENZ215 
Prolia® 
N/A 
N/A 
Type 
Biologic 
Biologic 
Drug 
Drug 
Dosage Formulation 
PFS 
PFS 
Tablet 
Tablet 
Unit Dose Strength(s) 
60 mg/mL 
60 mg/mL 
400 IU daily 
1 g daily 
Dosage Level(s) 
60 mg 
60 mg 
At least 
400 IU 
At least 1 g 
Route of Administration 
SC injection 
SC injection 
Oral 
Oral 
Use 
Experimental 
Active comparator Supplement 
Supplement 
IP/NIP 
IP 
IP 
NIP 
NIP 
Sourcing 
EU 
Manufactured 
by: Enzene 
Biosciences 
Ltd. India 
EU marketing 
authorization 
holder: Amgen 
Europe B.V. 
Minervum 7061, 
4817 ZK Breda, 
The Netherlands. 
Locally 
sourced 
Locally 
sourced 
Packaging and Labeling 
Study 
intervention 
will be 
provided in a 
PFS. Each 
PFS will be 
labeled as 
required per 
country 
requirement. 
Study Intervention 
will be provided 
in a PFS. Each 
PFS will be 
labeled as required 
per country 
requirement. 
Per local 
labelling 
requirement 
Per local 
labelling 
requirement 
Current Name 
ENZ215 
(denosumab) 
Prolia® 
(denosumab) 
N/A 
N/A 
EU = European Union, IP = Investigational product, NIP = Non-investigational product PFS = Prefilled syringe, 
SC = Subcutaneous 

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6.1.1 Calcium and Vitamin D supplementation 
Compliance with daily calcium and vitamin D intake will be monitored and assessed throughout 
the study. If hypercalcemia or hypocalcemia occurs, the Investigator can modify the dietary 
intake of calcium and adjust the calcium and/or vitamin D dosage if needed, according to local 
practice. The change should be reported in the eCRF and hypercalcemia or hypocalcemia should 
be reported as an AE if clinically significant. 
Intolerance to non-IMP may occur, especially for calcium. Calcium intolerance can manifest as 
bloating or constipation. The formulation and/or dose frequency (e.g., dose divided twice daily) 
can be changed to reduce intolerance and increase compliance at the Investigator’s discretion. If 
intolerance continues after lowering the dose, temporary discontinuation may be considered. 
Permanent discontinuation of calcium and/or vitamin D should be discussed with the Medical 
Monitor and should be documented in the source data. Further participation of these patients in 
the study should be reconsidered after discussion with Medical Monitor. 
6.2 Preparation, Handling, Storage, and Accountability 
Clinical supplies (both test and reference product) will be packed, labeled, handled, and stored in 
accordance with current Good Manufacturing Practice of IPs. 
IP (test and reference products) will be supplied by Enzene Biosciences Ltd./Alkem Laboratories 
Ltd. in sufficient quantities as required by the study. Individual patient containers as required will 
be shipped to the sites (centers). The received IPs will be verified with certificates of analysis for 
the sealed condition of packs and adequacy of the label, including product name, strength, 
number of dosage units, lot number or batch number, expiry date/retest date, and storage 
condition mentioned clearly. 
It is the Investigator’s responsibility to perform the accountability check and verify that the 
shipment contains all the items noted in the shipment inventory including a check for any 
damages or unusable IP. A record of the inventory received should be documented in the drug 
accountability form. The Investigator or the Investigator’s designated personnel should verify the 
IP, sign and date the drug receipt, and maintain a copy of the receipt at the study center. 
Investigational product labels will be prepared in compliance to the applicable regulatory 
requirements and will have the following information: 
• Name, address, and telephone number of Sponsor 
• Pharmaceutical dosage form, route of administration, quantity of dosage units 

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• Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the patient or staff administering the product) 
• Study number 
• Randomization ID 
• Investigator and site details 
• Patient details 
• Lot/batch number 
• Storage conditions 
• Manufacturing date 
• Expiry/Retest date 
• Statement: ‘For clinical trial use only” 
Temperature will be monitored on a daily basis during the conduct of the study. The IPs will be 
stored as per the product requirements.  
The Investigator, site pharmacist, or other Investigator’s assigned personnel allowed to receive, 
store, issue, and dispense the IPs will be responsible for ensuring that the IPs to be used in the 
clinical study are securely maintained as specified by the Sponsor and in accordance with the 
current Good Clinical Practice. 
All IPs shall be issued and used in accordance with the protocol and it is the Investigator’s 
responsibility to ensure that an accurate record of the IPs issued and returned is maintained. 
Under no circumstances will the Investigator supply the IP to a third party, allow the IP to be 
used other than as directed by this clinical study protocol, or dispose the IP in any other manner. 
Further guidance and information for the final disposition of unused study intervention are 
provided in the Investigator manual. 
6.3 Retrieval of Study Interventions 
As the IP is an injectable, IP (test or reference) will be administered to the patient at the site 
during the applicable visit.  
At the completion of the study, there will be a final reconciliation of IP shipped, drug consumed, 
and drug remaining. This reconciliation will be logged on the drug reconciliation form. Any 
discrepancies noted will be investigated, resolved, and documented prior to return of unused IP. 

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6.4 Unused Study Interventions 
Units of IPs that have not been dispensed will be retained in their original containers. Any 
product that were dispensed but not used will be labeled as “unused” and returned, along with 
other unused products to the Sponsor at the end of the study. 
Note: If IPs are to be destroyed on site, it is the Investigator’s responsibility to ensure that 
arrangements have been made for disposal and written authorization has been granted by the 
Sponsor, and the procedures for proper disposal have been established according to applicable 
regulations, guidelines, Sponsor’s instructions, and institutional procedures. Appropriate records 
of the disposal must be maintained. The unused study products can only be destroyed after being 
inspected and reconciled by the responsible study monitor. 
6.5 Measures to Minimize Bias: Randomization and Blinding 
6.5.1 Randomization 
Patients will be randomized in a 1:1 ratio to receive either ENZ215 or Prolia® (60 mg SC 
injection) at baseline and Month 6. A subset of 120 patients initially randomized to Prolia® arm 
will be re-randomized in a 1:1 ratio (i.e. 60 patients in each arm) in order to have 100 evaluable 
patients (i.e. 50 patients in each arm) at Month 12. 
Patient allocation will be stratified by age (≥ 55 to < 70 years and ≥ 70 to ≤ 85 years) and based 
on prior use of bisphosphonate. 
All patients will be centrally randomized using an Interactive Response Technology (IRT). Each 
patient will be assigned a unique number (randomization number) that encodes the patient’s 
assignment to one of the 2 arms of the study, according to the randomization schedule. The 
randomization schedule will be generated by the IRT vendor. 
6.5.2 Blinding 
This is a double-blind study (till Month 12) in which patients and Investigators are blinded to 
study intervention. The IRT will be programmed with blind-breaking instructions. In case of an 
emergency, the Investigator has the sole responsibility for determining if unblinding of a 
patient’s study intervention assignment is warranted. Patient safety must always be the first 
consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, the Investigator should make every effort to contact the Sponsor prior to unblinding a 
patient’s study intervention assignment unless this could delay emergency treatment for the 
patient. If a patient’s study intervention assignment is unblinded, the Sponsor must be notified 
within 24 hours of this occurrence. The date and reason for the unblinding must be recorded. 

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The duration of the double-blind study is 12 months after which study analysis will be carried 
out and the study report will be submitted to the EMA. The further study period, i.e. open-label 
switch-over period till Month 18, is part of the safety study for US FDA regulatory submission. 
Primary analysis will be performed once all patients complete Month 12 (including early-drop 
outs) and after partial lock of Month 12 data. 
Data will be frozen at patient level before patient transition from the double-blind treatment 
period to the open-label extension study. Further details of transition of patients to the open-label 
extension study will be outlined in the Data Management Plan. 
6.6 Study Intervention Compliance 
The Investigator or his/her designated and qualified representatives will administer IP only to 
patients who are eligible to participate in the study in accordance with the protocol. The IP must 
not be used for reasons other than that described in the protocol. 
If there are any significant irregularities in compliance in the opinion of the Investigator, the 
patient should be discontinued from the study. 
The Investigator or Investigator’s designated personnel will maintain a careful record of the 
inventory and disposition of all agents received for study using a drug accountability form or log. 
Records or logs must comply with applicable regulations and guidelines, and should include: 
• Amount received  
• Amount currently in place 
• Label ID number or batch number and use by date or expiry date 
• Dates and initials of person responsible for IP inventory  
• Amount dispensed, including unique patient identifiers 
• Non-study disposition (e.g., lost, wasted, broken) 
• Amount returned to Sponsor 
• Amount destroyed at study site, if applicable 
6.7 Dose Modification 
Not applicable. 

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6.8 Continued Access to Study Intervention After the End of the Study 
Not applicable as standard of care is approved and available. 
6.9 Treatment of Overdose 
Incidences of overdose are not expected as ENZ215 and Prolia® are supplied in pre-filled 
syringes and patients will not self-administer the IP. Any overdose must be recorded in the AE 
section of the eCRF and the source documents. Any case of overdose leading to SAEs must be 
reported in an expedited manner using the SAE reporting form. Overdose (with associated 
symptoms or without any associated symptoms) should be reported as an AE using the Preferred 
Term “overdose”. 
For this study, any dose of ENZ215 or Prolia® (60 mg) SC greater than indicated in this protocol 
will be considered an overdose. 
Sponsor does not recommend specific treatment for an overdose as up to 180 mg of ENZ215 is 
tolerated without any significant events. However, patients should be followed-up specifically 
for hypocalcemia and any other adverse events for safety purposes. 
In the event of an overdose, the Investigator/treating physician should: 
• Contact the Medical Monitor immediately. 
• Evaluate the patient to determine, in consultation with the Medical Monitor, whether study 
intervention should be interrupted or whether the dose should be reduced. 
• Closely monitor the patient for any AE/SAE and follow-up until planned study completion or 
until 3 half-lives, i.e. 90 days. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
6.10 Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins 
and/or herbal supplements) that the patient receives during her participation in the study should 
be reported in the eCRF. In addition, any diagnostic, therapeutic or surgical procedure performed 
during the study period (from screening to EOS assessment) should be recorded. The 
Investigator should be contacted if there are any questions regarding concomitant or prior 
therapy(ies). At screening visit, all relevant prior medication history must be recorded while 
concomitant medication details will be recorded throughout the study i.e. from screening visit to 
safety EOS assessment visit. The Medical Monitor should be contacted if there are any questions 
regarding concomitant or prior therapy. 

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Patients will receive daily supplementation with at least 1 g of elementary calcium and at least 
400 IU of vitamin D. Patients with thyroid dysfunction on L-thyroxine therapy should have 
thyroid function test (TSH) done at least at Month 6 or earlier per discretion of the Investigator. 
6.11 Prohibited Medications 
• Patients are not allowed to take Xgeva during the study as ENZ215 and Prolia® contain the 
same active ingredient as in Xgeva® (denosumab). 
• Use of the following medications is also prohibited during the study: 
Any osteoporosis treatment (other than calcium and vitamin D supplements) such as: 
• 
Intravenous or oral bisphosphonates 
• 
Teriparatide 
• 
Romosozumab 
• 
Strontium ranelate or fluoride 
• 
Calcitonin or its derivates and calcimimetics (such as cinacalcet or etelcalcetide) 
• 
Parathyroid hormone or its derivatives, hormone replacement therapy (oral or 
transdermal oestrogen; exceptionally, occasional non-systemic vaginal oestrogen 
treatment is permitted), selective estrogen-receptor modulators, or tibolone 
Drugs affecting bone metabolism: 
• 
ACTH 
• 
Anabolic steroids 
• 
Androgens  
• 
Anti-epileptics (except for benzodiazepines and pregabalin) 
• 
Aromatase inhibitors 
• 
Barbiturates 
• 
Calcimimetics 
• 
Systemic glucocorticoids (Topical and inhaled glucocorticosteroids are allowed). 
• 
Growth hormone-releasing hormone 
• 
GnRH agonists 
• 
Heparin (including unfractionated heparin and low molecular weight heparins) 
• 
Immunosuppressants, e.g., cyclosporine A, tacrolimus, methotrexate 
• 
Lithium 
• 
Protease inhibitors 
• 
Systemic ketoconazole 
• 
Tamoxifen  
• 
Thiazolidinediones 
• 
Warfarin 

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• 
Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) as well as 
Serotonin and norepinephrine reuptake inhibitors (SNRIs) 
• 
Antipsychotics 
If, in addition to the above, any medication(s) in the opinion of the Investigator is likely to affect 
the study outcome, the use of these medications should be prohibited. 
This prohibition must continue until EOS assessment. All such instances in which prohibited 
therapies are administered or required to be administered, should be notified to the Sponsor. 
For any concomitant therapy given as a treatment for a new AE or a worsening of an existing 
AE, the condition must be documented on the AE page in the eCRF. 
Invasive dental procedures (e.g., dental implants or oral surgery) and major surgeries or bone 
surgeries (unless required for AE/SAE management) should be avoided during the study period 
as far as possible. 
7 Discontinuation of Study Intervention and Patient Discontinuation 
Discontinuation of specific sites or of the study as a whole are handled as part of the appendix on 
Governance, Appendix 1, Section 10.1.13. 
7.1 Discontinuation of Study Intervention 
It may be necessary for a patient to permanently discontinue study intervention. However, 
following discontinuation of IP administration, increased fracture risk can be expected, including 
the risk of multiple vertebral fractures. Patients should be informed of this risk and Investigators 
should ensure prescription of appropriate follow-up osteoporosis treatment per their medical 
judgement and according to local guidelines. 
Delay in administering the study intervention for not longer than 28 days is allowed in 
exceptional cases such as patients diagnosed with any transient disease/SAE/reversible 
hypocalcemic condition where IP administration would not be possible or would be 
contraindicated. 
7.2 Patient Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at their own request or may be withdrawn at 
any time at the discretion of the Investigator for safety, behavioral, or compliance reasons. The 
patients will be permanently discontinued from the study intervention and the study at that time. 
A patient may be withdrawn / discontinued from the study due to the following reasons: 

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• A patient suffers from significant inter-current illness or undergoes surgery during the course 
of the study that warrants withdrawal in the Investigator’s or Sponsor’s judgment. 
• Patient’s voluntary withdrawal of consent 
• Protocol violation that may affect the patient’s safety seriously and/or the integrity of data 
(including ineligibility) agreed by the Investigator (e.g., IP dosing out of visit window, 
non-compliance with calcium/vitamin D supplementation, or using prohibited medication 
during the study period) 
• In Investigator’s opinion, it is not in the patient’s best interest to continue 
• Patient develops the risk of ONJ during the study duration  
• Patient is found to conceal important medical history which in opinion of Investigator may 
compromise her safety during participation in this study. 
• Any AE or SAE which requires discontinuation of patient in the opinion of Investigator 
• Potential Hy’s law (ALT or AST ≥ 3 × upper limit of normal (ULN) and total bilirubin 
≥ 2 × ULN (>35% direct bilirubin) or ALT or AST ≥ 3 × ULN and INR > 1.5 (if INR 
measured) 
• Study termination by the Sponsor 
• Unblinding of treatment arm to patient or Investigator during the double-blind study period 
• Any other justifiable reason, which should be adequately documented 
Investigator should try to obtain the reason from the patient for withdrawing consent. Reason for 
withdrawal from the study shall be documented, whenever possible. 
If a patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such withdrawal of consent. 
If a patient withdraws from the study, she may request destruction of any samples taken and not 
tested, and the Investigator must document this in the site study records. 
EOS assessments (as per Table 1-1) shall be performed for all prematurely discontinued and 
withdrawn patients. For all discontinued patients, data collected till the time of discontinuation 
shall be reported in eCRF. 
In case of discontinuation for safety reason, the patient should be followed-up for safety purpose 
for 6 months and all the protocol specific assessment should be performed as planned. At the last 
visit, all the assessments planned for EOS visit shall be performed. See the SoA (Table 1-1) for 

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data to be collected at the time of discontinuation of study intervention and follow-up and for any 
further evaluations that need to be completed. 
Safety data shall be collected for all discontinued patients, who are discontinued due to an AE or 
SAE. In any case, every effort must be made to undertake protocol-specified safety follow-up 
procedures. If the patient is discontinued due to an event, patient should be given appropriate 
care under medical supervision until the symptoms of any AE resolve or the patient’s condition 
becomes stable. Fifteen percent dropout rate has been considered while estimating the sample 
size, hence patients who withdraw or are withdrawn from the study will not be replaced. 
7.3 Loss to Follow-up 
A patient will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patients and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined), counsel the patient on the 
importance of maintaining the assigned visit schedule and ascertain whether the patient 
wishes to and/or should continue in the study. 
• In cases in which the patient is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical 
record/eCRF. 
• Should the patient continue to be unreachable, she will be considered to have withdrawn 
from the study. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1). Protocol waivers or 
exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 

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All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
All reasonable measures will be taken to decrease potential transmission of COVID-19; for 
example, clinic staff and physicians will wear surgical masks and gloves while meeting with 
patients and will wash their hands per the Center for Disease Control5 guidelines before, 
between, and after meeting each participant.  
The study procedures described below will be carried out at the study visits: 
Visit 1 / Screening Period (Day -35 to Day -1) 
The screening procedures will be completed within up to 35 days (5 weeks) from the signing of 
the ICF. 
• Written informed consent will be taken from the patients. No study related procedure will be 
conducted prior to obtaining informed consent. 
• While patient consent is being recorded for the main study, consent should also be obtained 
for continued participation into the open-label, switch-over study until Month 18. For 
patients volunteering to participate in PK sub-study, an additional written signed and dated 
consent will be obtained prior to randomization. 
• Assessment of patient eligibility as per inclusion and exclusion criteria 
• Demographics (age, sex, body weight [in kg], height, race, ethnicity) will be noted 
• Complete physical examination (including oro-dental examination) 
• Medical/Surgical history: Relevant medical history will be collected including prior and 
ongoing medical illnesses, conditions, and surgical procedures (including fracture history and 
family history of premature cardiovascular disease) 
• Prior medication/surgical history 
• Current medical conditions 

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• Signs and symptoms of COVID-19 (especially fever, cough, difficulty in breathing, loss of 
taste and smell) along with recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine shall be evaluated. Patients having signs and symptoms of 
COVID-19 or recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine will be further evaluated for SARS-CoV-2 infection as per the 
local guidelines. Patient may be contacted by phone one day prior to every visit for assessing 
COVID-19 symptoms and signs and will be asked not to attend the site in case of suspected 
reports 
• Vital signs will be recorded as described in the Section 8.2.2. 
• 12-lead ECG 
• Vitamin D supplements will be dispensed during the screening period, if required, for 
replenishment of vitamin D deposits. 
• Lateral thoracic and lumbar spine X-ray for fracture/vertebral abnormality assessment 
• DXA for lumbar spine, total hip, and femoral neck assessment  
• Blood sample collection: 
• 
Hematology: total leukocyte count (white blood cell [WBC] count), total erythrocyte 
count (red blood cell [RBC] count), hemoglobin, platelet count and absolute neutrophil 
count (ANC) 
• 
Serology: HIV, HBsAg, HCV assessment 
• 
Serum chemistry: liver function tests (ALT, ASP, ALP, total bilirubin, albumin and 
total proteins), kidney function tests (blood urea nitrogen [BUN], creatinine, and 
estimated glomerular filtration rate [eGFR]), electrolytes (sodium, potassium, and 
chloride), glucose, serum calcium, albumin-adjusted calcium, magnesium, and 
phosphorus. 
• 
25 (OH) vitamin D level assessment. 
Note: During screening, if the 25 (OH) vitamin D level of a patient is < 20 ng/mL (<50 
mmol/L), replenishment of vitamin D deposits can be attempted following sites 
standard of care (e.g., loading dose of Vitamin D). After replenishment, vitamin D 
should be retested to confirm value is within the eligibility range. 
• 
FSH assessment 
• 
Thyroid function tests (T3, T4, TSH) 
• 
Intact Parathyroid hormone test (iPTH) 
• Urine sample collection for routine urine analysis: Color, transparency, pH, specific gravity, 
glucose, ketones, bilirubin, blood, nitrite, urobilinogen, leukocyte esterase, and microscopic 
examination including RBC, leucocytes, epithelial cell, bacteria, and crystals 

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• AE/SAE recording and reporting 
• Concomitant medications assessment 
Visit 2/Day 1 
• Assessment of patient eligibility as per inclusion and exclusion criteria 
• Brief physical examination including oro-dental examination which should be performed 
before IP administration 
• Signs and symptoms of COVID-19 (especially fever, cough, difficulty in breathing, loss of 
taste and smell) along with recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine shall be evaluated. Patients having signs and symptoms of 
COVID-19 or recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine will be further evaluated for SARS-CoV-2 infection as per the 
local guidelines. Patient may be contacted by phone one day prior to every visit for assessing 
COVID-19 symptoms and signs and will be asked not to attend the site in case of suspected 
reports 
• Vital signs will be recorded as described in Section 8.2.2 
• Randomization 
• Patient diary will be dispensed and patients will be instructed on how to fill the diary 
• IP administration 
• Monitoring of injection site reaction at least for - one hour 
• Dispensing of calcium and vitamin D supplements for daily dosing 
• Blood sample collection 
• 
Anti-denosumab antibodies (ADA) assessment 
• 
PK assessment (only for patients participating in the PK sub-study) 
• 
sCTX and sP1NP 
• AE/SAE recording and reporting 
• Concomitant medication assessment 
Visit 3 / Day 8 (Month 1) and Visit 4 / Day 15 (Month 1): ± 3 Days 
Day 8 will be an additional visit for patients participating in the PK sub-study. Details pertaining 
to sampling time points are provided in Section 8.4. 

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• Brief physical examination 
• Signs and symptoms of COVID-19 (especially fever, cough, difficulty in breathing, loss of 
taste and smell) along with recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine shall be evaluated. Patients having signs and symptoms of 
COVID-19 or recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine will be further evaluated for SARS-CoV-2 infection as per the 
local guidelines. Patient may be contacted by phone one day prior to every visit for assessing 
COVID-19 symptoms and signs and will be asked not to attend the site in case of suspected 
reports 
• Vital signs will be recorded as described in Section 8.2.2 
• Patient diary will be reviewed 
• Dispensing of calcium and vitamin D supplements for daily dosing 
• Serum calcium levels will be monitored for all patients on Day 15 
• Blood sample will be collected for PK assessment on Day 8 and Day 15 
• Blood sample collection for assessment of sCTX and sP1NP 
• AE/SAE recording and reporting 
• Concomitant medication assessment 
Visit 5 /Month 1 (Day 30) and Visit 6/Month 3 (Day 90): ± 3 days; 
Visit 7 / Month 6 (Day 180), Visit 8/Month 9 (Day 270): ±7 days 
• Brief physical examination on all visits: This examination will also include oro-dental 
examination before IP administration only on Month 6 
• Signs and symptoms of COVID-19 on all visits (especially fever, cough, difficulty in 
breathing, loss of taste and smell) along with recent history of travel/contact with any 
COVID-19 positive patient/isolation/quarantine shall be evaluated. Patients having signs and 
symptoms of COVID-19 or recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine will be further evaluated for SARS-CoV-2 infection as per the 
local guidelines. Patient may be contacted by phone one day prior to every visit for assessing 
COVID-19 symptoms and signs and will be asked not to attend the site in case of suspected 
reports 
• Vital signs will be recorded as described in Section 8.2.2 on all visits 
• 12-lead ECG at Month 6 

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• Patient diary review on all visits 
• IP will be administered at Month 6 
• Monitoring of injection site reaction at least for - one hour at Month 6 
• Dispensing of calcium and vitamin D supplements for daily dosing 
• The 25 (OH) vitamin D level of all patients will be re-tested at Month 6 
• TSH at Month 6 
• DXA for lumbar spine, total hip and femoral neck assessment at Month 6 
• Blood sample collection for the following: 
• 
Hematology: total leukocyte count (WBC count), total erythrocyte count (RBC count), 
hemoglobin, platelet count and absolute ANC at Month 6 
• 
Serum chemistry: liver function tests (ALT, AST, ALP, total bilirubin, albumin and total 
proteins), kidney function tests (BUN, creatinine, and eGFR, electrolytes [sodium, 
potassium, and chloride]), glucose, serum calcium, albumin-adjusted calcium, 
magnesium, and phosphorus at Months 3, 6, and 9 
• 
sCTX and sP1NP at Months 1 (Day 30), Month 3 and Month 6 
• 
ADA assessment at Month 1, Month 3, Month 6, and Month 9 
• 
PK assessment will be measured at Month 1 (Day 30), Month 3 and Month 6 (prior to 
second dose) (only for patients consenting to participate in the PK sub-study) 
• Urine sample collection for routine urine analysis: Color, transparency, pH, specific gravity, 
glucose, ketones, bilirubin, blood, nitrite, urobilinogen, leukocyte esterase, and microscopic 
examination including RBC, leukocytes, epithelial cells and bacteria, crystals at Month 3, 
Month 6, and Month 9. 
• AE/SAE recording and reporting 
• Concomitant medications assessment 
Visit 9/Month 12 (Day 360) [±7 days] 
• Re-consent on Month 12 from patients initially randomized to Prolia® arm who volunteer to 
continue to participate in the open-label, switch-over study. 
• Brief physical examination including oro-dental examination before IP administration  

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• Signs and symptoms of COVID-19 (especially fever, cough, difficulty in breathing, loss of 
taste and smell) along with recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine shall be evaluated. Patients having signs and symptoms of 
COVID-19 or recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine will be further evaluated for SARS-CoV-2 infection as per the 
local guidelines. Patient may be contacted by phone one day prior to every visit for assessing 
COVID-19 symptoms and signs and will be asked not to attend the site in case of suspected 
reports 
• Vital signs will be recorded as described in Section 8.2.2 
• Re-randomization of patients initially randomized to Prolia® arm who volunteer to continue 
to participate in the open-label, switch-over study 
• 12-lead ECG 
• Patient diary review 
• IP administration 
• Monitoring of injection site reaction at least for - one hour 
• Dispensing of calcium and vitamin D supplements for daily dosing 
• Lateral thoracic and lumbar spine X-ray for fracture/vertebral abnormality assessment 
• DXA for lumbar spine, total hip and femoral neck assessment 
• Blood sample collection for the following: 
• 
Hematology: total leukocyte count (WBC count), total erythrocyte count (RBC count), 
hemoglobin, platelet count and absolute ANC 
• 
Serum chemistry: liver function tests (ALT, AST, ALP, total bilirubin, albumin and total 
proteins), kidney function tests (BUN, creatinine, and eGFR, electrolytes [sodium, 
potassium, and chloride]), glucose, serum calcium, albumin-adjusted calcium, 
magnesium, and phosphorus 
• 
PK assessment 
• 
ADA assessment 
• Urine sample collection for routine urine analysis: Color, transparency, pH, specific gravity, 
glucose, ketones, bilirubin, blood, nitrite, urobilinogen, leukocyte esterase, and microscopic 
examination including RBC, leukocytes, epithelial cells and bacteria, crystals  
• AE/SAE recording and reporting 
• Concomitant medications assessment 

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Visit 10 / Month 15 (Day 450) [±7 days] 
This visit is applicable only for those patients participating in the open-label switch-over period. 
• Brief physical examination 
• Signs and symptoms of COVID-19 (especially fever, cough, difficulty in breathing, loss of 
taste and smell) along with recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine shall be evaluated. Patients having signs and symptoms of 
COVID-19 or recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine will be further evaluated for SARS-CoV-2 infection as per the 
local guidelines. Patient may be contacted by phone one day prior to every visit for assessing 
COVID-19 symptoms and signs and will be asked not to attend the site in case of suspected 
reports 
• Vital signs will be recorded as described in Section 8.2.2 
• Patient diary review 
• Dispensing of calcium and vitamin D supplements for daily dosing 
• Blood sample will be collected for ADA assessment 
• AE/SAE recording and reporting 
• Concomitant medication assessment 
End of Study assessment at Month 18 (Day 540) or Month 12 or Early 
Discontinuation/Withdrawal  
EOS will be conducted at Month 12 for patients initially randomized to receive ENZ215. 
• Brief physical examination 
• Signs and symptoms of COVID-19 (especially fever, cough, difficulty in breathing, loss of 
taste and smell) along with recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine shall be evaluated. Patients having signs and symptoms of 
COVID-19 or recent history of travel/contact with any COVID-19 positive 
patient/isolation/quarantine will be further evaluated for SARS-CoV-2 infection as per the 
local guidelines. Patient may be contacted by phone one day prior to every visit for assessing 
COVID-19 symptoms and signs and will be asked not to attend the site in case of suspected 
reports 
• Vital signs will be recorded as described in Section 8.2.2 

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• 12-lead ECG 
• Patient diary review and collection 
• Lateral thoracic and lumbar spine X-ray for fracture/vertebral abnormality assessment 
• Blood sample collection for the following: 
• 
Hematology: total leukocyte count (WBC count), total erythrocyte count (RBC count), 
hemoglobin, platelet count and ANC 
• 
Serum chemistry: liver function tests (ALT, AST, ALP, total bilirubin, albumin and total 
proteins), kidney function tests (BUN, creatinine, and eGFR), electrolytes (sodium, 
potassium, and chloride), glucose, serum calcium, albumin-adjusted calcium, 
magnesium, and phosphorus 
• 
ADA assessment at Month 18 
• Urine sample collection for routine urine analysis: Color, transparency, pH, specific gravity, 
glucose, ketones, bilirubin, blood, nitrite, urobilinogen, leukocyte esterase, and microscopic 
examination including RBC, leukocytes, epithelial cells, bacteria, and crystals 
• AE/SAE recording and reporting 
• Concomitant medications assessment 
Unscheduled Visit 
During the study, patients are free to contact the Investigator. Patient can come for unscheduled 
visits anytime during the study duration in case of AEs or aggravation of an existing disorder. 
During an Unscheduled Visit, laboratory tests and other investigations, if required, will be done 
at the Investigator’s discretion. 
Serum calcium levels will be tested locally in patients prior to dosing at Month 6 and Month 12. 
However, this can either be done on the same day as the dosing visit or at a separate unscheduled 
visit if required per local standard of care. If hypocalcemia is identified, the patient should not be 
dosed until calcium levels are corrected. 
PK sample collection 
A total of seven (7) PK blood samples will be collected from each patient in the study. Blood 
samples of about 3.5 mL each will be collected at baseline (Day 1), Day 8, Day 15, Month 1, 
Month 3, Month 6 (prior to second dose) and Month 12. For PK sampling on Day 8 and Day 15, 
a window period of ± 2 hours is allowed in relation to the time of IP administration on Day 1. 

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8.1 Efficacy Assessments 
The efficacy assessments will be performed as per timing summarized in the SoA (Table 1-1). 
BMD: DXA Spine and hip and femoral neck: All patients will undergo BMD assessments of 
the lumbar spine, total hip, and femoral neck performed by DXA at baseline (screening/Day 1), 
Month 6, and Month 12 and ET visit (if after Month 6 and prior to Month 12). 
DXA should be done and submitted as early as possible during the screening period to allow for 
enough time in case a repeat exam is requested by Medical Imaging. In addition, as far as 
possible, DXA should be done during the applicable study visits and before dosing. 
Exceptionally, in case DXA cannot be done before dosing and/or on the same day as the rest of 
the visit procedures at Month 6 and Month 12, it can be performed within the allowed window 
period of ±7 days (refer Section 1.3). The results will be evaluated by a central assessor. The 
same DXA machine will be used for all study procedures for a particular patient. Detailed 
instructions on DXA scan acquisition are provided separately in the Image Acquisition 
Guideline. 
Instrument quality control (IQC) is carried out in order to allow for correction of any DXA 
instrument calibration shifts or drift that may occur during the course of the study. Local spine 
phantom data will be obtained regularly from each DXA machine in the course of the study and 
this will be analyzed by cumulative sum analysis (CUSUM; analysis done by the software) to 
identify significant shifts or drifts in calibration and generate IQC corrections accordingly. These 
IQC corrections can then be applied to patient DXA BMD results accordingly. IQC BMD 
corrections are scanner and time-specific and are applied where necessary to the final DXA data 
set. Further information is provided in the BMD charter document.7 
8.2 Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Table 1-1). 
8.2.1 Physical Examinations 
The physical examination will be performed as per timing summarized in the SoA (Table 1-1). 
• A complete physical examination will be performed at screening only and will include, at a 
minimum, assessments of the cardiovascular, respiratory, gastrointestinal and neurological 
systems, and oro-dental examination. Height and weight will also be measured and recorded. 

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• A brief physical examination will be performed at all other visits and will include, at a 
minimum, general appearance, assessments of the skin, lungs, cardiovascular system, and 
abdomen (liver and spleen). Weight will also be measured and recorded at least 3 monthly 
i.e. at Visit 6, 7, 8, 9, 10, and 11. Oro-dental examination should be done at dosing visits prior 
to administration of study intervention. However, a complete physical examination may be 
done at other visits at the Investigator’s discretion.  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 Vital Signs 
Vital signs will be performed as per timing summarized in the SoA (Table 1-1). -Body 
temperature, heart rate, respiratory rate, and blood pressure will be assessed. Vital signs will be 
recorded in supine position after 5 minutes of rest: heart rate (beats/minute), blood pressure 
measurement (mmHg), respiratory rate (breaths/minute), and body temperature (°F/°C). 
8.2.3 Injection site reaction 
Patients will be observed at least for one hour for any injection site reaction after administration 
of the study intervention. An injection site reaction will be reported as AE. The intensity will be 
recorded as mild, moderate, or severe per CTCAE definitions: 
Intensity Grade 
Definition 
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 
8.2.4 Electrocardiograms 
Twelve-lead ECG(s) will be obtained as outlined in the SoA (Table 1-1) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT interval 
(QTc) intervals. 
8.2.5 Clinical Safety Laboratory Tests 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and the SoA 
(Table 1-1) for the timing and frequency. Laboratory samples for all patients will be assessed 

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using an accredited central laboratory and if required by a certified local laboratory. ADA 
assessment will be done at a bioanalytical laboratory. 
Qualified medical staff at the site will review, initial, and date all laboratory results. Any 
laboratory value outside the reference range that is considered clinically significant by the 
Investigator will be reported as AE and followed as appropriate. Reports from the central 
laboratory should be filed with the source documents for each patient. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents. 
Laboratory abnormalities that are considered clinically significant by the Investigator constitute 
an AE and should be recorded on the AE eCRF. Sample collection date and time shall be 
considered as AE onset date and time. Abnormal laboratory values or abnormal clinical findings 
at the time of screening will be considered as medical history and not AE. Whenever possible, a 
diagnosis, rather than a symptom should be provided (e.g., anemia instead of low hemoglobin). 
When an abnormal laboratory or test result corresponds to a sign/symptom of an already reported 
AE, it is not necessary to separately record the laboratory/test result as an additional event. 
All laboratory tests with values considered clinically abnormal during participation in the study 
or within 90 days after the last dose of study intervention should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the Investigator 
or Medical Monitor. 
• If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, where possible, and the 
Sponsor notified. 
• All protocol-required laboratory tests, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the SoA (Table 1-1). 
• If laboratory values from laboratory tests not specified in the protocol and performed at the 
institution’s local laboratory result in the need for a change in patient management or are 
considered clinically relevant by the Investigator (e.g., are considered to be an SAE or an AE 
or require dose modification), then the results must be recorded. 

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8.3 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix 4. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or a legally 
authorized representative [LAR]), investigator, or designated medically qualified staff. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs. 
All AEs regardless of seriousness or relationship to IP, spanning from the first visit planned in 
the Clinical Study Protocol/signature of the ICF (i.e. occurring during the screening period even 
in the absence of any administration of IP), up to EOS are to be recorded on the corresponding 
page of the CRF, i.e. AE/SAE form. 
Whenever possible, diagnosis or single syndrome should be reported instead of individual, 
separate symptoms. The Investigator should specify the date of onset, intensity, action taken with 
respect to IP, corrective treatment/therapy given, additional investigations performed, outcome 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused by the 
Investigational Product. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 
The outcome of the AEs will be assessed and recorded as per the following categories: 
• Recovered/resolved 
• Ongoing (Not resolved or stabilized on follow-up) 
• Recovered with sequelae 
• Unknown 
• Death 
8.3.1 Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the signing of informed consent until the end of study at the 
timepoints specified in the SoA (Table 1-1). 

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In addition, AE questioning will include specific questions regarding symptoms of COVID-19: 
fever, cough, dry throat, difficulty breathing, and potential exposure in the past 2 weeks. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of awareness, 
as indicated in Appendix 4. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
Confirmed and suspected SARS-CoV-2 infection and COVID-19 will be recorded as an 
AE/SAE. 
Investigators are not obliged to actively seek information on AEs or SAEs after the conclusion of 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a patient has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrence. 
8.3.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs and AESI will be followed until resolution, stabilization, or 
the patient is lost to follow-up (as defined in Section 7.3). Further information on follow-up 
procedures is given in Appendix 4.  
8.3.4 Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, see Appendix 4) by the Investigator to the Sponsor of an 
SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
patients and the safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. 

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An Investigator who receives an Investigator Safety Report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the Package insert and will notify the Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC), if appropriate according to local requirements. 
All SAEs that occur during the study, and all SAEs occurring up to 90 days after receiving the 
last dose of study intervention, whether considered to be associated with the study intervention 
or not, must be reported within 24 hours to the Parexel Safety Contact using the numbers in the 
List of Study Personnel. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
8.3.5 AEs of Special Interest 
AEs of special interest (AESI) include hypocalcemia, ONJ, atypical femoral fracture, fracture 
healing complications, severe infection (including skin infection) not leading to hospitalization, 
hypersensitivity leading to emergency room visit, and potential Hy’s law. Any AESI should be 
reported within 24 hours to Parexel. Clinical monitoring of calcium levels will be done at each 
pre-defined visit. If any patient presents with suspected symptoms of hypocalcemia during the 
study, calcium levels should be measured. If a patient develops hypocalcemia over the course of 
the study, calcium and/or vitamin D supplementation may be adjusted per Investigator’s medical 
judgment until the serum calcium concentration returns to the normal range. In addition, patients 
will be encouraged to report symptoms indicative of hypocalcemia. 
8.4 Pharmacokinetics 
PK study will be conducted in a subset of the population, i.e. 60 patients in each arm in order to 
have 50 evaluable patients in each arm. Summary of PK concentration will be provided.  
A total of seven (7) PK blood samples will be collected from each patient in the study. Blood 
sample of 3.5 mL each will be collected at baseline (Day 1), Day 8, Day 15, Month 1, Month 3 
Month 6 (prior to second dose), and Month 12. For PK sampling on Day 8 and Day 15, the visit 
window is ±3 days but a window period of ± 2 hours is allowed in relation to the time of IP 
administration on Day 1. 
8.5 Pharmacodynamics 
sCTX and sP1NP concentrations will be measured as specified in Table 1-1. All blood samples 
for a given patient should be collected prior to IP administration (if applicable for the visit) at 

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approximately the same time, in the morning (between 07:30 and 10:00 am), and after a 
minimum of 8 hours of fasting. Patients should refrain from strenuous physical exercise 24 hours 
prior to each blood collection for PD analysis. 
8.6 Genetics 
Genetics are not evaluated in this study. 
8.7 Biomarkers 
Biomarkers are not evaluated in this study. 
8.8 Immunogenicity Assessments 
A total of eight (8) blood samples will be collected from each patient in the study at baseline 
(Day 1), Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and Month 18. 
Antibodies to the study intervention will be evaluated in serum samples collected from all 
patients according to the SoA (Table 1-1). Additionally, blood samples should also be collected at 
the final visit from patients who discontinued study intervention or were withdrawn from the 
study. These samples will be tested by the Sponsor or Sponsor’s designee. 
Blood samples will be screened for antibodies binding to denosumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to denosumab and/or further characterize the immunogenicity of denosumab. 
The detection and characterization of antibodies to denosumab will be performed using a 
validated assay method by or under the supervision of the Sponsor. All samples collected for 
detection of antibodies to study intervention will also be evaluated for denosumab serum 
concentration to enable interpretation of the antibody data. Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study 
intervention(s). 
Samples may be stored for a maximum of 15 years following the last patient’s last visit for the 
study at a facility selected by the Sponsor to enable further analysis of immune responses to 
denosumab. 

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9 Statistical Considerations 
The statistical analysis plan (SAP) will be developed and finalized prior to database lock and 
unblinding. The SAP will include a detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses including primary and 
secondary endpoints. 
9.1 Statistical Hypotheses 
9.1.1 Multiplicity Adjustment 
Percentage change in BMD at lumbar spine (LS-BMD) from baseline to Month 12 and AUEC of 
sCTX over the initial 6 months [sCTX0-6m] (from Day 1 pre-dose to Month 6 pre-dose) are 
defined as co-primary endpoints. No multiplicity adjustment will be required to test hypotheses 
for the co-primary endpoints. 
9.2 Analysis Sets 
Intent-to-Treat (ITT) population: The ITT analysis population consists of all randomized 
patients who received at least one dose of study intervention in the double-blind treatment 
period. In the ITT analysis set, treatment is assigned based on the study intervention to which 
patients are randomized, regardless of which treatment they actually receive. 
Modified ITT (mITT) population: The mITT analysis population consists of all ITT patients 
who have baseline assessment and post-baseline LS-BMD value. 
Per-Protocol (PP) population: The PP population is a subset of the ITT population with the 
LS-BMD assessments at baseline and Month 12 and consists of all patients who do not have any 
major protocol deviations, receive the study intervention at baseline and Month 6, and have 
baseline and Month 12 data. 
Safety population: The safety population includes all randomized patients who receive at least 
one dose of study intervention. Patients will be analyzed according to treatment received. 
PD Population: The PD population consists of all patients in the safety population whose sCTX 
values are available in order to calculate pharmacodynamic parameter AUEC values for primary 
analysis and do not have any major protocol deviations which would affect sCTX or sP1NP 
measurement. 

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PK Population: The PK population is a subset of safety population with at least one evaluable PK 
endpoint (Cmax or AUC0-6 months) and no major protocol deviations affecting the PK parameters up 
to Month 12. 
9.3 Statistical Analyses 
9.3.1 General Considerations 
All data will be listed and descriptive analysis along with appropriate graphs will be provided by 
treatment. Categorical data shall be summarized by means of absolute and relative frequencies 
(counts and percentages) and continuous data by means of the number of observations, the 
arithmetic mean, standard deviation, minimum, median, maximum, confidence interval (CI), 
geometric mean and coefficient of variation as appropriate. 
Protocol deviations (missing assessments/visits) related to COVID-19 will be listed separately. 
9.3.2 Primary Endpoint Analysis 
The primary analyses will be performed at Month 12 for this study. 
The main objective of this study is to demonstrate similar efficacy and PD of ENZ215 and 
Prolia® in postmenopausal women with osteoporosis. This will be performed by comparing 
percentage change from baseline to Month 12 in LS-BMD as well as AUEC of percentage 
change from baseline in sCTX0-6m.   
The mean percentage change from baseline to Month 12 in LS-BMD will be analyzed using an 
analysis of covariance (ANCOVA) model including treatment, age strata, previous treatment 
with bisphosphonate and baseline BMD value as covariates. 
Summary statistics for the results include least-squares means (LSM) point estimates of the mean 
percentage change from baseline for each treatment group at Month 12. The point estimate of the 
difference in LSM between the groups as well as its two-sided 95% CI and associated p-value 
will be provided. 
The test product and reference product will be declared comparable if 95% CI of the treatment 
difference (test minus reference), the mean percentage change from baseline to Month 12 in 
LS-BMD is within the pre-defined equivalence margin of ± 1.45. 
The primary analysis population for LS-BMD analyses will be the ITT population. Sensitivity 
analyses will be performed on the mITT and PP population. 

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For the ITT analysis of LS-BMD, missing data in the reference arm will be assumed to be 
missing at random (MAR) and imputed assuming they would have behaved like patients in the 
same arm with complete data. Missing data in the treatment arm will be imputed using the 
“impute under the null” method by conducting two separate one-sided tests (for non-inferiority 
and non-superiority) at alpha=0.05 using a suitable multiple imputation technique. A sensitivity 
analysis will be performed to assess the robustness of the primary results by imputation under the 
MNAR (missing not at random) assumption using the tipping-point approach. 
Missing data in the secondary efficacy endpoints will be imputed using a suitable multiple 
imputation technique such as completer case missing value (CCMV) imputation. 
Primary Pharmacodynamic Analysis 
The individual serum concentration of sCTX will be listed and summarized by treatment group 
at each planned sampling time using descriptive statistics. Percent change from baseline derived 
from sCTX concentrations will be listed and summarized. 
The assessment of equivalence for the co-primary endpoint will be assessed based upon the 
90% CI of the ratio of the geometric mean (test/reference) for the percentage change from 
baseline in AUEC sCTX over the initial 6 Months contained within the pre-specified acceptance 
limits of 80% to 125%.  
ANCOVA will be performed on the log-transformed AUEC. The ANCOVA model will include 
treatment group as fixed effect, and baseline sCTX value as a covariate. The ANCOVA will 
include calculation of LSM for the treatment groups. The ratios of LSM will be calculated using 
the exponentiation of the LSM from the analyses on the corresponding log-transformed AUEC 
on the PD population. 
Descriptive statistics of AUEC of percentage change from baseline in sCTX after the first dose 
will be provided by treatment group. 
9.3.3 Secondary Endpoint(s) Analysis 
9.3.3.1 
Efficacy Endpoints 
The individual serum concentration of P1NP will be summarized by treatment group at each 
planned sampling time using descriptive statistics. Percent change from baseline of P1NP will be 
summarized in tabular and graphical format using PD population. 
The following secondary endpoints will be analyzed descriptively by treatment group using ITT 
population and sensitivity analyses will also be performed on the mITT and PP population: 

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• Percentage change in LS-BMD from baseline to Month 6 
• Percentage change in BMD at total hip and femoral neck from baseline to Month 6 and 
Month 12 
9.3.3.2 
Safety Endpoints 
The incidence of patients who develop binding and neutralizing anti-drug antibodies (ADAs) 
will be summarized by treatment descriptively for safety population.  
9.3.3.3 
Pharmacokinetics Endpoints 
Descriptive summary statistics of drug serum concentrations will be provided by treatment group 
and visit/sampling time points. 
Concentrations below the lower limit of quantification (LLOQ) will be considered as zero in 
summary statistics. Geometric means will not be reported if there are values below LLOQ. 
Summary statistics will be presented at baseline (Day 1), Day 8, Day 15, Month 1, Month 3, 
Month 6 (prior to second dose), and Month 12, as well as summary figures of mean 
concentrations over time by treatment. The analysis will be carried out on the PK population.  
More detail will be provided in the SAP. 
9.3.4 Safety Analyses 
Safety parameters such as incidence of AEs, clinically significant changes in physical 
examination findings, safety laboratory analytes (serum chemistry, hematology, and urinalysis), 
vital signs, and ECG will be descriptively summarized, for the treatment groups as appropriate. 
All safety analyses will be performed on the safety population. 
9.3.5 Other Analyses 
Analysis methodologies for other efficacy, immunogenicity, PK, and safety endpoints will be 
elaborated in the SAP. 
9.4 Interim Analyses 
Not applicable. 

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9.5 Sample Size Determination 
The sample size for study is computed to demonstrate equivalence of ENZ215 and Prolia® in the 
percent change from baseline in LS-BMD at 12 months. The equivalence margin is pre-defined 
at ±1.45%. Assuming a standard deviation (SD) of 4.16%, the study will have 90% power to 
demonstrate equivalence at the (2-sided) 2.5% level of significance with 214 evaluable patients 
in each treatment group. Allowing for a 15% dropout rate, 504 patients (252 per treatment group) 
will be required to be randomized in the study.7 
Considering the PD co-primary endpoint (percentage change from baseline in AUEC sCTX0-6m), 
healthy volunteer data8 were used for the sample size calculations due to the lack of information 
on AUEC sCTX0-m6 derived from the patient population. The expected variability to the proposed 
PD endpoint is considered to be significantly lower than that of the proposed efficacy endpoint 
(in the NCT2053753 study8, the inter-subject CV of AUEC sCTX0-m6 was approximately 28%). 
The correlation between the sCTX and LS-BMD is assumed to be zero. Most likely there will be 
a correlation between percentage change from baseline in LS-BMD and log(AUEC). It is 
difficult to estimate the value a-priori and the correlation of zero will provide a conservative 
estimate of the power. 
A total sample size of 428 patients will have >99.9% power for the co-primary endpoint 
percentage change from baseline in AUEC sCTX0-6m considering the CV of 28%. The overall 
power of the study will be approximately 90% to succeed on both the equivalence tests for 
co-primary endpoints. 

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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
The clinical study will be conducted as per the principles and requirements of Declaration of 
Helsinki (Ethical principles for medical research involving human subjects, revised by the 64th 
WMA General Assembly, Brazil, 2013) and are consistent with the ICH-GCP E6 (R2) 
guidelines, relevant United States Food and Drug Administration (US FDA) and European 
Medicines Agency (EMA) guidelines and applicable local regulatory requirements. 
Sponsor or each participating institution/hospital must provide this protocol (protocol 
amendment, if applicable) and associated documents for the review and approval to Ethics 
Committee registered with US FDA and EMA, for the formal approval of the study conduct. The 
decision of the EC signed by its chairman with EC composition, concerning the conduct of the 
study will be made in writing to the Investigator and a copy of this decision will be provided to 
the Sponsor before commencement of this study. If requested, a progress report during the study 
and a summary of the study at the end of the clinical study will be sent to the EC. The study will 
not commence until the committee has approved the final version of the protocol. 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
patients. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. 
• Notifying the IRB/IEC of SAE or other significant safety findings as required by IRB/IEC 
procedures 
10.1.2 Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 

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accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
Deviation from the study Protocol, especially the prescription of a dose other than that scheduled 
in the study Protocol, other modes of administration, other indication, and longer treatment 
periods, is not permitted and shall not be covered by the statutory patient Insurance scheme. 
10.1.3 Responsibilities of Investigators 
The Investigator(s) and delegated Investigator staff undertake(s) to perform the Clinical Study in 
accordance with this Clinical Study Protocol, guidelines for Good Clinical Practice and the 
applicable regulatory requirements. 
The Investigator must maintain confidentiality of all study related documents and take measures 
to prevent accidental or premature destruction of these documents. 
The Investigator is required to ensure compliance with all procedures required by the Clinical 
Study Protocol and with all study procedures provided by the Sponsor (including security rules). 
The Investigator agrees to provide reliable data and all information requested by the Clinical 
Study Protocol in an accurate and legible manner according to the instructions provided and to 
ensure direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data, particular attention should be paid to the confidentiality of 
the patient’s data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Sub-Investigators to assist in the conduct of the Clinical Study in accordance with the Clinical 
Study Protocol. All Sub-Investigators shall be appointed and listed in a timely manner. The 
Sub-Investigators will be supervised by and will work under the responsibility of the 
Investigator. The Investigator will provide them with a copy of the Clinical Study Protocol and 
all necessary information. 
10.1.4 Responsibilities of Sponsor and Study Management 
The Sponsor of this clinical study shall take all reasonable steps to ensure proper conduct of the 
Clinical Study Protocol as regards ethics, Clinical Study Protocol compliance, integrity and 
validity of the data recorded on the eCRFs. Thus, the main duty of the Monitoring Team is to 
help the Investigator and the Sponsor in maintaining a high level of ethical, scientific, technical, 
and regulatory quality in all aspects of the clinical study. 

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At regular intervals during the clinical study, the site will be contacted, through monitoring 
visits, letters or telephone calls, by a representative of the Monitoring Team to review study 
progress, Investigator and patient compliance with Clinical Study Protocol requirements, and any 
emergent problems. These monitoring visits will include, but not be limited to, review of the 
following aspects: patient informed consent, patient recruitment and follow-up, source data 
verification, SAE documentation and reporting, AEs with pre-specified monitoring 
documentation and reporting, AE documentation, IP allocation, patient compliance with the IP 
regimen, IP accountability, concomitant therapy use, and quality of data. 
10.1.5 Informed Consent Process 
The Investigator or a person designated by the Investigator, and under the Investigator’s 
responsibility, should completely inform the patients and/or their families describing this study 
and providing sufficient information to them for making an informed decision about their 
participation in this study. 
All the patients should be informed to the complete extent possible about the study, in language 
and terms they are able to understand. Consent form must be IRB/IEC approved and the patient 
will be provided the same in local language(s).  
Prior to patient’s participation in this study, the written informed consent form must be signed, 
name filled in and personally dated by the patient and by the person who conducted the informed 
consent discussion. A copy of the signed and dated written informed consent form will be 
provided to the patient. 
Patients must be informed that their participation is voluntary. Patients or the patient’s LAR will 
be required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, an international Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines, privacy and data protection requirements, 
where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB and 

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signed by all patients subsequently enrolled in the study as well as those currently enrolled in the 
study. 
10.1.6 Patient and Data Confidentiality 
Patient confidentiality along with the information disclosed/provided/produced by the Sponsor 
during the clinical study, including, but not limited to, the clinical study protocol, the eCRF, ICFs 
and results are strictly held in trust by the Sponsor, Sponsor’s authorized personnel, Investigator 
and their staff members. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor may inspect all documents 
and records required to be maintained by the Investigator, and pharmacy records for the patients 
in this study. The clinical study site will permit access to such records. 
However, the submission of this clinical study protocol and other necessary documentation to the 
ethics committee is expressly permitted, the EC members having the same obligation of 
confidentiality. The European Union (EU) General Data Protection Regulation (GDPR) will be 
followed for data protection and privacy for EU submission. 
10.1.7 Committees Structure 
10.1.7.1 Data Monitoring Committee 
A data monitoring committee (DMC) has been appointed for this study. The DMC is a group of 
independent scientists who are appointed to monitor the safety of a human research intervention. 
The composition of the committee is dependent upon the scientific skills and knowledge required 
for monitoring the particular study. 
10.1.8 Dissemination of Clinical Study Data 
After completion of study at 12 months, a report will be prepared for submitting it to EMA 
regulatory agency. Another report will be prepared for further study, i.e. the extension period of 
6 months (Month 18) and this report will be submitted to the US FDA and EMA regulatory 
agency.  
A final clinical study report will be prepared in accordance with the ICH E3 guideline on 
structure and content of Clinical Study Report, regardless of whether the study is completed or 
prematurely terminated. The final report will be prepared according to the electronic Common 
Technical Document (eCTD) format. Deviations from the protocol will be documented as 
protocol deviations and presented in the final report. 

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10.1.9 Auditing and Inspection 
The Investigator will permit study-related monitoring, audits and inspections by the EC, the 
Sponsor, government regulatory bodies, and quality assurance groups of all study related 
documents (e.g., source documents, regulatory documents, data collection instruments, study 
data, etc.). The Investigator agrees to allow the auditors or inspectors to have direct access to 
patient’s study records for review being understood that these personnel are bound by 
professional secrecy and as such will not disclose any personal identity or personal medical 
information. The confidentiality of the data verified and the protection of the patients should be 
respected during these inspections. 
The Investigator will ensure the capacity for inspections of applicable study-related facilities 
(e.g., pharmacy, diagnostic laboratory, study documents, etc.). Participation as an Investigator in 
this study implies acceptance of potential inspection by government regulatory authorities and 
quality assurance offices. As soon as the Investigator is notified of a future inspection by the 
authorities, he/she will inform the Sponsor and authorize the Sponsor to participate in these 
inspections. Any result and information arising from the inspections by the regulatory authorities 
will be immediately communicated by the Investigator to the Sponsor. 
10.1.10 Data Quality Assurance 
The Investigator by careful planning, assigning responsibilities to well qualified study personnel, 
and through continuous review, verifies and maintains desired level of quality in the study 
process. 
The Sponsor or Sponsor’s designee will serve as the statistical and data coordinating center for 
the present study and will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
Sponsor or the Sponsor’s designee will monitor the study and site activity while ongoing, to 
verify that the: 
• Data are authentic, accurate and complete 
• Safety and rights of the patients are being protected 
• Study is conducted in accordance with the currently approved protocol and amendments and 
any other study agreements, GCP, and all applicable regulatory requirements 
The pharmacokinetic and bioanalytical site will be responsible for quality assurance audit of 
pharmacokinetic and bioanalytical data respectively. 

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The electronic Case Report/Record Form (eCRF) is the primary data collection instrument for 
the study. All data requested on the eCRF must be recorded. All missing data must be explained. 
The electronic data capture (EDC) system maintains an audit trail on entries, changes, or 
corrections in the eCRF. All the data entries on the eCRF will be authenticated by the 
Investigator. 
Authorized site personnel will record the data (consistent with the source documents) in the 
provided study (e)CRF, accurately and in a timely manner. The Investigator is responsible for 
confirming data entries are complete and accurate by physically or electronically signing the 
eCRF. Study monitors will perform ongoing source data verification to ensure that data entered 
into the eCRF by authorized site personnel are consistent with the source documents. 
Data cleaning and processing will be managed through the electronic data capture (EDC) and 
data management system. The database development process will include the production of a 
code book containing annotated eCRF screens detailing the variable names used in the database. 
The EDC system will be programmed to capture all data in a dedicated database through the 
specified eCRF screens in a secure manner. Clinical Data will be recorded directly into an eCRF 
by assigned site personnel.  
All data should be recorded as early as possible within the eCRF. Access via the internet to the 
eCRF is defined through permission based roles, for example data entry or read-only. All 
changes to the eCRF are recorded, along with a reason for change, in the system audit trail. 
Username, password, and web-address will be provided to study personnel. 
When the database is complete and accurate, it will be locked. After the data have been entered 
and verified, various edit checks will be performed by Data Management Team for the purpose 
of ensuring the accuracy, integrity, and validity of the database against the eCRF. These should 
include: 
• Missing value checks 
• Range checks 
• Consistency checks 
• Sequence checks 
• Probabilistic checks and 
• Protocol adherence checks 

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It is the responsibility of the Investigator to resolve all data queries that arise during data 
management in a timely manner. 
10.1.11 Record Retention 
It is the responsibility of Sponsor to plan for safe and secure custody of all study related 
documents and material for a period of 5 years after the completion of the study or submission of 
the data to the regulatory authority(ies) whichever is later. These documents should be retained 
for a longer period of time, if required by an agreement with the Sponsor. In such an instance, it 
is the responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. The PK and bioanalytical data will be archived at the 
laboratories performing these tests. 
10.1.12 Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data reported in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
10.1.13 Study and Site Start and Closure 
First Act of Recruitment 
The study start date and first act of recruitment is the date when the first patient is screened for 
the study. 

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Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development. 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of patients by the 
Investigator. 
• Total number of patients included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow-up. 
10.1.14 Publication Policy 
It is the responsibility of Parexel to register this study on an applicable trial registry. On the basis 
of the statistical and clinical evaluation of the pooled results across the study centers, a clinical 
study report will be prepared. This can form the basis of a manuscript for publication in a peer-
reviewed journal. The Sponsor will hold the right to publish the results of present study at any 
time. An Investigator may seek permission to publish results of the study from the Sponsor. 

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10.1.15 Protocol Approval and Amendment 
Any change or addition to the protocol, other than administrative ones (i.e. typographical or 
logistical), can only be made in a written protocol amendment that must be approved by Sponsor, 
EMA where required, and the EC. Only amendments that are required for patient safety may be 
implemented prior to EC approval. 
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 violation of the protocol. In such cases, Sponsor should be 
notified of this action and the EC should be informed immediately. 
Changes to the protocol affecting only administrative aspects of the study do not require formal 
protocol amendments or EC approval but the EC must be kept informed of such administrative 
changes. Examples of administrative changes not requiring formal protocol amendments and EC 
approval include: 
• Changes in the staff used to monitor studies 
• Changes in shipping address for eCRF 
10.1.16 Protocol Deviations and Violations 
A protocol deviation/violation that is generally an unplanned excursion from the protocol that is 
not implemented or intended as a systematic change. A deviation or violation is any 
noncompliance with the requirements of clinical study protocol, Standard Operating Procedures 
(SOPs), and ICH-GCP-E6 (R2) guidelines. The noncompliance may be either on the part of the 
patient, the Investigator, or the study site staff. As a result of deviations or violation, corrective 
actions are to be developed by the site and implemented promptly. 
It is the responsibility of the site to observe vigilance to identify and report deviations 
immediately upon identification of the protocol deviation. All deviations must be promptly 
reported to Sponsor through written communication. All deviations from the protocol must be 
addressed in study patient source documents. A completed copy of the protocol deviation form 
must be maintained in the regulatory file as well as in the patient’s source document. Protocol 
deviations must be sent to the local EC, if required, per guidelines. The site Investigator/study 
staff is responsible for adhering to EC requirements. 

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10.1.17 Liability and Insurance 
Sponsor undertakes to maintain an appropriate clinical study insurance and indemnity policy. 
The insurance policy is in accordance with local laws and requirements. A copy of the insurance 
certificate will be provided to the EC. In the case of an injury occurring to the patient during the 
study, free medical management will be provided to the patients as long as required or till such 
time it is established that the injury is not related to the clinical study, whichever is earlier. 
10.1.18 Property Rights and Data Protection 
All information, documents, and IP provided by the Sponsor or its assignee are and remain the 
sole property of the Sponsor. The Investigator shall not mention any information or the product 
name in any application for a patent or for any other intellectual property rights. All the results, 
documents and inventions, which arise directly or indirectly from the clinical study in any form, 
shall be the exclusive property of the Sponsor. Any Investigator involved with this study is 
obliged to provide the Sponsor with complete test results and all data derived from the study. The 
Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical study. 
The data collected during the entire study will be included in the Sponsor database and shall be 
treated in compliance with the SOPs prepared according to applicable laws and regulations. 
When archiving or processing the data, Sponsor shall take all appropriate measures to safeguard 
and prevent access to this data by any unauthorized third party. 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. The patient must be informed 
that their personal study-related data will be used by the Sponsor in accordance with local data 
protection law. The level of disclosure must also be explained to the patient who will be required 
to give consent for their data to be used as described in the informed consent. The patient must 
be informed that their medical records may be examined by Clinical Quality Assurance auditors 
or other authorized personnel appointed by the Sponsor, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. 
 

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10.2 Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10-1 will be performed by the central laboratory. 
All patients will have the laboratory samples drawn as outlined in Table 1-1. Laboratory samples 
for all patients will be assessed using a certified central laboratory. PK and anti-denosumab 
antibody assessment will be done at bioanalytical laboratory. 
Qualified medical staff at the site will review, initial and date all laboratory results. Any 
laboratory value outside the reference range that is considered clinically significant by the 
Investigator will be reported as AE and followed as appropriate. Reports from the central 
laboratory should be filed with the source documents for each patient. 
Additional tests or safety assessments may be performed at any time in a certified local 
laboratory during the study as determined necessary by the Investigator or as required by local 
regulations. 
Investigators must document their review of each laboratory safety report. 
All samples collected for PK, PD, and immunogenicity assessment will be analyzed using 
validated bioanalytical methods. The details of collection, processing and shipment of biological 
samples will be outlined in a laboratory manual. 
Table 10-1 
Protocol-required Safety Laboratory Tests 
Laboratory Tests 
Parameters 
Hematology 
Leukocyte count (WBC count) 
Total erythrocyte count (RBC count), 
Hemoglobin 
Platelet count  
Absolute neutrophil count (ANC) 
Serum chemistry 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase (ALP) 
Total bilirubin 
Albumin  
Total proteins 
Kidney function tests: (Blood urea nitrogen [BUN], Creatinine, 
Glomerular filtration rate [eGFR]) 
Electrolytes (sodium, potassium, chloride) 
Glucose 

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Serum calcium, Albumin-adjusted calcium 
Magnesium 
Phosphorus 
Routine urinalysis 
Routine examination (Color, transparency, pH, specific gravity, 
glucose, ketones, bilirubin, blood, nitrite, urobilinogen, leukocyte 
esterase) 
Microscopic examination if blood, protein, leukocyte esterase or 
Nitrite is positive or if deemed necessary by the Investigator. 
Other blood tests 
Anti-Denosumab antibody 
sCTX 
sP1NP 
Serology: HIV, HBV, HCV 
25 (OH) vitamin D level 
Follicle stimulating hormone (FSH) 
Thyroid function test (T3, T4, TSH) 
Parathyroid hormone test (iPTH) 
NOTES: 
Liver chemistry stopping criteria: All events of ALT or AST ≥3 × upper limit of normal (ULN) and total bilirubin 
≥2 × ULN (>35% direct bilirubin) or ALT or AST ≥3 × ULN and INR >1.5, (if INR measured) which may 
indicate severe liver injury (possible Hy’s Law), must be reported to Parexel in an expedited manner. 
If alkaline phosphatase is elevated, consider fractionating. 
For further investigations such as USG, gastroenterologist or hepatologist should be consulted to rule out any 
other cause of deranged LFTs. Only if there is confirmed DILI should the patient be withdrawn from the study 
and should be followed-up until resolution or until the event has stabilized. 

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10.3 Appendix 3: Total blood loss 
Total volume of blood drawn for study will not exceed 166.5 mL+ 10 mL (if required) per 
patient during the entire study. 
Blood samples not collected at the scheduled time will be documented as sampling deviations. 
The actual time of collection of each blood sample will be used for statistical analysis. 
If patients are willing to participate in the PK assessment sub-study, an additional 
24.5 mL + 5 mL (if required) blood will be drawn from each patient as part of the PK 
assessment. 
Details of Blood Withdrawal 
Amount of Blood required 
Blood withdrawn for PK assessment on D1, D8, D15, M1, M3, M6, and M12 (07 
samples of 3.5 mL each)   
24.5 mL 
Total amount of blood required from each patient  
24.5 mL + 5 mL 
(if required) 
 
 
Details of Blood Withdrawal 
Amount of blood required 
Blood withdrawn for screening procedures  
20.0 mL 
Blood withdrawn for Hematology on M6, M12, and M18 (03 samples of 
3.0 ml each) 
09.0 mL 
Blood withdrawn for serum chemistry on D15, M3, M6, M9, M12 and 
M18 (06 samples of 5.0 ml each) 
30.0 mL 
Blood volume for sCTX and sP1NP on D1, D15, M1, M3 and M6 (05 
samples of 3.5 mL each) 
17.5 mL 
Blood volume for Denosumab Antibody Assay (ADAs) on D1, M1, M3, 
M6, M9, M12, M15 and M18 (08 samples of 10.0 mL each) 
80.0 mL 
Blood withdrawn for end of study safety assessment 
10.0 mL 
Total amount of blood required for each patient 
166.5 mL + 10 mL (If required) 

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10.4 Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.4.1 Definition of AE 
AE Definition 
As per ICH-GCP E6 (R2) guidelines, adverse event (AE) is any untoward medical occurrence 
in a patient or clinical investigation patient administered a pharmaceutical product regardless 
of its causal relationship to the study intervention. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of IP. 
 
Events Meeting the AE Definition 
Any medical condition that is present at the time that the patient is screened should be 
considered as baseline and not reported as an AE. However, if it deteriorates at any time during 
the study, it should be recorded as an AE. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (e.g., not related to progression of underlying disease) should be 
recorded as an AE. 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
New condition detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention interaction. 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae. 
 

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Events NOT Meeting the AE Definition 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
that are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the patient’s condition. 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s condition. 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
10.4.2 Definition of SAE 
An SAE is an AE that: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or intervention 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AE. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective intervention of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 

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f. Malignancy 
g. Other situations 
Medical or scientific judgment should be exercised by the Investigator in deciding whether 
SAE reporting is appropriate in other situations such as significant medical events that may 
jeopardize the patient or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be considered 
serious. 
Examples of such events 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 drug dependency or drug abuse. 
10.4.3 Recording and Follow-up of AE and SAE 
AE and SAE Recording 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) related to the 
event. 
The Investigator will then record all relevant AE/SAE information. 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to 
the Sponsor in lieu of completion of the eCRF/SAE reporting form. 
There may be instances when copies of medical records for certain cases are requested by the 
Ethic committee. In this case, all patient identifiers, with the exception of the patient number, 
will be blinded on the copies of the medical records before submission to the Ethic committee. 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 
Assessment of Intensity 
 The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories: 
Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category used for rating the intensity of an 
event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 

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Assessment of Causality 
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The Investigator will use clinical judgment to determine the 
relationship. 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in their assessment. 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report in the electronic data collection tool. However, it is 
very important that the Investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the electronic data collection tool. 
The Investigator may change their opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
The following “binary” decision choice will be used by the Investigator to describe the initial 
causality assessment: 
• Related: Reasonable possibility of a relatedness 
• Not related: No reasonable possibility of relatedness. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 

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Follow-up of AE and SAE 
Any follow-up information received for the SAE should be analyzed and reported as per the 
process and timelines mentioned for initial SAE reporting. 
The Investigator should take all appropriate measures to ensure the safety of the patients, 
notably he/she should follow up the outcome of any AE (clinical signs, laboratory values or 
other, etc.) until the patient returns to normal or consolidation of the patient’s condition. 
In case of any SAE, the patient must be followed up until clinical recovery is complete and 
laboratory results have returned to normal, or until progression has been stabilized. 
This may imply that follow-up will continue after the patient has left the clinical study. 
New or updated information will be recorded in the originally completed form. 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt 
of the information. 
10.4.4 Reporting of SAE 
SAE Reporting via Electronic/Paper Data Collection Tool 
For all sites:  If any SAE occurs in the course of the study, then Investigators or other site 
personnel inform the Parexel Global Safety Processing Group within 1 day, i.e. immediately 
but no later than 24 hours of when he or she becomes aware of the event. The Parexel Global 
Safety Processing Group works with the Investigator to ensure that all the necessary 
information is provided. 
Any AE considered serious by the Investigator or sub-investigator or which meets the 
aforementioned criteria is subjected for expedited reporting. All the SAEs will be reported as 
applicable to the local regulatory requirement.  
All serious and unexpected AEs will be followed until a satisfactory resolution or until the 
Investigator deems the event to be chronic or the patient to be stable. The further course of 
action for all SAEs; shall be observed as per current applicable rules and regulations. 
The primary mechanism for reporting an SAE will be the electronic data collection tool. If the 
electronic system is unavailable, then the site will use the paper SAE data collection tool (see 
next table) to report the event within 24 hours. The site will enter the SAE data into the 
electronic system as soon as it becomes available. 
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to Parexel Global Safety Processing Group mailbox 
(NorthAmerica_Medical@Parexel.com). 
If the EDC system is not available, then the Investigator or other study site staff reports a SAE 
to Parexel Global Safety Processing Group by email by completing the SAE report form and 
faxing the documents to Parexel Global Safety Processing Group, using the appropriate 
regional Parexel SAE fax number: NA (Billerica): +1 781 434 5957. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE report 
and the Sponsor/Parexel will evaluate the seriousness and the causal relationship of the event 
to study intervention. In addition, the Sponsor (or Sponsor’s designated agent) will evaluate 
the expectedness according to the Reference Safety Information (Investigator Brochure or 

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Summary of Product Characteristics). Based on the Investigator and Sponsor’s assessment of 
the event, a decision will be made concerning the need for further action. 
After the study is completed at a given site, the electronic data collection tool will be taken 
offline to prevent the entry of new data or changes to existing data. 
If a site receives a report of a new SAE from a study patient or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken offline, then 
the site can report this information on a paper SAE form. 
 
 
 

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10.5 Appendix 7: Abbreviations 
Abbreviation 
Description 
ACTH 
Adrenocorticotrophic Hormone 
ADAs 
Anti denosumab antibodies 
AE  
Adverse Event  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUEC 
Area Under the Effect Curve 
BMD 
Bone Mineral Density 
CDSCO 
Central Drugs Standard Control Organization 
CI 
Confidence Interval 
COA 
Certificates of Analysis 
COVID-19 
Corona Virus Disease 2019 
CRO  
Contract Research Organization  
DMC 
Data Monitoring Committee 
DXA 
Dual-energy X-ray Absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
ENZ215 
Proposed biosimilar to Prolia® 
EOS 
End of Study 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin-Releasing Hormone 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV  
Human Immunodeficiency Virus  
ICF  
Informed Consent Form  
ICH  
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC  
Independent Ethics Committee  
IP  
Investigational Product  
iPTH 
Intact Parathyroid Hormone 
IQC 
Instrument Quality Control 

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Abbreviation 
Description 
ITT 
Intent-to-Treat 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LAR 
Legally Authorized Representative 
LS-BMD 
Bone Mineral Density at Lumbar Spine 
LSM 
Least-Squares Means 
MVF 
Multiple Vertebral Fractures 
ONJ 
Osteonecrosis of the Jaw 
PA 
Posteroanterior 
P1NP 
Procollagen Type 1 N-terminal Propeptide 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
Q6M 
Once Every 6 months 
RANKL 
Receptor Activator of Nuclear Factor Kappa-B Ligand 
RBC 
Red Blood Cell 
SAE  
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome CoronaVirus-2 
SC 
Subcutaneously 
sCTX 
Serum C-Telopeptide of Type 1 Collagen 
SD 
Standard Deviation 
SOA 
Schedule of Activities 
SOP  
Standard Operating Procedure  
ULN 
Upper Limit of Normal 
USA 
United States of America  
USFDA 
United States Food and Drug Administration 
WBC 
White Blood Cell 
 
 
 

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10.6 Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). 
Amendment 2: (8 April 2022) 
Section 
Description of Change 
Brief 
Rationale 
Section 2.3.1 
Risk 
Assessment 
Table 2-3 Risk Assessment: Fertility, pregnancy and 
lactation mitigation was changed from “Pregnant women 
and women of child-bearing potential not using 
contraception will not be enrolled in the study” to “Only 
postmenopausal women aged ≥ 55 and ≤ 85 years will be 
enrolled in the study”. 
For consistency 
with inclusion 
criteria 
Section 5.2 
Exclusion 
Criteria 
Exclusion criteria #10 language has been updated. 
Clarify 
 
Amendment 1: (16 December 2021) 
Summary of Changes 
Section 
Description of Change 
Brief Rationale 
Title Page 
Updated the address of Co-Sponsor, Enzene 
Biosciences Ltd 
Change in address 
of the Co-Sponsor 
Section 5.2 
Exclusion 
Criteria 
Exclusion criteria #13 was changed from “Total hip 
or femoral neck T-score <4.0” to “Total hip or 
femoral neck T-score <−4.0” 
Clarify 

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11 References 
 United States Food and Drug Administration. Guidance for Industry: Scientific 
Considerations in Demonstrating Biosimilarity to a Reference Product. April 2015. Scientific 
Considerations in Demonstrating Biosimilarity to a Reference Product | FDA. Accessed 
September 2021 
 Summary of Product Characteristics (SmPC): Prolia® 60 mg solution for injection in pre-
filled syringe; Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands, 
Updated 22 July 2021 
 USFDA Prescribing Information of Prolia® (denosumab) Injection, for subcutaneous use; 
Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799, May 2021 
 Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus) 
pandemic, EMA, Version 4 (04/02/2021). 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdfFDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Public Health Emergency, March 2020, Updated on 
January 27, 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-
health-emergency  
 https://www.cdc.gov/handwashing/when-how-handwashing.html 
 Lu Y, Mathur AK, Blunt BA et al. Dual X-Ray Absorptiometry Quality Control: Comparison 
of Visual Examination and Process-Control Charts. Journal of Bone and Mineral Research. 
1996;11:626-637 
 USFDA's Guidance for Industry: Statistical Approaches to Establishing Bioequivalence; 
January 2001 
 Bioequivalence Study of Denosumab CP4 Drug Product and Commercially Available 
Denosumab CP2 Drug Product - Study Results - ClinicalTrials.gov. Accessed on 22 October 
2021 
 
 

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Investigator Agreement Page 
Declaration of the Principal or Global Coordinating Investigator 
Title: A Phase 3, Randomized, Double-blind, Parallel-group, Active-controlled Study to Compare 
the Efficacy, Safety, Pharmacodynamics, Pharmacokinetics and Immunogenicity of Enzene 
Denosumab (ENZ215) and Prolia® in Postmenopausal Women with Osteoporosis 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the IP as well as 
with the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki (Ethical principles for medical research involving human subjects, 
revised by the 64th WMA General Assembly, Brazil, 2013) and the guidelines on Good Clinical 
Practice. 
Principal or Global Coordinating Investigator 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 
 
 

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Declaration of the Investigator 
Title: A Phase 3, Randomized, Double-blind, Parallel-group, Active-controlled Study to 
Compare the Efficacy, Safety, Pharmacodynamics, Pharmacokinetics and Immunogenicity of 
Enzene Denosumab (ENZ215) and Prolia® in Postmenopausal Women with Osteoporosis 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, EDCs/eCRF, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
IRB or IEC. No changes will be made to the study protocol without the prior written approval of 
the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the 
patients. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the Local Study Center 
 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number