A Double-blind, Randomized, Active-controlled, Phase 3 Study to Compare Efficacy, Pharmacokinetics, Pharmacodynamics, and Safety of CT-P41 and US-licensed Prolia in Postmenopausal Women With Osteoporosis
Phase: PHASE3
Conditions: Postmenopausal Women With Osteoporosis
Sponsor: Celltrion

 
 
CLINICAL STUDY PROTOCOL 
A Double-blind, Randomized, Active-controlled, Phase 3 Study to Compare 
Efficacy, Pharmacokinetics, Pharmacodynamics, and Safety of CT-P41 and 
US-licensed Prolia in Postmenopausal Women with Osteoporosis 
PROTOCOL NUMBER CT-P41 3.1 
 
EudraCT Number: 
2020-005974-91 
Investigational Product: 
CT-P41 (proposed Prolia biosimilar) 
Sponsor: 
CELLTRION, Inc. 
23, Academy-ro, Yeonsu-gu, Incheon, 
22014, Republic of Korea 
Phone: +82 32 850 5000 
Fax: +82 32 850 5050 
E-mail: contact@celltrion.com 
 
 
 
 
 
 
  
 
 
 
 
 
Version and Date of Protocol 
Protocol Version 2.1, including country specific A.0, 18 
April 2022 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by CELLTRION, Inc. The concepts and 
information contained in this document or generated during the study are considered proprietary and may not 
be disclosed in whole or in part without the expressed, written consent of CELTLRION, Inc. The study will 
be conducted according to the protocol and in compliance with the International Conference on 
Harmonization harmonized tripartite guideline E6(R2): Good Clinical Practice. With declaration of Helsinki 
(WMA 2013). Throughout this document, symbols indicating proprietary names (®, ™) are not displayed. 
The appearance of product names without these symbols does not imply that these names are not protected. 

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DECLARATION OF INVESTIGATOR 
I have read and understood all sections of the protocol entitled ‘A Double-blind, 
Randomized, Active-controlled, Phase 3 Study to Compare Efficacy, Pharmacokinetics, 
Pharmacodynamics, and Safety of CT-P41 and US-licensed Prolia in Postmenopausal 
Women with Osteoporosis’ and the accompanying current Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Protocol Version 2.1, including country specific A.0, dated 18 
April 2022, the International Council for Harmonisation harmonised tripartite guideline 
E6(R2): Good Clinical Practice, Declaration of Helsinki (World Medical Association 2013), 
and all applicable government regulations. I will not make changes to the protocol before 
consulting with CELLTRION, Inc. or implement protocol changes without Independent 
Ethics Committee (or Institutional Review Board) approval except to eliminate an immediate 
risk to patients. I agree to administer study drug only to patients under my personal 
supervision or the supervision of a Sub-Investigator. 
I will not supply the study drug to any person not authorized to receive it. Confidentiality 
will be protected. Patient identity will not be disclosed to third parties or appear in any study 
reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from CELLTRION, Inc. 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 
 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ......................................................................................................... 1 
PROTOCOL APPROVAL .................................................................................................................. 2 
DECLARATION OF INVESTIGATOR............................................................................................ 3 
TABLE OF CONTENTS ..................................................................................................................... 4 
LIST OF TABLES ................................................................................................................................. 9 
LIST OF FIGURES .............................................................................................................................. 10 
PROTOCOL SYNOPSIS ................................................................................................................... 11 
LIST OF ABBREVIATIONS ............................................................................................................ 18 
1 
Introduction ................................................................................................................................ 20 
1.1 
Background ................................................................................................................... 20 
1.1.1 
Osteoporosis .................................................................................................................. 20 
1.1.2 
Denosumab .................................................................................................................... 21 
1.2 
CT-P41 .......................................................................................................................... 21 
1.2.1 
Nonclinical Studies........................................................................................................ 22 
1.2.2 
Clinical Studies.............................................................................................................. 22 
1.3 
Study Rationale ............................................................................................................. 22 
1.3.1 
Rationale for Study Population ..................................................................................... 23 
1.3.2 
Rationale for Dose Selection ......................................................................................... 24 
1.4 
Benefit and Risk Assessment ........................................................................................ 24 
2 
Study Objectives ......................................................................................................................... 25 
2.1 
Primary Objective.......................................................................................................... 25 
2.2 
Secondary Objective ...................................................................................................... 25 
3 
Investigational Plan .................................................................................................................... 26 
3.1 
Study Design ................................................................................................................. 26 
4 
Patient Selection and Withdrawal Criteria .............................................................................. 29 
4.1 
Selection of Study Population ....................................................................................... 29 
4.1.1 
Inclusion Criteria ........................................................................................................... 29 
4.1.2 
Exclusion Criteria .......................................................................................................... 30 
4.2 
Withdrawal of Patients from the Study ......................................................................... 33 
4.2.1 
Discontinuation of Study Treatment ............................................................................. 33 
4.2.2 
Termination of the Study ............................................................................................... 34 
4.3 
Replacement and Rescreening of Patients ..................................................................... 35 

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4.4 
Premature Termination of the Study ............................................................................. 35 
5 
Study Treatment ......................................................................................................................... 37 
5.1 
Method of Assigning Patients to Treatment Groups ..................................................... 37 
5.2 
Identity of Investigational Products............................................................................... 37 
5.3 
Treatment Administered ................................................................................................ 38 
5.3.1 
CT-P41 and US-licensed Prolia..................................................................................... 38 
5.3.2 
Co-administration of Calcium and Vitamin D .............................................................. 38 
5.4 
Prior, Concomitant, and Subsequent Therapy ............................................................... 39 
5.5 
Prohibited Therapy ........................................................................................................ 40 
5.6 
Management of Clinical Supplies ................................................................................. 41 
5.6.1 
Study Drug Package, Labeling, and Storage ................................................................. 41 
5.6.2 
Study Drug Accountability ............................................................................................ 42 
5.7 
Blinding ......................................................................................................................... 42 
5.7.1 
Breaking the Blind......................................................................................................... 43 
5.8 
Treatment Compliance .................................................................................................. 43 
6 
Study Assessments and Procedures .......................................................................................... 45 
6.1 
Efficacy Assessments .................................................................................................... 45 
6.1.1 
Bone Mineral Density ................................................................................................... 45 
6.1.1.1 
Screening Bone Mineral Density Assessment ............................................................... 46 
6.1.1.2 
On-Study Bone Mineral Density Assessment ............................................................... 46 
6.1.2 
Incidences of Fractures .................................................................................................. 46 
6.1.2.1 
Vertebral Fractures ........................................................................................................ 47 
6.1.2.2 
Nonvertebral Fractures .................................................................................................. 48 
6.1.3 
Quality of Life Assessment ........................................................................................... 48 
6.1.3.1 
Osteoporosis Assessment Questionnaire Short Version (OPAQ-SV ) .......................... 48 
6.1.3.2 
EuroQoL-5 Dimensions-5 Levels Health Survey (EQ-5D-5L) ..................................... 49 
6.2 
Pharmacokinetic Assessments ....................................................................................... 49 
6.3 
Pharmacodynamic Assessments .................................................................................... 49 
6.4 
Safety Assessments ....................................................................................................... 50 
6.4.1 
Adverse Events .............................................................................................................. 50 
6.4.1.1 
Definitions of Adverse Events ...................................................................................... 50 
6.4.1.1.1 
Adverse Events of Special Interest ........................................................................ 51 
6.4.1.1.2 
Serious Adverse Events ......................................................................................... 52 
6.4.1.1.3 
Unlisted (Unexpected) Serious Adverse Events .................................................... 53 

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6.4.1.2 
Eliciting and Documenting Adverse Events .................................................................. 53 
6.4.1.3 
Reporting Adverse Events ............................................................................................. 54 
6.4.1.4 
Reporting Serious Adverse Events ................................................................................ 55 
6.4.1.5 
Suspected Unexpected Serious Adverse Reactions ....................................................... 56 
6.4.1.6 
Assessment of Severity ................................................................................................. 56 
6.4.1.7 
Assessment of Causality ................................................................................................ 57 
6.4.2 
Other Safety Assessments ............................................................................................. 58 
6.4.2.1 
Medical History, Disease History, and Demographic Information ............................... 58 
6.4.2.2 
Immunogenicity Assessment ......................................................................................... 58 
6.4.2.3 
Injection Site Reaction Monitoring ............................................................................... 58 
6.4.2.4 
Hypersensitivity/Allergic Reaction Monitoring ............................................................ 59 
6.4.2.5 
Vital Signs, Weight, Height, and Body Mass Index ...................................................... 59 
6.4.2.6 
Electrocardiogram ......................................................................................................... 60 
6.4.2.7 
New York Heart Association Functional Classification................................................ 60 
6.4.2.8 
Physical Examination .................................................................................................... 60 
6.4.2.9 
Osteonecrosis of the Jaw ............................................................................................... 61 
6.4.2.10 
Atypical Femoral Fracture ..................................................................................... 61 
6.4.2.11 
Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus ............................ 61 
6.4.2.12 
Pregnancy .............................................................................................................. 63 
6.4.2.13 
Clinical Laboratory Analyses ................................................................................ 63 
6.4.2.14 
Patient’s Assessment of Local Site Pain ................................................................ 65 
6.5 
Sample Collections ........................................................................................................ 65 
6.5.1 
Pharmacokinetic Blood Sampling ................................................................................. 65 
6.5.2 
Pharmacodynamic Blood Sampling .............................................................................. 65 
6.5.3 
Immunogenicity Blood Sampling ................................................................................. 65 
6.5.4 
Routine Safety Blood Sampling .................................................................................... 66 
6.6 
Labeling, Storage, and Transportation of Samples........................................................ 66 
6.6.1 
Sample Labeling ............................................................................................................ 66 
6.6.2 
Sample Storage and Shipment ....................................................................................... 66 
7 
Statistical Analysis Plan ............................................................................................................. 67 
7.1 
Primary Endpoint .......................................................................................................... 67 
7.2 
Secondary Endpoints ..................................................................................................... 67 
7.2.1 
Efficacy Endpoints ........................................................................................................ 67 
7.2.2 
Pharmacokinetic Endpoints ........................................................................................... 67 

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7.2.3 
Pharmacodynamic Endpoints ........................................................................................ 68 
7.2.4 
Safety Endpoints............................................................................................................ 68 
7.3 
Sample Size Calculation ................................................................................................ 69 
7.4 
Analysis Sets ................................................................................................................. 69 
7.5 
Description of Subgroups to be Analyzed ..................................................................... 70 
7.6 
Statistical Analysis Methodology .................................................................................. 70 
7.6.1 
General Consideration ................................................................................................... 70 
7.6.2 
Demographics, Baseline and Background Characteristics ............................................ 70 
7.6.3 
Efficacy Analyses .......................................................................................................... 71 
7.6.3.1 
Primary Efficacy Endpoint ............................................................................................ 71 
7.6.3.1.1 
Sensitivity Analysis of Primary Efficacy Endpoint ............................................... 72 
7.6.3.1.2 
Subgroup Analysis by Race and Age .................................................................... 72 
7.6.3.2 
Secondary Efficacy Endpoints ...................................................................................... 72 
7.6.4 
Pharmacokinetic Analyses ............................................................................................ 73 
7.6.5 
Pharmacodynamic Analyses .......................................................................................... 73 
7.6.6 
Safety Analyses ............................................................................................................. 73 
7.6.6.1 
Adverse Events .............................................................................................................. 74 
7.6.6.2 
Immunogenicity............................................................................................................. 74 
7.6.6.3 
Electrocardiograms, Physical Examinations, Vital Signs, Weight, Height, and Body 
Mass Index.................................................................................................................................... 74 
7.6.6.4 
Clinical Laboratory Analyses ........................................................................................ 74 
7.6.6.5 
Prior and Concomitant Medications .............................................................................. 75 
7.6.6.6 
Patient’s Assessment of Local Site Pain ....................................................................... 75 
7.6.6.7 
Other Safety Analyses ................................................................................................... 75 
7.7 
Interim Analysis ............................................................................................................ 75 
7.8 
Data Quality Assurance ................................................................................................. 75 
8 
Investigator’s Obligations .......................................................................................................... 77 
8.1 
Confidentiality ............................................................................................................... 77 
8.2 
Independent Ethics Committee or Institutional Review Board ..................................... 77 
8.3 
Patient Information and Consent ................................................................................... 78 
8.4 
Study Reporting Requirements ..................................................................................... 79 
8.5 
Financial Disclosure and Obligations ............................................................................ 79 
8.6 
Investigator Documentation .......................................................................................... 80 
8.7 
Study Conduct ............................................................................................................... 81 

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8.8 
Data Collection .............................................................................................................. 81 
8.8.1 
Electronic Case Report Forms and Source Documents ................................................. 81 
8.9 
Adherence to Protocol ................................................................................................... 82 
8.10 
Adverse Events and Study Report Requirements .......................................................... 82 
8.11 
Investigator’s Final Report ............................................................................................ 82 
8.12 
Record Retention ........................................................................................................... 82 
8.13 
Patients Identification Register...................................................................................... 82 
8.14 
Publications ................................................................................................................... 83 
9 
Study Management ..................................................................................................................... 84 
9.1 
Sponsor .......................................................................................................................... 84 
9.2 
Vendor Contact.............................................................................................................. 84 
9.3 
Central Analytical Facilities .......................................................................................... 85 
9.4 
Monitoring ..................................................................................................................... 85 
9.4.1 
Data Safety Monitoring Board ...................................................................................... 85 
9.4.2 
Monitoring of the Study ................................................................................................ 85 
9.4.3 
Inspection of Records .................................................................................................... 85 
9.5 
Management of Protocol Amendments and Deviations ................................................ 86 
9.5.1 
Modification of the Protocol ......................................................................................... 86 
9.5.2 
Protocol Deviations ....................................................................................................... 86 
9.6 
Study Termination ......................................................................................................... 87 
9.7 
Final Report ................................................................................................................... 87 
10 Reference List ............................................................................................................................. 88 
11 Appendices .................................................................................................................................. 92 
11.1 
Schedule of Assessments ............................................................................................... 92 
11.2 
Osteoporosis Assessment Questionnaire Short Version (OPAQ-SV) ........................... 96 
11.3 
EuroQoL-5D-5L (EQ-5D-5L) ....................................................................................... 99 
11.4 
Visual Analog Scale (VAS) Local Site Pain ............................................................... 101 
11.5 
New York Heart Association Functional Classification.............................................. 102 
11.6 
Risk Assessment and Mitigation Plan due to COVID-19 ........................................... 103 
 
 

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LIST OF TABLES 
Table 6-1 
Eligibility Based on Serologic Markers for Hepatitis B Infection ......... 62 

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LIST OF FIGURES 
Figure 3-1 
Study Design Overview  .................................................... 28 
 

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PROTOCOL SYNOPSIS 
Protocol Number: CT-P41 3.1 
Title: A Double-Blind, Randomized, Active-Controlled, Phase 3 Study to Compare Efficacy, 
Pharmacokinetics, Pharmacodynamics, and Safety of CT-P41 and US-licensed Prolia in Postmenopausal 
Women with Osteoporosis. 
Study Phase: Phase 3 
Study Centers: Approximately 20 study centers in 4 countries  
Test Drug Formulation, Dose, and Regimen: 
CT-P41 will be subcutaneously administered using a prefilled syringe (PFS) of 60 mg/mL solution for 
injection on Weeks 0 (Day 1), 26, and 52 (6-month interval).  
All patients will also receive daily supplementation containing at least 1,000 mg of elemental calcium and at 
least 400 IU vitamin D from randomization to end-of-study (EOS) visit. 
Reference Drug Formulation, Dose, and Regimen: 
United States (US)-licensed Prolia will be subcutaneously administered using a PFS of 60 mg/mL solution 
for injection Weeks 0 (Day 1), 26, and 52 (6-month interval).  
All patients will also receive daily supplementation containing at least 1,000 mg of elemental calcium and at 
least 400 IU vitamin D from randomization to EOS visit. 
Objectives: 
Primary Objective 
• 
To demonstrate the equivalence of CT-P41 to US-licensed Prolia in terms of efficacy in postmenopausal 
women with osteoporosis as determined by percent change from baseline in bone mineral density 
(BMD) for lumbar spine (L1 to L4) at Week 52 
Secondary Objective 
• 
To evaluate the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and safety including 
immunogenicity of CT-P41 and US-licensed Prolia 
Main Selection Criteria: 
Postmenopausal women with BMD T-score ≤ − 2.5 and ≥ − 4.0 at the lumbar spine (L1 to L4) and evaluable 
region (at least three lumbar spine [L1 to L4] and at least one hip joint) by dual-energy X-ray absorptiometry 
(DXA) assessment, will be considered for enrollment in the study if they meet all of the inclusion criteria and 
none of the exclusion criteria. 
Inclusion Criteria: 
Each patient must meet all of the following criteria to be randomized in this study: 
1. Women, 50 to 80 years of age, both inclusive. 
2. Body weight between 40.0 and 99.9 kg, both inclusive, when rounded to the nearest tenth. 
3. Postmenopausal, as defined by: 
a) No menstrual period for at least 12 consecutive months prior to the Screening visit with follicle-
stimulating hormone (FSH) level ≥ 30 mIU/mL assessed by central laboratory at Screening 
visit, or 
b) Surgical menopause (bilateral oophorectomy with or without hysterectomy) ≥ 12 months prior 
to the Screening visit 
4. Bone mineral density T-score ≤ − 2.5 and ≥ − 4.0 at the lumbar spine (L1 to L4) as assessed by the 
central imaging vendor based on DXA scan at Screening. 
5. Patient must have at least 3 vertebrae considered evaluable at the lumbar spine (L1 to L4) and at 
least 1 hip considered evaluable by DXA scan assessed by the central imaging vendor at Screening. 
Patient with unilateral metal in hips that would be allowed for the other side of 1 evaluable hip is 
included. 
6. Patient with albumin-adjusted total serum calcium ≥ 8.5 mg/dL (≥ 2.125 mmol/L) at Screening.  
7. Patient has adequate hepatic function at Screening as defined by the following clinical chemistry 
results: 
a) Aspartate aminotransferase and alanine aminotransferase ≤ 3 × upper limit of normal (ULN) 
b) Alkaline phosphatase ≤ 2 × ULN and total bilirubin ≤ 2 × ULN 

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8. In good general health as determined by medical history, physical examination, and laboratory tests 
and able to walk without assistance, at the Investigator’s discretion. 
9. Patient and/or their legally authorized representative must be informed and given ample time and 
opportunity to read and/or understand the nature and purpose of this study including possible risks, 
side effects and requirements for supplementation, and must sign the informed consent form before 
any study specific procedures. 
Exclusion Criteria: 
Patients meeting any of the following criteria will be excluded from the study: 
1. Patient who has previously received denosumab (Prolia, Xgeva, or biosimilar denosumab), any 
other monoclonal antibodies (e.g., romosozumab), or biologic agents for osteoporosis. 
2. Patient with a hypersensitivity to any component of denosumab or dry natural rubber (a derivative 
of latex). 
3. Patient who is confirmed or suspected with infection of coronavirus disease 2019 (COVID-19) at 
Screening, or has contact with COVID-19 patient within 14 days from Screening. 
4. Patient who currently has, or has a history of, any of the following infections: 
a) A known infection with active hepatitis B, hepatitis C, or human immunodeficiency virus 
(HIV). A patient with past hepatitis B virus is allowed if resolved 
b) Any severe or active infection or history of any infection requiring hospitalization, parenteral 
antibiotics within 4 weeks prior to the first administration of the study drug, or oral antibiotics 
within 2 weeks prior to the first administration of the study drug 
5. Patient who has a medical history of and/or current disease including any of the following(s): 
a) 
One severe or > 2 moderate vertebral fractures (severe fracture is defined as > 40% vertebral 
height loss and moderate fracture is defined as 25% to 40% vertebral height loss [Genant et al., 
1993]) as determined by central reading of lateral spine X-ray 
b) 
Hip fracture 
c) Hyperparathyroidism or hypoparathyroidism, irrespective of current controlled or uncontrolled 
status 
d) Current hyperthyroidism (unless well controlled on stable antithyroid therapy)  
e) Current hypothyroidism (unless well controlled on stable thyroid replacement therapy)  
f) 
Bone disease and metabolic disease (except for osteoporosis) that may interfere with the 
interpretation of the results including osteomalacia, osteogenesis imperfecta, Paget’s disease, 
rheumatoid arthritis, ankylosing spondylitis, osteopetrosis, fibrous dysplasia, an elevation of 
alkaline phosphatase at the Investigator’s discretion, Cushing’s disease, hyperprolactinemia, 
malabsorption syndrome, advanced scoliosis or extensive lumbar fusion  
g) History of severe skeletal pain with bisphosphonates 
h) History and/or current oral or dental conditions including osteomyelitis or osteonecrosis of the 
jaw; active dental or jaw condition which requires oral surgery; planned invasive dental 
procedure (e.g., tooth extraction, dental implants, oral surgery); unhealed dental oral surgery  
i) 
History of any malignancy within 5 years prior to the first administration of the study drug 
except adequately treated squamous or basal cell carcinoma of the skin or cervical carcinoma in 
situ. Any history of bone metastases, implant radiation involving the skeleton, or skeletal 
malignancies are exclusionary 
j) 
New York Heart Association (NYHA) Class III or IV chronic heart failure, any unstable 
cardiovascular disease, pulmonary disease, autoimmune disease, or electrocardiogram 
abnormalities which can be judged as clinically significant at the Investigator’s discretion 
6. Patient has one of the following laboratory test results at Screening: 
a) Serum 25-OH vitamin D < 20 ng/mL (if vitamin D deficiency has been supplemented at the 
Investigator’s discretion, and retest result shows the level above 20 ng/mL within the Screening 
period, the patient can be enrolled in the study. The retest is limited up to twice within the 
Screening period.) 
b) Estimated glomerular filtration rate < 30 mL/min/1.73 m2 
c) Hemoglobin < 10 g/dL 
7. Patient who has a history of and/or concurrent use of medications including any of the following: 
a) Receipt of intravenous bisphosphonates, fluoride, and strontium for osteoporosis within the last 

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5 years prior to the first administration of the study drug 
b) Receipt of oral bisphosphonates ≥ 3 years cumulatively prior to Screening or receipt of any dose 
of oral bisphosphonates within 12 months prior to Screening 
c) Use of parathyroid hormone or its derivatives, systemic hormone-replacement therapy (estrogen 
with or without progestogen), selective estrogen-receptor modulator, tibolone, calcitonin, or 
calcitriol within 12 months prior to the first administration of the study drug 
d) Use of other bone active drugs including heparin, anticonvulsive (except benzodiazepines), 
systemic ketoconazole, anabolic steroids, testosterone, androgens, adrenocorticotropic hormone, 
cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, or gonadotropin-releasing 
hormone agonists within 3 months prior to the first administration of the study drug 
e) Use of oral or parenteral glucocorticosteroids (> 5 mg/prednisone daily or equivalent for 
> 10 days) within 3 months prior to the first administration of the study drug 
f) 
Receipt of any investigational drug within 4 weeks or five half-lives (whichever is longer) prior 
to the first administration of the study drug 
g) Receipt of any authorized COVID-19 vaccines within 2 weeks prior and after the first 
administration of the study drug (total of 4 weeks) 
8. Patient who currently abuses alcohol or drugs or has a history of alcohol or drug abuse within 12 
months prior to the first administration of the study drug. 
9. Patient who has evidence of any other coexisting disease or medical or psychological condition, 
metabolic dysfunction, physical examination finding, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that contraindicates the use of an investigational 
product or could have interfere with the interpretation of study results, or patient is at high risk for 
treatment complication in the opinion of the Investigator. 
Study Design: 
This is a double-blind, randomized, active-controlled, Phase 3 study to evaluate the efficacy, PK, PD, and 
safety including immunogenicity of CT-P41 compared with US-licensed Prolia in postmenopausal women 
with osteoporosis. All patients will also receive daily supplementation containing at least 1,000 mg of 
elemental calcium and at least 400 IU vitamin D from randomization to EOS visit and the data will be 
collected via patient’s diary.  
 
A schematic of the study design is presented in Figure S1. 
Screening Period (From Day − 28 to Day − 1) 
Screening evaluations will be completed within 28 days prior to the randomization.   
Treatment Period I (From Week 0 [Day 1] to Week 52 Predose) 
On Day 1, Week 0, patients who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled in the study and randomly assigned in a 1:1 ratio to 1 of the 2 treatment groups to receive 60 mg of 
CT-P41 or US-licensed Prolia. Patients will receive a total of 2 doses of 60 mg of CT-P41 or US-licensed 
Prolia at Day 1, Week 0 (the same date of the randomization) and Week 26. The randomization will be 
balanced by using permuted blocks. The randomization will be stratified by age (< 65 versus ≥ 65), baseline 
BMD T-score at the lumbar spine (≤ − 3.0 versus > − 3.0) and prior bisphosphonates therapy (Yes versus 
No). 
The primary efficacy endpoint of percent change from baseline in BMD for lumbar spine will be measured at 
Week 52. Efficacy, PK, PD, and safety including immunogenicity data will be collected. 
Treatment Period II (From Week 52 to Prior to Week 78 [EOS Visit]) 
All patients who completed the Treatment Period I will undergo the second randomization process prior to 
the study drug administration at Week 52 to ensure blinding and will enter the Treatment Period II to receive 
an additional 1 dose of study drug. 
The second randomization will be stratified by change from baseline in BMD for lumbar spine at Week 52 
(≥ 3% versus < 3%) (baseline: central reading; Week 52: local reading). Patients who are initially 
randomized to CT-P41 in Treatment Period I will continue to receive CT-P41. Patients who are initially 
randomized to US-licensed Prolia in Treatment Period I, will be re-randomized in a ratio of 1:1 to switching 

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arm (CT-P41) or non-switching arm (US-licensed Prolia). The study drug during the Treatment Period II will 
be given at Week 52 study visit. All assessments including efficacy, PK, PD, and safety including 
immunogenicity will be performed.  
End-of-Study Visit (Week 78) 
The EOS visit will be performed at Week 78 and assessments including efficacy, PK, PD, and safety 
including immunogenicity will be performed.  
For patients who discontinue study treatment early or initiate different osteoporosis medication (including 
those prohibited by the protocol), every effort should be made to complete regularly scheduled study visits, 
and PK, PD, and immunogenicity samples will be collected until the next study drug administration 
scheduled visit. When a patient discontinues study treatment after administration of the study drug at Week 
52, the PK, PD, and immunogenicity samples will be collected until Week 78 visit. Especially, if a patient 
discontinues the study treatment prior to Week 52, the patient should return to the study center at Week 52 
for the primary efficacy assessment. If a patient cannot or is unwilling to attend any visit(s), a safety follow-
up will be conducted by telephone according to the study visit schedule.  
 
Figure S1. Study Design Overview 
 
Abbreviations: BMD, bone mineral density; D, day; DXA, dual-energy X-ray absorptiometry; EOS, end-of-study; M, 
month; Q6M, every 6 months; SC, subcutaneous; US, United States; W, Week. 
The study will be performed in a double-blind manner. To minimize the risk of unblinding, the study drug 
will be administered by unblinded healthcare professional. The unblinded healthcare professionals who are 
responsible for administering study drugs will not be permitted to conduct any patient assessments. 
Efficacy Assessments: 
Bone mineral density as evaluated on DXA will be measured at scheduled time points. Bone images will be 
assessed at the central imaging vendor. 
Primary Efficacy Endpoint 
• 
Percent change from baseline in BMD for lumbar spine (L1 to L4) by DXA at Week 52 
Secondary Efficacy Endpoints 
• 
Percent change from baseline in BMD for lumbar spine (L1 to L4), total hip, and femoral neck by DXA 
at Weeks 26, 52, and 78 

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• 
The incidences of new vertebral, nonvertebral, and hip fractures during the study 
• 
Change from baseline in health-related quality of life at Weeks 26, 52, and 78 
Pharmacokinetic Assessments: 
Secondary PK Endpoints 
• 
Serum concentration of denosumab (up to Week 78) 
• 
Maximum serum concentration (Cmax) after the first administration of study drug (over the initial 6 
months [26 weeks]) 
• 
Trough serum concentration (Ctrough) (concentration prior to the next study drug administration up to 
Week 78) 
Pharmacodynamic Assessments: 
Serum concentrations of bone turnover markers will be measured in the morning after fasting overnight for 8 
hours prior to the assessment at the scheduled time points.  
Secondary PD Endpoints 
• 
Area under the effect curve (AUEC) of serum carboxy-terminal cross-linking telopeptide of type I 
collagen (s-CTX) and procollagen type 1 N-terminal propeptide (P1NP) over the initial 6 months (from 
Day 1 predose to Week 26 predose) 
• 
Percent change from baseline of s-CTX and P1NP at Weeks 26, 52, and 78 
Safety Assessments: 
Safety assessments will be performed on adverse events (AEs), serious adverse events, AEs of special 
interest (injection site reaction, drug-related hypersensitivity/allergic reaction, infection, hypocalcaemia, 
osteonecrosis of the jaw, atypical femoral fracture, and dermatologic reactions), hypersensitivity/allergic 
reaction assessment by vital sign monitoring (including systolic and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature), local site pain using 100 mm visual analog scale, vital sign, weight, 
height, body mass index measurement, physical examination (including oral examination), clinical laboratory 
analyses, 12-lead electrocardiogram, prior and concomitant medication, and immunogenicity (incidence of 
antidrug antibody and neutralizing antibody). Hepatitis B, C, HIV, and FSH testing and NYHA functional 
classification will be assessed to determine patients’ eligibility.  
Sample Size: 
A sample size of 440 patients (220 patients in each treatment group of CT-P41 and US-licensed Prolia) will 
achieve approximately 90% statistical power for the demonstration of similarity of percent change from 
baseline in BMD for lumbar spine at Week 52, based on the two-one sided 5% significance level and an 
equivalence margin of ± 1.45%. In this sample size calculation, the common standard deviation (SD) is 
assumed to be 4.0% and the expected mean difference of percent change from baseline to be 0. The dropout 
rate has been hypothesized as 20%. 
Statistical Methods: 
Data Analyses: 
The study will be double-blinded. The study will be unblinded for the reporting purposes after database lock 
for data up to Week 52 or Week 78 for all patients. The second randomization process will be conducted in 
all treatment groups to maintain the study blind. The study will remain blinded to the Investigators, patients, 
and predefined blinded personnel from the Sponsor and contract research organization until all patients 
complete the study and the database is finalized for study termination. 
Statistical Analysis: 
All statistical analyses will be conducted 
 
 The statistical methods for this study will be described in detail in a Statistical Analysis Plan 
(SAP), which will be finalized prior to database lock. Changes from analyses planned in this protocol will be 
documented in the SAP. Any deviations from the planned analysis as described in the SAP will be justified 
and recorded in the study report. 
Continuous variables will be summarized by reporting the number of observations (n), mean, SD, median, 
minimum, maximum, unless otherwise indicated. Categorical variables will be summarized using frequency 

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tables showing the number and percentage of patients within a particular category. Data will be listed in data 
listings. 
Definition of Analysis Set: 
• 
Intent-to-Treat (ITT) Set: The ITT Set is defined as all patients randomly assigned to receive study 
drug (CT-P41 or US-licensed Prolia), regardless of whether or not any study drug was administered. 
• 
ITT – Treatment Period II subset: The ITT – Treatment Period II subset is defined as all patients in 
ITT set who are randomly assigned to receive study drug (CT-P41 or US-licensed Prolia) at Week 52 
prior to dosing, regardless of whether or not any study drug was administered. 
• 
Full Analysis Set (FAS): The FAS is defined as all randomly assigned patients who receive at least 1 
full dose of study drug (CT-P41 or US-licensed Prolia). 
• 
FAS – Treatment Period II subset: The FAS – Treatment Period II subset is defined as all patients in 
FAS who are randomly assigned at Week 52 prior to dosing and receive 1 full dose of study drug (CT-
P41 or US-licensed Prolia) at Week 52. 
• 
Per-Protocol Set (PPS): The PPS is defined as all randomly assigned patients who receive all 2 doses 
(full) of study drug (CT-P41 or US-licensed Prolia) at Weeks 0 (Day 1) and 26, and have BMD 
assessments from lumbar spine at baseline and Week 52. Patients with a major protocol deviation that 
may affect the interpretation of study results of primary efficacy endpoint will be excluded from the 
PPS. Final determinations of the PPS will be made at the blinded data review meeting (DRM) before 
unblinding. 
• 
Pharmacokinetic Set: The PK Set is defined as all patients who receive at least 1 full dose of study drug 
(CT-P41 or US-licensed Prolia) and have at least 1 post-treatment PK result.   
• 
PK – Treatment Period II subset: The PK – Treatment Period II subset will consist of all patients in 
PK Set who receive 1 full dose of either of study drug (CT-P41 or US-licensed Prolia) at Week 52 and 
have at least 1 post-treatment PK result at or after Week 52.  
• 
Pharmacodynamic Set: The PD Set is defined as all patients who receive at least 1 full dose of study 
drug (CT-P41 or US-licensed Prolia) and have at least 1 post-treatment PD result. 
• 
PD – Treatment Period II subset: The PD – Treatment Period II subset will consist of all patients in 
PD Set who receive 1 full dose of either of study drug (CT-P41 or US-licensed Prolia) at Week 52 and 
have at least 1 post-treatment PD result at or after Week 52. 
• 
Safety Set: The Safety Set will consist of all patients who receive at least 1 dose (full or partial) of study 
drug (CT-P41 or US-licensed Prolia). 
• 
Safety – Treatment Period II subset: The Safety – Treatment Period II subset will consist of all 
patients in Safety Set who receive 1 dose (full or partial) of study drug (CT-P41 or US-licensed Prolia) at 
Week 52. 
Efficacy Analysis: 
• 
Primary Endpoint: To evaluate the difference between 2 treatment groups in the primary efficacy 
endpoint, percent change from baseline in BMD for lumbar spine (L1 to L4) by DXA at Week 52 will 
be analyzed using an analysis of covariance (ANCOVA) model coupled with multiple imputation 
assuming the data to be missing at random. The ANCOVA model will include the treatment as a fixed 
effect and age, baseline BMD T-score at the lumbar spine, and prior bisphosphonates therapy (Yes 
versus No) as covariates. Statistical equivalence will be declared if the 90% confidence interval (CI) of 
the difference in the mean of the primary efficacy endpoint between treatment groups falls entirely 
within an equivalence margin, [− 1.45, + 1.45]. The primary analysis will be performed using the FAS. 
A supportive analysis will be performed using the PPS. Sensitivity analysis will be conducted in the 
FAS to examine the impact of missing data on primary analysis result by imputing missing data over a 
range of possible scenarios for the treatment effect. Subgroup analysis by race and age will be 
performed in FAS.  
• 
Secondary Endpoints: Percent change from baseline in BMD for lumbar spine, total hip, and femoral 
neck by DXA, incidences of new vertebral, nonvertebral, and hip fractures, and change from baseline in 
health-related quality of life will be assessed as secondary efficacy endpoints. The secondary efficacy 
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data for Treatment Period II will be summarized on the FAS – Treatment Period II subset, unless 
otherwise specified. 
Pharmacokinetic Analysis: 
The serum concentration and PK parameters of Cmax and Ctrough will be summarized by treatment group using 
descriptive statistics including geometric mean and coefficient of variation (CV), as appropriate. 
Pharmacokinetic analysis for Treatment Period I will be summarized using the PK Set and that for Treatment 
Period II will be summarized on the PK – Treatment Period II subset, unless otherwise specified. 
Pharmacodynamic Analysis: 
The AUEC of s-CTX and P1NP over the initial 6 months (from Day 1 predose to Week 26 predose) and 
percent change from baseline of s-CTX and P1NP at Weeks 26, 52, and 78 will be assessed as secondary PD 
endpoints. Serum concentration and percent change from baseline of s-CTX and P1NP will be summarized 
using descriptive statistics (including geometric mean and CV, as appropriate). Pharmacodynamic analysis 
for Treatment Period I will be summarized on the PD Set and that for Treatment Period II will be 
summarized on the PD – Treatment Period II subset, unless otherwise specified. 
Safety Analysis: 
Adverse events will be coded to system organ class and preferred term according to Medical Dictionary for 
Regulatory Activities and severity grading of AEs will be recorded according to the Common Terminology 
Criteria for Adverse Events Version 5.0. Prior and concomitant medications will be coded to drug class and 
preferred term using the World Health Organization drug dictionary. All safety data including 
immunogenicity for Treatment Period I will be summarized for the Safety Set and that for Treatment Period 
II will be summarized for the Safety – Treatment Period II subset, unless otherwise specified.  
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUEC 
area under the effect curve 
BMD 
bone mineral density 
BMI 
body mass index 
CFR 
code of federal regulation 
CI 
confidence interval 
Cmax 
maximum serum concentration 
COVID-19 
Coronavirus disease 2019 
CRO 
contract research organization 
Ctrough 
trough serum concentration 
CSR 
clinical study report 
CTCAE 
common terminology criteria for adverse events 
CV 
coefficient of variation 
DNA 
deoxyribonucleic acid 
DRM 
data review meeting 
DSMB 
data safety monitoring board 
DXA 
dual-energy X-ray absorptiometry 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EQ-5D-5L 
EuroQol-5 Dimention-5 Levels Health Survey 
EOS 
end-of-study 
EU 
European Union 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
food and drug administration 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
HBeAb 
hepatitis B e antibody 
HBeAg 
hepatitis B e antigen 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus  
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IL 
interleukin 

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IP 
investigational product 
IRB 
institutional review board 
ITT 
intent-to-treat 
IU 
international unit 
IWRS 
interactive web response system 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
NAb 
neutralizing antibody 
NI 
non-inferiority 
NYHA 
New York Heart Association 
PD 
pharmacodynamics(s) 
PFS 
prefilled syringe 
P1NP 
procollagen type 1 N-terminal propeptide 
PK 
Pharmacokinetic(s) 
PPS 
per-protocol set 
PT 
preferred term 
PTH 
parathyroid hormone 
PVG 
pharmacovigilance 
QoL 
quality of life 
RANK 
receptor activator of NF-κB 
RANKL 
receptor activator of NF-κB ligand 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
s-CTX 
serum carboxy-terminal cross-linking telopeptide of type I collagen 
SD 
standard deviation 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ONJ 
osteonecrosis of the jaw 
OPAQ-SV 
osteoporosis assessment questionnaire-short version 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
VAS 
visual analog assessment 
WHO 
World Health Organization 
 

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1 
Introduction 
1.1 Background 
1.1.1 Osteoporosis 
Osteoporosis is a systemic skeletal disease that is characterized by low bone mass and 
micro-architectural deterioration of bone tissue, with a low bone mineral density (BMD) and 
consequent increase in bone fragility and susceptibility to fracture. The incidence of fractures 
varies greatly by country, but on average up to 50% of women > 50 years of age are at risk of 
fractures. Fractures severely affect the quality of life of an individual and are a major public 
health problem owing to the aging population. Postmenopausal osteoporosis, resulting from 
estrogen deficiency, is the most common type of osteoporosis. The estrogen deficiency 
results in an increase in bone turnover owing to effects on all types of bone cells (Eastell et 
al., 2016). 
According to World Health Organizations (WHO) criteria, osteoporosis is defined as the 
T-score of ≤ − 2.5 standard deviation (SD) and osteopenia as the T-score between − 1.0 SD 
and − 2.5 SD. The femoral neck and lumbar spine are recommended as the anatomic region 
of interest (Ji et al., 2015). 
Osteoclasts (bone resorbing cells) and osteoblasts (bone forming cells) are 2 kinds of cells 
that essentially form the bone multi-cellular unit, coordinating well to regulate the balance of 
bone resorption and bone formation. The enhanced expression of cytokines known to 
stimulate osteoclastogenesis, such as interleukin (IL)-1, IL-6, and tumor necrosis factor, or 
enhanced expression of macrophage colony-stimulating factor and receptor activator of NF-
κB ligand (RANKL) in osteoblasts/stromal cells may also play an important role (Ji et al., 
2015). 
Receptor activator of NF-κB ligand is released by bone forming cells known as osteoblasts 
and stimulates receptor activator of NF-κB (RANK) on the surface of stem cells to form 
osteoclasts, which are cells that mediate bone resorption. The same pair of proteins can also 
signal in reverse. In this case, RANK is released from osteoclasts in vesicles, and clusters of 
membrane-bound RANK activate signaling by RANKL molecules on the surface of 
osteoblasts to promote bone formation. Separating these 2 signals could prove beneficial to 
combat the excessive bone resorption that occurs during osteoporosis (Ray 2018). 
Receptor activator of NF-κB ligand/RANK plays an important role in the pathway modulated 
by osteoblasts which affect bone mass density via the regulation of osteoblast and osteoclast 

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functions. In the RANKL/RANK pathway, RANKL binds to RANK as its receptor 
and eventually leads to osteoclast precursor maturation (Tobeiha et al., 2020). 
RANKL inhibition blocks osteoclast maturation, function and survival, thus reducing bone 
resorption. With reduced RANK–RANKL binding, osteoclast formation, function and 
survival, and bone resorption decreases and bone mass increases (Hanley et al., 2012). 
1.1.2 Denosumab 
Denosumab, is a fully human monoclonal antibody that binds the cytokine RANKL which is 
an essential factor initiating bone turnover (Hanley et al., 2012). Denosumab binds to and 
neutralizes the activity of human RANKL, preventing RANKL from activating RANK, its 
receptor on the osteoclast surface. 
Denosumab is a human monoclonal IgG2 antibody produced in a mammalian cell line 
(Chinese hamster ovary cells) by recombinant deoxyribonucleic acid (DNA) technology. 
Denosumab has been licensed for the treatment of postmenopausal women with osteoporosis 
at high risk for fracture and to increase bone mass in men with osteoporosis at high risk for 
fracture in the United States (US) (Prolia United States Prescribing Information [USPI] 
2020). In Europe, it is approved for the treatment of osteoporosis in postmenopausal women 
and in men at increased risk of fractures (Prolia Summary of Product Characteristics [SmPC] 
2021). It is also approved in both the US and European Union (EU) for the treatment of 
glucocorticoid-induced osteoporosis in men and women at high risk for fracture, to increase 
bone mass in men at high risk for fracture receiving androgen deprivation therapy for 
nonmetastatic prostate cancer, to increase bone mass in women at high risk for fracture 
receiving adjuvant aromatase inhibitor therapy for breast cancer. 
1.2 CT-P41 
CT-P41 is a human monoclonal IgG2 antibody that is being developed and manufactured as a 
proposed biosimilar to Prolia (denosumab) by CELLTRION, Inc. CT-P41 is identical to 
Prolia with respect to concentration, formulation, and presentation. 
The 60 mg of drug product (CT-P41) will have the same pharmaceutical form and strength as 
60 mg Prolia (subcutaneous [SC] injection) and is intended to have a similar quality profile 
compared with Prolia. CELLTRION, Inc. plans to seek approval for all indications for which 
the innovator product has been approved by demonstrating similarity of CT-P41 with the 

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reference product through an extensive array of quality, nonclinical, and clinical 
comparability assessments. 
1.2.1 Nonclinical Studies 
The nonclinical program for CT-P41 has been designed to support clinical studies and to 
demonstrate similarity in binding profiles and functional activities between CT-P41 and 
Prolia. CT-P41 was evaluated in nonclinical in vitro and in vivo studies in order to 
demonstrate comparability of CT-P41 and Prolia. The in vivo study was conducted in 
accordance to Good Laboratory Practice standards. 
Detailed information regarding the nonclinical pharmacology and toxicology of CT-P41 can 
be found in the Investigator’s Brochure (IB). 
1.2.2 Clinical Studies 
Clinical data on Prolia has been published in scientific literature, regulatory submissions, and 
approved product information (Prolia USPI 2020; Prolia SmPC 2021). As CT-P41 is 
developed as a proposed biosimilar to Prolia, the clinical findings for CT-P41 are expected to 
be in line with those of Prolia in terms of safety, pharmacokinetics (PK), pharmacodynamics 
(PD), and efficacy. 
Study CT-P41 1.1 is a Pilot Phase I, randomized, double-blind, two-arm, parallel group, 
single-dose study to evaluate the safety and PK of CT-P41 and EU-approved Prolia in healthy 
male subjects. This study is performed to evaluate the safety of a single 60 mg SC injection 
and to evaluate the additional safety, immunogenicity, PK, and PD of CT-P41 and EU-
approved Prolia in healthy male subjects. Study CT-P41 1.2 is a randomized, double-blind, 
two-arm, parallel group, single-dose, Phase I study to compare the PK, PD, and safety of CT-
P41 and US-licensed Prolia in healthy male subjects. 
The current Phase 3 study, CT-P41 3.1, is a double-blind, randomized, active-controlled 
study to compare efficacy, PK, PD, and safety including immunogenicity of CT-P41 and US-
licensed Prolia in patients with postmenopausal women with osteoporosis.  
1.3 Study Rationale 
CT-P41 is currently being developed by CELLTRION, Inc. and is intended to be developed 
as a proposed biosimilar to Prolia. For a proposed biosimilar to be approved, it must be 
proven that there are no clinically meaningful differences between the drug products. The 
safety and PK as well as PD and immunogenicity of CT-P41 and EU-approved Prolia was 

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compared in a Pilot Phase I study in healthy male subjects (CT-P41 1.1). The PK similarity of 
CT-P41 and US-licensed Prolia will be compared in a Phase I study in healthy male subjects 
(CT-P41 1.2). Assessments of the therapeutic equivalence in efficacy of CT-P41 and the US-
licensed Prolia will be demonstrated in a Phase III study in postmenopausal women with 
osteoporosis (CT-P41 3.1). CELLTRION, Inc. considers that the proposed clinical 
development programs will be sufficient to demonstrate similar profile of safety and PK 
(Pilot Study CT-P41 1.1 safety and PK similarity healthy volunteer study), PK, PD, and 
safety (Study CT-P41 1.2 PK similarity healthy volunteer study), and therapeutic equivalence 
and safety (Study CT-P41 3.1 comparative clinical similarity) of CT-P41 to the reference 
product. 
The design of this study takes into account the EU Guideline on Similar Biological 
Medicinal Products Containing Monoclonal Antibodies: Nonclinical and Clinical Issues 
(EMA 2012) and the Food and Drug Administration (FDA) Guidance on Scientific 
Considerations in Demonstrating Biosimilarity to a reference product (FDA 2015). 
1.3.1 Rationale for Study Population 
International regulations (WHO 2013; EMA 2012;  FDA 2015; FDA 2019) suggest that 
proposed biosimilars should be tested in a population representative of the approved 
therapeutic indications of the reference product and sufficiently sensitive for detecting 
potential differences between the proposed biosimilar and the reference product. 
The study population in this study was selected in order to be representative of the other 
clinical studies supporting the development and marketing of the reference product (Prolia), 
and to align with the indications approved for the reference product. 
Postmenopausal female patients between the ages of 50 to 80 with BMD T-score at the 
lumbar spine (L1 to L4) ≤ − 2.5 and ≥ − 4.0 will be enrolled in this study. The age group has 
been selected based on the statistics that the mean age of natural menopause is 51 years in 
industrialized nations, compared with 48 years in poor and nonindustrialized nations. With 
the average life span extended to 70 years, the upper age limit is selected as 80 years old (Ji 
et al., 2015). The WHO operational definition of osteoporosis is based on the T-score for 
BMD assessed by dual-energy X-ray absorptiometry (DXA) at the femoral neck or spine and 
is defined as a value for BMD − 2.5 SD or more below the young female adult mean 
(Camacho et al., 2020; Kanis et al., 2019). The BMD T-score inclusion criteria is based on a 
3-year, randomized, double-blind, placebo-controlled trial conducted in 7,808 women to 
evaluate efficacy and safety of Prolia in the treatment of postmenopausal osteoporosis which 

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had enrolled women with a baseline BMD T-score between − 2.5 and − 4.0 at either the 
lumbar spine or total hip (Prolia USPI 2020; Prolia SmPC 2021). 
1.3.2 Rationale for Dose Selection 
The recommended dose of Prolia is 60 mg administered as a single SC injection once every 
6 months. The same dose has been selected for CT-P41 to allow comparisons between the 
reference drug and the proposed biosimilar. 
1.4 Benefit and Risk Assessment 
CT-P41 will have the same pharmaceutical formulation and strength as Prolia (60 mg). The 
proposed dosing regimen is in line with the approved labeling for Prolia (Prolia USPI 2020; 
Prolia SmPC 2021). 
The proposed safety monitoring is deemed to be sufficient to monitor potential risks of 
CT-P41 administration. In view of the structural, biological, and toxicological similarity to 
Prolia, CT-P41 is expected to display a similar safety profile. 
Based upon the clinical evidence as well as the proven safety profile of Prolia, the benefits of 
the conduct of the proposed clinical study outweigh the associated risks. 
The benefit and risk assessments and the risk mitigation plans for coronavirus disease 2019 
(COVID-19) are specified in Appendix 11.6. Risk assessments will be conducted during the 
study by the Sponsor through a sufficient discussion with the Investigators and data safety 
monitoring board (DSMB).  

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2 
Study Objectives 
2.1 Primary Objective 
 
To demonstrate the equivalence of CT-P41 to US-licensed Prolia in terms of efficacy in 
postmenopausal women with osteoporosis as determined by percent change from 
baseline in BMD for lumbar spine (L1 to L4) at Week 52 
2.2 Secondary Objective 
 
To evaluate the efficacy, PK, PD, and safety including immunogenicity of CT-P41 and 
US-licensed Prolia 

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3 
Investigational Plan 
3.1 Study Design 
This is a double-blind, randomized, active-controlled Phase 3 study to evaluate the efficacy, 
PK, PD, and safety including immunogenicity of CT-P41 compared with US-licensed Prolia 
in postmenopausal women with osteoporosis. 
Approximately 440 patients with postmenopausal osteoporosis will be enrolled and randomly 
assigned to receive 60 mg of CT-P41 or US-licensed Prolia. All patients will also receive 
daily supplementation containing at least 1,000 mg of elemental calcium and at least 400 IU 
vitamin D from randomization to end-of-study (EOS) visit and the data will be collected via 
patient’s diary. 
The study will comprise of 4 study periods (Screening Period, Treatment Period I, Treatment 
Period II, and EOS visit) and the duration of the study will be up to 82 weeks. 
The study will be performed in a double-blind manner. To minimize the risk of unblinding, 
the study drug will be administered by unblinded study site personnel. The unblinded 
personnel who are responsible for administering study drugs will not be involved in any 
clinical or safety evaluations that are part of the blinded protocol or have other patient 
contact. 
Patients will comply with all appropriate visits and assessments that will be performed at the 
time points specified in the schedule of assessments (Appendix 11.1). 
Screening Period (from Day − 28 to Day − 1) 
Screening evaluations will be completed within 28 days prior to the randomization. 
Treatment Period I (from Week 0 [Day 1] to Week 52 Predose) 
On Day 1, Week 0, patients who meet all of the inclusion criteria and none of the exclusion 
criteria will be enrolled in the study and randomly assigned in a 1:1 ratio to 1 of 2 treatment 
groups to receive 60 mg of CT-P41 or US-licensed Prolia. Patients will receive a total of 2 
doses of 60 mg of CT-P41 or US-licensed Prolia at Day 1, Week 0 (the same date of the 
randomization) and Week 26. The randomization will be balanced by using permuted blocks. 
The randomization will be stratified by age (< 65 versus ≥ 65), baseline BMD T-score at the 
lumbar spine (≤ − 3.0 versus > − 3.0), and prior bisphosphonates therapy (Yes versus No). 

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The primary efficacy endpoint of percent change from baseline in BMD for lumbar spine (L1 
to L4) will be measured at Week 52. Efficacy, PK, PD, and safety including immunogenicity 
data will be also collected. 
Treatment Period II (from Week 52 to Prior to Week 78 [EOS Visit]) 
All patients who completed the Treatment Period I will undergo the second randomization 
process prior to the study drug administration at Week 52 to ensure blinding and will enter 
the Treatment Period II to receive an additional 1 dose of study drug. 
The second randomization will be stratified by change from baseline in BMD for lumbar 
spine at Week 52 (≥ 3% versus < 3%) (baseline: central reading; Week 52: local reading). 
Patients who are initially randomized to CT-P41 in Treatment Period I will continue to 
receive CT-P41. Patients who are initially randomized to US-licensed Prolia in Treatment 
Period I, will be re-randomized in a 1:1 ratio to switching arm (CT-P41) or non-switching 
arm (US-licensed Prolia). The study drug during the Treatment Period II will be given at 
Week 52 study visit. All assessments including efficacy, PK, PD, and safety including 
immunogenicity will be performed.  
End-of-Study Visit (Week 78) 
The EOS visit will be performed at Week 78 and assessments including efficacy, PK, PD, and 
safety including immunogenicity will be performed. 
For patients who discontinue study treatment early or initiate different osteoporosis 
medication (including those prohibited by the protocol), every effort should be made to 
complete regularly scheduled study visits for planned clinical assessments, and PK, PD, and 
immunogenicity samples will be collected until the next study drug administration scheduled 
visit. When a patient discontinues study treatment after administration of the study drug at 
Week 52, the PK, PD, and immunogenicity samples will be collected until Week 78 visit. 
Especially, if a patient discontinues the study treatment prior to Week 52, the patient should 
return to the study center at Week 52 for the primary efficacy assessment. If a patient cannot 
or is unwilling to attend any visit(s), a safety follow-up (e.g., adverse events [AEs], 
concomitant medication) will be conducted by telephone according to the study visit 
schedule. 
The study design and patient assessment overview is presented in Figure 3-1. 

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Figure 3-1 
Study Design Overview 
Abbreviations: BMD, bone mineral density; D, day; DXA, dual-energy X-ray absorptiometry; EOS, end-of-study; M, 
month; Q6M, every 6 months; SC, subcutaneous; US, United States; W, Week. 

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4 
Patient Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
It is expected that approximately 440 patients will be enrolled at approximately 20 study 
centers in 4 countries. Postmenopausal female patients with osteoporosis will be considered 
for enrollment in the study if they meet all the inclusion criteria and none of the exclusion 
criteria. 
4.1.1 Inclusion Criteria 
Each patient must meet all of the following criteria to be randomized in this study: 
1. Women, 50 to 80 years of age, both inclusive.
2. Body weight between 40.0 and 99.9 kg, both inclusive, when rounded to the nearest
tenth.
3. Postmenopausal, as defined by:
a) No menstrual period for at least 12 consecutive months prior to the Screening visit
with follicle-stimulating hormone (FSH) level ≥ 30 mIU/mL assessed by central
laboratory at Screening visit, or
b) Surgical menopause (bilateral oophorectomy with or without hysterectomy)
≥ 12 months prior to the Screening visit
4. Bone mineral density T-score ≤ − 2.5 and ≥ − 4.0 at the lumbar spine (L1 to L4) as
assessed by the central imaging vendor based on DXA scan at Screening.
5. Patient must have at least 3 vertebrae considered evaluable at the lumbar spine (L1 to L4)
and at least 1 hip considered evaluable by DXA scan assessed by the central imaging
vendor at Screening. Patient with unilateral metal in hips that would be allowed for the
other side of 1 evaluable hip is included.
6. Patient with albumin-adjusted total serum calcium ≥ 8.5 mg/dL (≥ 2.125 mmol/L) at
Screening.
7. Patient has adequate hepatic function at Screening as defined by the following clinical
chemistry results:
a)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper
limit of normal (ULN)

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b) Alkaline phosphatase (ALP) ≤ 2 × ULN and total bilirubin ≤ 2 × ULN
8. In good general health as determined by medical history, physical examination, and
laboratory tests and able to walk without assistance, at the Investigator’s discretion.
9. Patient and/or their legally authorized representative must be informed and given ample
time and opportunity to read and/or understand the nature and purpose of this study
including possible risks, side effects and requirements for supplementation, and must sign
the informed consent form (ICF) before any study specific procedures.
4.1.2 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. Patient who has previously received denosumab (Prolia, Xgeva, or biosimilar
denosumab), any other monoclonal antibodies (e.g., romosozumab), or biologic agents
for osteoporosis.
2. Patient with a hypersensitivity to any component of denosumab or dry natural rubber (a
derivative of latex).
3. Patient who is confirmed or suspected with infection of COVID-19 at Screening, or has
contact with COVID-19 patient within 14 days from Screening.
4. Patient who currently has, or has a history of, any of the following infections:
a) A known infection with active hepatitis B, hepatitis C, or human immunodeficiency
virus (HIV). A patient with past hepatitis B virus is allowed if resolved
b) Any severe or active infection or history of any infection requiring hospitalization,
parenteral antibiotics within 4 weeks prior to the first administration of the study
drug, or oral antibiotics within 2 weeks prior to the first administration of the study
drug
5. Patient who has a medical history of and/or current disease including any of the
following(s):
a) One severe or > 2 moderate vertebral fractures (severe fracture is defined as > 40%
vertebral height loss and moderate fracture is defined as 25% to 40% vertebral height
loss [Genant et al., 1993]) as determined by central reading of lateral spine X-ray
b) Hip fracture

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c) Hyperparathyroidism or hypoparathyroidism, irrespective of current controlled or
uncontrolled status
d) Current hyperthyroidism (unless well controlled on stable antithyroid therapy)
e) Current hypothyroidism (unless well controlled on stable thyroid replacement
therapy)
f)
Bone disease and metabolic disease (except for osteoporosis) that may interfere with
the interpretation of the results including osteomalacia, osteogenesis imperfecta,
Paget’s disease, rheumatoid arthritis, ankylosing spondylitis, osteopetrosis, fibrous
dysplasia, an elevation of ALP at the Investigator’s discretion, Cushing’s disease,
hyperprolactinemia, malabsorption syndrome, advanced scoliosis or extensive lumbar
fusion
g) History of severe skeletal pain with bisphosphonates
h) History and/or current oral or dental conditions including osteomyelitis or
osteonecrosis of the jaw (ONJ); active dental or jaw condition which requires oral
surgery; planned invasive dental procedure (e.g., tooth extraction, dental implants,
oral surgery); unhealed dental oral surgery
i)
History of any malignancy within 5 years prior to the first administration of the study
drug except adequately treated squamous or basal cell carcinoma of the skin or
cervical carcinoma in situ. Any history of bone metastases, implant radiation
involving the skeleton, or skeletal malignancies are exclusionary
j)
New York Heart Association (NYHA) Class III or IV chronic heart failure, any
unstable cardiovascular disease, pulmonary disease, autoimmune disease or
electrocardiogram (ECG) abnormalities which can be judged as clinically significant
at the Investigator’s discretion
6. Patient has one of the following laboratory test result at Screening:
a) Serum 25-OH vitamin D < 20 ng/mL (if vitamin D deficiency has been supplemented
at the Investigator’s discretion, and retest result shows the level above 20 ng/mL
within the Screening period, the patient can be enrolled in the study. The retest is
limited up to twice within the Screening period)
b) Estimated glomerular filtration rate < 30 mL/min/1.73 m2
c) Hemoglobin < 10 g/dL

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7. Patient who has a history of and/or concurrent use of medications including any of the
following:
a) Receipt of intravenous bisphosphonates, fluoride, and strontium for osteoporosis
within the last 5 years prior to the first administration of the study drug
b) Receipt of oral bisphosphonates ≥ 3 years cumulatively prior to Screening or receipt
of any dose of oral bisphosphonates within 12 months prior to Screening
c) Use of parathyroid hormone (PTH) or its derivatives, systemic hormone-replacement
therapy (estrogen with or without progestogen), selective estrogen-receptor
modulator, tibolone, calcitonin, or calcitriol within 12 months prior to the first
administration of the study drug
d) Use of other bone active drugs including heparin, anticonvulsives (except
benzodiazepines), systemic ketoconazole, anabolic steroids, testosterone, androgens,
adrenocorticotropic hormone, cinacalcet, aluminum, lithium, protease inhibitors,
methotrexate, or gonadotropin-releasing hormone agonists within 3 months prior to
the first administration of the study drug
e) Use of oral or parenteral glucocorticosteroids (> 5 mg/prednisone daily or equivalent
for > 10 days) within 3 months prior to the first administration of the study drug
f)
Receipt of any investigational drug within 4 weeks or five half-lives (whichever is
longer) prior to the first administration of the study drug
g) Receipt of any authorized COVID-19 vaccines within 2 weeks prior and after the first
administration of the study drug (total of 4 weeks)
8. Patient who currently abuses alcohol or drugs or has a history of alcohol or drug abuse
within 12 months prior to the first administration of the study drug.
9. Patient who has evidence of any other coexisting disease or medical or psychological
condition, metabolic dysfunction, physical examination finding, or clinical laboratory
finding giving reasonable suspicion of a disease or condition that contraindicates the use
of an investigational product (IP) or could have interfere with the interpretation of study
results, or patient is at high risk for treatment complication in the opinion of the
Investigator.

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4.2 Withdrawal of Patients from the Study 
Patients have the right to withdraw from the study treatment, procedures/observations, or the 
study at any time and for any reason. The Investigator and/or CELLTRION, Inc. also can 
decide to withdraw a patient from the study treatment, procedures/observations, or the study 
at any time prior to study completion.  
Patients who are discontinued from the study treatment or are terminated from the study 
could be transitioned to another anti-resorptive therapies at the Investigator’s discretion. 
The primary reason for the discontinuation of the study treatment and study termination must 
be recorded in the patient’s medical record and in the electronic case report form (eCRF) with 
any comments (spontaneous or elicited) or complaints made by the patient, date of cessation 
of study treatment, and the total amount of study treatment administered. 
As it is vital to obtain follow-up data in all patients, even after study treatment 
discontinuation or initiation of different osteoporosis medication (including those prohibited 
by the protocol), the Investigator should attempt to contact the patient and reschedule the 
missed visit as soon as possible and counsel the patient on the importance of maintaining the 
assigned visit schedule. 
If the patient is lost to follow-up, the Investigator or designee must make every effort to 
contact the patient (e.g., telephone calls to patient or family members, and if necessary, a 
letter requesting contact to the last known address).  
4.2.1 Discontinuation of Study Treatment 
Patients are free to discontinue the study treatment at any time for any reason. The 
Investigator may also discontinue the study treatment at any time in the interest of patient 
safety. Study treatment discontinuation should not be considered as study termination.  
If necessary, the Investigator may discuss any patient’s reason for study treatment 
discontinuation with CELLTRION, Inc. or its designee. CELLTRION, Inc. may be contacted 
if clarification is required on a case-by-case basis. 
Reasons for study treatment discontinuation include the followings: 
 
Patient develops signs of disease progression in the judgment of the Investigator 
 
Patient has any AE that would compromise her safety if she continues to receive the 

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study treatment 
 
Patient has a significant protocol deviation(s) 
 
Investigator’s decision 
 
Patient withdraws consent or refuses treatment 
 
Patient is lost to follow-up 
 
Patient dies 
 
Patient becomes pregnant 
 
Requirement for alternative therapy: If a patient experiences BMD loss from 
baseline of 7% or more at lumbar spine or total hip during a 12-month period, 
decrease in BMD T-score below – 4.0 at lumbar spine or total hip during the study, 
or osteoporosis-related fracture (e.g., vertebral compression fracture, hip fracture), 
the Investigator is required to discuss implication for individual fracture risk, 
alternative treatment options and options for continuing in the study with the patient, 
and to document that discussion. If a decision is made to begin alternative treatment, 
the study treatment must be discontinued and every effort should be made to 
complete all remaining study visits, regardless of any alternative treatment chosen by 
the patient.  
For patients who are discontinued from the study treatment or are initiated different 
osteoporosis medication (including those prohibited by the protocol), every effort should be 
made to complete regularly scheduled study visits for planned clinical assessments, and PK, 
PD, and immunogenicity samples will be collected until the next study drug administration 
scheduled visit. When a patient discontinues study treatment after administration of the study 
drug at Week 52, the PK, PD, and immunogenicity samples will be collected until Week 78 
visit. Especially, if a patient discontinues the study treatment prior to Week 52, the patient 
should return to the study center at Week 52 for the primary efficacy assessment. If a patient 
cannot or is unwilling to attend any visit(s), a safety follow-up (e.g., AEs, concomitant 
medications) will be conducted by telephone according to the study visit schedule and should 
be recorded in both the source document and eCRF. 
4.2.2 Termination of the Study 
Patients are free to withdraw the study at any time for any reason. The Investigator may also 
decide to terminate the study at any time in the interest of patient safety.  

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If necessary, the Investigator may discuss any patient’s reason for withdrawal from the study 
with CELLTRION, Inc. or its designee. CELLTRION, Inc. may be contacted if clarification 
is required on a case-by-case basis. All patients who are terminated from the study will retain 
their patient identification number. 
Reasons for study termination include the followings: 
 
Patient withdraws consent or refuses to procedures/observations 
 
Patient is lost to follow-up 
 
Patient dies 
 
Investigator’s decision 
 
Study is terminated by the Sponsor 
4.3 Replacement and Rescreening of Patients 
Patients who receive study drug and discontinue before the study completion will not be 
replaced.  
Patients who are screen failed, for any reason, can be rescreened only once. If there is 
unusual situation so that additional rescreening should be considered, the Investigator is 
recommended to discuss with CELLTRION, Inc. Rescreened patient will be assigned with 
new patient identification number. The following procedures do not need to be repeated 
during the rescreening if the assessment date for collected samples or performed scans or X-
rays under the previous screening number is within 28 days prior to the first study drug 
administration and the screening results are eligible for the study. 
 
DXA scan 
 
Lateral spine X-ray (lumbar and thoracic) 
 
Laboratory assessments including hepatitis B and C, HIV, FSH, urinalysis, hematology, 
and clinical chemistry 
4.4 Premature Termination of the Study 
CELLTRION, Inc. reserves the right to terminate the study at any time for reasonable 
medical and/or administrative reasons. As far as possible, this should occur after mutual 
consultation. 

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If the study is terminated prematurely by CELLTRION, Inc., all patients will be kept fully 
informed and an appropriate follow-up examination of the patients will be arranged. The 
Investigator will inform the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) of any premature termination or suspension of the study, where applicable. 

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5 
Study Treatment 
5.1 Method of Assigning Patients to Treatment Groups 
An interactive web response system (IWRS) will be used for the randomization. Unblinded 
biostatisticians will generate the randomization schedule for IWRS, which will link 
sequential patient randomization numbers to treatment codes. 
First Randomization for Treatment Period I 
Approximately 440 patients will be enrolled and randomly assigned to one of the 2 treatment 
groups in a 1:1 ratio (approximately each 220 patients in the CT-P41 and US-licensed Prolia). 
During the Treatment Period I, the randomization will be stratified by: 
•
age (< 65 versus ≥ 65)
•
baseline BMD T-score at the lumbar spine (≤ − 3.0 versus > − 3.0)
•
prior bisphosphonates therapy (Yes versus No)
Second Randomization for Treatment Period II 
Prior to dosing at Week 52, patients in the US-licensed Prolia treatment group will be 
randomly assigned again in a ratio of 1:1 to either switching arm (CT-P41) or non-switching 
arm (US-licensed Prolia). All patients who were initially randomly assigned to the CT-P41 on 
Day 1 (Week 0) will continue their treatment.  
The second randomization process will be conducted in all treatment groups to maintain the 
study blind.  
During the Treatment Period II, the randomization will be stratified by change from baseline 
in BMD for lumbar spine at Week 52 (≥ 3% versus < 3%) (baseline: central reading; Week 
52: local reading). 
5.2 Identity of Investigational Products 
CT-P41 is a monoclonal antibody which is being developed by CELLTRION, Inc. as a 
proposed biosimilar to US-licensed Prolia. The company code of the product is CT-P41. 
The International Nonprioprietary Name of the Commercially available reference material 
(Prolia) is denosumab and the Anatomical Therapeutic Chemical Classification System code 

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is M05BX04. Denosumab is a human IgG2 monoclonal antibody with affinity and specificity 
for human RANKL.   
The reference product, US-licensed Prolia, is supplied as sterile, preservative-free, clear, 
colorless to pale yellow solution for SC administration. Each 1 mL single-dose prefilled 
syringe (PFS) of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 
mM acetate, 0.01% polysorbate 20, Water for Injection, and sodium hydroxide to a pH of 5.2 
(Prolia USPI 2020).  
CT-P41 is supplied as a sterile, preservative-free solution of denosumab for SC 
administration in a single-use PFS. CT-P41 is a clear to slightly opalescent, colorless to pale 
yellow solution for injection, with a pH 5.0 – 5.4 and is formulated at 60 mg of denosumab in 
1 mL for SC use. Each 1 mL single-dose PFS contains 60 mg denosumab (60 mg/mL 
solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, and Water for Injection. For 
further details, see the IB.   
5.3 Treatment Administered 
5.3.1 CT-P41 and US-licensed Prolia 
During the Treatment Period I, patients will receive 60 mg of CT-P41 or US-licensed Prolia 
on Week 0 (Day 1) and Week 26, respectively, as per the first randomization. During the 
Treatment Period II, patients will receive 60 mg of CT-P41 or US-licensed Prolia at Week 52 
as per the second randomization. 
The study drug will be administered as a single SC injection in the upper arm, the upper 
thigh, or the abdomen. 
The study drug is required to be administered by the site-qualified and trained clinical staff 
member(s) (e.g., nurse/physician, etc.), who is designated as an unblinded study site 
personnel. The people sensitive to latex should not handle the needle cap on the single-dose 
PFS, which contains dry natural rubber (a derivative of latex). Patients will be blinded 
through the use of a blindfold, screen, or similar method during the dosing procedure so that 
the injection syringe will not be visible to the patient. The detail regarding blinding is 
described in Section 5.7. 
5.3.2 Co-administration of Calcium and Vitamin D 
Calcium and Vitamin D are co-administered to prevent low serum calcium level while taking 
study drugs. Therefore, all patients will receive daily supplementation containing at least 

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1,000 mg of elemental calcium and at least 400 IU vitamin D from randomization to EOS 
visit. Information about Calcium and Vitamin D administration will be collected via patient’s 
diary and will be also recorded in both the source documents and eCRF. 
If a patient becomes hypercalcaemia during the study, the calcium and/or vitamin D 
supplementation may be discontinued or reduced by Investigator’s discretion until the serum 
calcium concentration has returned to the normal range.  
If a patient becomes hypocalcaemia including albumin-adjusted total serum calcium < 8.5 
mg/dL (< 2.125 mmol/L) during the study, appropriate additional supplementation should be 
instituted as deemed acceptable by local guidelines to return the serum calcium concentration 
within the normal range. 
If a patient is intolerant of the daily calcium or vitamin D supplementation, the formulation 
may be changed or the dose could be lowered by Investigator’s discretion. The intolerance as 
well as the resolution (e.g., change in formulation or dosage) should be recorded in both the 
source documents and the eCRF. 
5.4 Prior, Concomitant, and Subsequent Therapy 
Information (e.g., drug name, date[s] of administration, etc.) about prior medications taken 
by the patient within 30 days prior to the signed date of ICF (inclusive of the applicable 
periods for prohibited medications as defined in Section 5.5) will be recorded until the EOS 
visit in both the source documents and eCRF. In order to check eligibility, prior medications 
will be reviewed for the times specified in the related exclusion criteria. This will include all 
prescription drugs, over-the-counter medicines, vitamins, and herbal supplements.  
Any concomitant medication deemed necessary for the welfare of the patient during the study 
may be given at the discretion of the Investigator. All concomitant medications should be 
reported to the Investigator and recorded on the appropriate eCRF and source document. Any 
changes in concomitant medications also will be recorded in the source documents and 
patient’s eCRF. All concomitant medications used during the study will be recorded until the 
EOS visit. 
Use of all prior and concomitant medications for the treatment of osteoporosis, from the 
diagnosis of disease until the EOS visit, will be recorded in the source documents and 
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It is the Investigator’s responsibility to ensure that details regarding the medication are 
adequately recorded in both the source documents and eCRF. 
5.5 Prohibited Therapy 
The following medications, treatments, or procedures are prohibited during the study 
(Section 4.1.2). Patients who receive any prohibited therapy during the Screening period 
should be considered a screen failure. Intake of any of the following prohibited therapy by 
the patients after randomization will be considered as protocol deviation. 
•
Denosumab other than study drug or any other monoclonal antibodies (e.g.,
romosozumab), protein, fusion protein, or other biologic agent targeting IgG
•
Treatments for osteoporosis (such as oral/intravenous bisphosphonates, fluoride,
strontium, PTH or its derivatives, systemic hormone-replacement therapy [estrogen
with or without progestogen], selective estrogen-receptor modulator, tibolone,
calcitonin, or calcitriol)
•
Treatments that can affect bone metabolism (such as heparin, anticonvulsives [except
benzodiazepines], systemic ketoconazole, anabolic steroids, testosterone, androgens,
adrenocorticotropic hormone, cinacalcet, aluminum, lithium, protease inhibitors,
methotrexate, or gonadotropin-releasing hormone agonists)
•
Use of oral or parenteral glucocorticosteriods (> 5 mg/prednisone daily or equivalent
for more than 10 days)
•
Any other investigational drugs
Patients who completed the study or are permanently discontinued from the study treatment 
can be transitioned to another anti-resorptive therapies at the Investigator’s discretion.  
Any authorized COVID-19 vaccines are prohibited for 2 weeks prior and after the study drug 
administration (total of 4 weeks). During the study, the interval of COVID-19 vaccination 
schedule would be adjusted to have an interval of at least 2 weeks prior and after the study 
drug administration scheduled for Weeks 0 (Day 1), 26, and 52. 

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5.6 Management of Clinical Supplies 
5.6.1 Study Drug Package, Labeling, and Storage 
The appropriate number of study drug syringes will be allocated to each patient via IWRS 
system at each visit. 
A label will be attached to the outside of each patient kit, as well as to the immediate 
container. The text will be compliant with local regulatory requirements and may include 
some of the following information: 
 
Protocol number 
 
Patient number/site number 
 
Contents and quantity 
 
Lot number 
 
Randomization code/kit number 
 
Investigator’s name 
 
Route of administration 
 
Directions for use 
 
Storage instructions 
 
Caution statement (for clinical trial use only) 
 
Sponsor’s contact name and address 
 
Expiry date 
All study drug supplies must be stored in secured area with limited access (e.g., a locked 
cabinet) and in accordance with the manufacturer’s instructions. They will be stored in a 
refrigerator at 2°C to 8°C (36°F to 46°F) and will not be frozen. The immediate containers 
must be kept in the outer carton until use to protect the study drug from light. The 
recommended storage conditions, and expiry date where required, are stated in the product 
label approved by each regulatory authority. 

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5.6.2 Study Drug Accountability 
It is the responsibility of the clinical Investigator to ensure that all study drug received at the 
study center will be inventoried and accounted for throughout the study and the result 
recorded in the drug accountability form will be maintained at the study center. The study 
drug accountability will be verified by the monitor during on-site monitoring visits. Study 
drug will be stored in a limited access area under appropriate environmental conditions. 
The Investigator agrees not to supply the study drug to any person other than 
Sub-Investigators, designated staff, and the patients participating in the study. Study drug 
may not be relabeled or reassigned for use by other patients unless approved by the Sponsor. 
The used syringes can only be destroyed if it is according to local standard operating 
procedures (SOP) and a specific authorization is given by the Sponsor. Permission will be 
granted by the Sponsor on a study-center-by-study-center basis after reviewing the study 
center destruction policy. This authorization may also be granted to destroy used syringes 
immediately after administering the study drug to patients. The list of destroyed syringes 
must be recorded. The Investigator agrees to neither dispense the study drug from, nor store it 
at, any study center other than the study centers agreed upon with the Sponsor. 
5.7 Blinding 
This study will be double-blind until the end of the study. The randomization codes will not 
be revealed to study patients, Investigators, and study site personnel, except for delegated 
unblinded staff who will handle the study drug and predefined unblinded personnel in the 
Sponsor and contract research organization (CRO) until all final clinical data have been 
entered into the database and the database is locked and released for analysis. 
As the presentation of the study drugs are not identical in visual appearance, the trained 
clinical staff member(s) responsible for drug administration (e.g., nurse/physician, etc.) will 
be designated as unblinded study site personnel and will not be involved in any clinical or 
safety evaluations that are part of the blinded protocol or have other patient contact. Patients 
will be blinded through the use of a blindfold, screen or similar method during the dosing 
procedure so that the injection syringe will not be visible to patient. Blinded staff will be 
absent during injection and remain blinded throughout the study. 

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5.7.1 Breaking the Blind 
Under normal circumstances, the blind should not be broken. The blind should be broken 
only if specific emergency treatment would be dictated as knowing the study drug 
assignment is required for medical management. In such cases, the Investigator may, in an 
emergency, determine the identity of the study drug by using the applicable procedure in the 
IWRS (see IWRS manual, which is provided as a separate document). 
The date, time, and reason for the unblinding must be documented in the appropriate field of 
the eCRF and the medical monitor will be informed as soon as possible. All calls resulting in 
an unblinding event will be recorded and reported by the IWRS to the medial monitor and the 
Sponsor. Any patients for whom the blind is broken may continue in the study and receive 
the study treatment at the Investigator’s discretion. 
Contract research organization pharmacovigilance (PVG) will have access to the 
randomization code, if suspected unexpected serious adverse reactions (SUSARs), which are 
subject to expedited reporting, should be unblinded before submission to the regulatory 
authorities. 
The DSMB and the statistical team of CRO who provide the safety analyses for the DSMB 
will also be unblinded upon the request from DSMB members during closed session. 
The overall randomization code will be broken only for reporting purposes. This will occur 
after database lock for data up to Week 52 or Week 78 for all patients. The unblinded 
personnel will be predefined and documented before breaking the study blind. The study will 
remain blinded to the Investigators, patients, and predefined blinded personnel from the 
Sponsor and CRO until all patients have completed the study and the database has been 
finalized for study closure. 
5.8 Treatment Compliance 
CT-P41 and US-licensed Prolia will be administered by the unblinded site staff while the 
patient is at the study center. The date and time of the study drug administration will be 
recorded in both the source documents and the eCRF. Administration of co-administered 
treatments (Calcium and Vitamin D) will be recorded throughout the study. 
Every effort will be made to encourage patients’ compliance with the study visits. A dosing 
visit window of ± 3 days is allowed for Week 26 visit and that of ± 5 days is allowed for 

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Week 52 visit. If any study visit has to be rescheduled, subsequent visits should follow the 
original visit date scheduled. 

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6 
Study Assessments and Procedures 
Prior to performing any study procedures, all potential patients will sign an ICF. Patients will 
have the opportunity to have any questions answered prior to signing the ICF. The 
Investigator must address all questions raised by the patient. The Investigator or designee 
will also sign the ICF. 
All patients will return to the study center by regular scheduled time intervals for clinical 
assessments and blood samplings. Patients will undergo the procedures at the time points 
specified in the schedule of events (Appendix 11.1). 
6.1 Efficacy Assessments 
6.1.1 Bone Mineral Density 
Bone mineral density will be assessed by DXA at Screening and at Weeks 26, 52, and 78 
(EOS visit). Only Hologic or Lunar bone densitometers will be allowed for the study. The 
same DXA instrument should be used for all study procedures for each patient during the 
study. If for unforeseeable reasons the same scanner is no longer available, the study site 
should follow the central imaging provider’s guidance on selecting an appropriate 
replacement scanner and follow a phantom scanning process to quantify any calibration 
differences. All DXA scans of lumbar spine, total hip, and femoral neck BMD will be 
submitted to and analyzed by the central imaging vendor.  
Primary efficacy assessment will be determined by percent change from baseline in BMD for 
lumbar spine at Week 52. Secondary efficacy assessments include percent change from 
baseline in BMD for lumbar spine, total hip and femoral neck at Weeks 26, 52, and 78. 
For lumbar spine DXA scan, L1 through L4 should be measured, only excluding vertebrae 
that are affected by local structural change or artifact, using at least 2 vertebrae for diagnostic 
classification. Anatomically abnormal vertebrae may be excluded from analysis if they are 
clearly abnormal and nonassessable within the resolution of the system and using a 1.0 T-
score difference between vertebra in question and adjacent vertebrae as a guideline in 
identifying vertebrae for exclusion (2019 International Society or Clinical Densitometry 
[ISCD Official Position - Adult).  
For femur DXA scan, the left side should be used for all scans at all study visits. If the right 
side must be used (e.g., due to implants) or is inadvertently used at baseline, then it must be 
used consistently throughout the study. If a patient fractures the hip that has been scanned 

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during the study up to the time of fracture, no further scans will be obtained for the affected 
location. 
6.1.1.1 Screening Bone Mineral Density Assessment 
To determine eligibility based on BMD T-score, lumbar spine DXA scans will be analyzed by 
the central imaging vendor. 
To be eligible for the study, patients must have at least 3 evaluable vertebrae at the lumbar 
spine (L1 to L4) and at least 1 evaluable hip by DXA scan assessed by the central imaging 
vendor. Patients with unilateral metal in hips that would be allowed for the other side of 1 
evaluable hip are included. 
6.1.1.2 On-Study Bone Mineral Density Assessment 
Bone mineral density changes for individual patients will be monitored by the central 
imaging vendor during the study. Investigators will be alerted if a patient experiences a BMD 
loss from baseline of 7% or more at the lumbar spine or total hip during a 12-month period, 
or decrease in BMD T-score below – 4.0 at lumbar spine or total hip during the study.  
If needed, Week 26 DXA scan can be occurred at a separate site visit within ± 3 days visit 
window of Week 26 visit, which is followed by the study drug administration occurring 
within the same visit window of Week 26 visit. 
At Week 52 visit, the DXA scan will be analyzed by both the central imaging vendor and the 
study center. If needed, Week 52 DXA scan can be occurred at a separate site visit within ± 5 
days visit window of Week 52 visit, which is followed by the study drug administration 
occurring within the same visit window of Week 52 visit. A BMD assessor for the local 
reading will be assigned to each study center. If possible, it is recommended that the local 
reading will be performed by the same person at each study center throughout the study 
period. The local reading result at Week 52 will be used for the stratification factor of the 
second randomization.  
6.1.2 Incidences of Fractures 
If any fractures occur, the information should be recorded as AE. 

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6.1.2.1 Vertebral Fractures 
Incidences of vertebral fractures which are confirmed radiographically regardless of patient-
reported symptoms indicative of a fracture will be reported throughout the study period. A 
new vertebral fracture is defined as an increase of at least one grade in any vertebra from T4 
to L4 that was normal at Screening (Cummings et al., 2009).  
It is difficult to determine the exact incidence of vertebral fractures due to the absence of 
specific symptoms in some and the difficulty in determining the cause of possible physical 
symptoms such as pain and height loss (Mikayel et al., 2003). Therefore, to increase the 
potential of therapeutic intervention to prevent subsequent fractures, the lateral spine X-ray 
will be performed at Screening, Weeks 26, 52, and 78 (EOS visit), and also could be 
performed as required for confirmation of suspected vertebral fractures. The vertebral 
fracture will be assessed by semi-quantitative grading at a central imaging vendor (Genant et 
al., 1993): 
 
Grade 0 = no fracture 
 
Grade 1 = mild fracture, 20 – 25% reduction in vertebral height (anterior, middle, or 
posterior) 
 
Grade 2 = moderate fracture, 25 – 40% reduction in any height 
 
Grade 3 = severe fracture, greater than 40% reduction in any height 
If needed, the lateral spine X-ray at Week 26 or Week 52 can be occurred at a separate site 
visit within ± 3 days or ± 5 days visit window of Week 26 or Week 52 visit respectively, 
which is followed by the study drug administration occurring within the same visit window 
of Week 26 or Week 52 visit. 
Information indicative of a vertebral fracture will be recorded. If a patient reports back pain 
that is considered by the Investigator to be possibly due to a vertebral fracture, a 
confirmatory lateral spine X-ray will be taken and the back pain (but not a vertebral fracture) 
will be reported as an AE. The lateral spine X-ray for vertebral fracture as well as copies of 
other diagnostic image and/or radiology report, surgical report, or discharge summary will be 
included in the patient’s individual source documents and will be submitted to the central 
imaging vendor for confirmation of fracture. The central imaging vendor will inform the sites 
if a vertebral fracture is identified. If necessary to support the patient’s medical care, these X-
rays could be read locally. Only fractures confirmed by the central imaging vendor will be 
included for the efficacy analysis. 

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6.1.2.2 Nonvertebral Fractures 
A nonvertebral fracture endpoint includes fractures other than those of the vertebra, 
excluding pathologic fractures and fractures of the skull, facial bones, mandible, metacarpals, 
and phalanges of fingers or toes as they are not associated with decreased BMD. The 
nonvertebral fracture endpoint will also exclude if they are associated with severe trauma as a 
fall from a height higher than a stool, chair, or first rung of a ladder or severe trauma other 
than a fall (Bone et al., 2008; Cummings et al., 2009).  
Information about nonvertebral fracture (e.g., details regarding the type of fracture and other 
pertinent data) and level of trauma causing the fracture will be recorded during the study. A 
copy of radiographs or other diagnostic image and/or radiology report, surgical report, or 
discharge summary will be included in the patient’s individual source documents and will be 
submitted to the central imaging vendor for confirmation of fracture. If the radiograph or 
diagnostic image is not available, then, at minimum, a copy of the radiology report, surgical 
report, clinical notes, or discharge summary should be submitted to the central imaging 
vendor. Only fractures confirmed by the central imaging vendor will be included for the 
efficacy analysis.  
6.1.3 Quality of Life Assessment 
Health-related quality of life will be assessed using osteoporosis assessment questionnaire 
short version (OPAQ-SV) and EuroQoL-5 Dimensions-5 Levels health survey (EQ-5D-5L) at 
baseline and Weeks 26, 52, and 78. 
6.1.3.1 Osteoporosis Assessment Questionnaire Short Version (OPAQ-
SV ) 
The OPAQ-SV is a 34-item osteoporosis-specific health-related questionnaire. The OPAQ-
SV evaluates the impact of vertebral and nonvertebral fractures on physical function, 
emotional status, and symptoms (one question on back pain) (Silverman 2000) (Appendix 
11.2). The physical function domain includes questions on walking/bending, transfers, and 
daily activity, and the emotional status domain includes questions on fear of falling, body 
image, and independence. Scores for each of the dimensions range from 0 to 100 with higher 
scores representing better health status. A negative change in score represents a decline in 
health status, and a positive change in score represents an improvement in health status.  

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6.1.3.2 EuroQoL-5 Dimensions-5 Levels Health Survey (EQ-5D-5L) 
The EQ-5D-5L is a preference-based measurement across 5 attributes (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) with 5 levels (no problem, slight 
problem, moderate problem, severe problem, and extreme problem) within each attribute 
(Appendix 11.3). The scale is measured by the visual analog scale (VAS) that requires 
patients to directly rate their current health. 0 means the worst health and 100 means the 
best health patients can imagine (Tosteson et al., 2002). 
6.2 Pharmacokinetic Assessments 
Pharmacokinetic blood samples for the determination of serum concentration of study drug 
will be collected from patients from both treatment groups (CT-P41 and US-licensed Prolia) 
at the time points specified in the schedule of assessments (Appendix 11.1). Predose samples 
(Weeks 0 [Day 1], 26 and 52) will be collected up to 30 minutes before the study drug 
administration. The postdose samples can be taken at any time of the scheduled visit. For 
patients who early discontinue study treatment, PK samples will be collected until the next 
study drug administration scheduled visit and further PK sampling is unnecessary. When a 
patient discontinues study treatment after administration of the study drug at Week 52, the 
PK samples will be collected until Week 78 visit. 
If the blood sample is unable to be analyzed or is missing at certain time point, some blood 
samples collected for PD or immunogenicity assessment at the same time point can be used 
for PK assessment after discussion and agreement from CELLTRION, Inc. Analysis will be 
performed at the central laboratory. 
Actual sampling times for each patient will be recorded in the patient’s eCRF and individual 
source documents. Details for PK blood sampling are provided in Section 6.5.1. 
6.3 Pharmacodynamic Assessments 
Determination of concentration of bone turnover markers will be measured from fasting 
serum samples at the time point specified in the schedule of assessments (Appendix 11.1). 
Patients will be required to refrain from intense exercise the day prior to assessment, to fast 
overnight for 8 hours prior to assessment and to visit the study center in the morning for PD 
assessment. For patients who early discontinue study treatment, PD samples will be collected 
until the next study drug administration scheduled visit and further PD sampling is 
unnecessary. When a patient discontinues study treatment after administration of the study 
drug at Week 52, the PD samples will be collected until Week 78 visit. 

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If the blood sample is unable to be analyzed or is missing at certain time point, some blood 
samples collected for PK or immunogenicity assessment at the same time point can be used 
for PD assessment after discussion and agreement from CELLTRION, Inc. Analysis will be 
performed at the central laboratory. 
Actual sampling times for each patient will be recorded in the patient’s eCRF and individual 
source documents. Details for PD blood sampling are provided in Section 6.5.2. 
6.4 Safety Assessments 
Safety assessments will be performed on AEs (including serious AEs [SAEs]), adverse events 
of special interest (AESI; injection site reaction, drug-related hypersensitivity/allergic 
reaction, infection, hypocalcaemia, ONJ, atypical femoral fracture, and dermatologic 
reactions), immunogenicity including antidrug antibody (ADA) and neutralizing antibody 
(NAb), hypersensitivity monitoring, vital sign assessments, body weight, height, body mass 
index (BMI), ECG, physical examination (including oral examination), clinical laboratory 
analyses, local site pain by VAS, and prior and concomitant medication. Hepatitis B, C, HIV, 
and FSH testing and NYHA functional classification will be assessed to determine patients’ 
eligibility. 
6.4.1 Adverse Events 
6.4.1.1 Definitions of Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. 
An AE is defined as any untoward medical occurrence in any patient enrolled into this study 
regardless of its causal relationship to study drug. Patients will be instructed to contact the 
Investigator at any time after the ICF was signed if any symptoms develop. Any new 
condition noted at Screening would be regarded as an AE, but not a treatment-emergent 
adverse event (TEAE). 
A TEAE is defined as any event not present before exposure to study drug or any event 
already present that worsens in severity or frequency after exposure to study drug. This 
includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition. 
Abnormal results of diagnostic procedures including laboratory test abnormalities are 
considered AEs if they fulfill the following: 

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 
Result in discontinuation from the study 
 
Require treatment or any other therapeutic intervention 
 
Require further diagnostic evaluation (excluding a repetition of the same procedure 
to confirm the abnormality) 
 
Are clinically significant as evaluated by the Investigator 
Disease progression of postmenopausal osteoporosis will not be recorded as an AE or SAE. 
Medical intervention such as surgery, diagnostic procedures, and therapeutic procedures are 
not AEs but the action taken to treat the medical condition. They should be recorded as 
treatment(s) of the AEs. The event term of primary cause should be recorded and reported 
instead of the term of surgery, diagnostic procedure, or therapeutic procedure. 
6.4.1.1.1 Adverse Events of Special Interest 
The following AEs are considered as AESIs and will be reported using the same process as 
for AEs: 
 
Injection site reaction 
Injection site reaction will be observed after study drug administration and assessed based on 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0. All AEs related to 
injection site reaction including erythema, itching, hemorrhage, pain, and swelling will be 
reported. 
 
Drug-related hypersensitivity/allergic reaction 
All AEs related to hypersensitivity/allergic reactions including anaphylaxis after study drug 
administration will be reported. Symptoms include but not limited to hypotension, dyspnea, 
throat tightness, facial and upper airway edema, pruritus, and urticaria will be reported. 
Diagnosis of anaphylaxis will be based on the anaphylaxis criteria of National Institute of 
Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network (Sampson et al., 
2006). 
 
Infection 
All AEs related to infections including but not limited to urinary tract infection, upper 
respiratory tract infections, skin infections including but not limited to erysipelas and 
cellulitis, abdomen infection and ear infection will be reported. 

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 
Hypocalcaemia 
All AEs related to hypocalcaemia include but not limited to paraesthesia or muscle stiffness, 
twitching, spasms and muscle cramps, QT interval prolongation, tetany, seizures and altered 
mental status will be reported.  
 
Osteonecrosis of the jaw 
All AEs related to ONJ include but not limited to jaw pain, osteomyelitis, osteitis, bone 
erosion, tooth or periodontal infection, toothache, gingival ulceration, and gingival erosion 
will be reported. 
 
Atypical femoral fracture 
All AEs related to atypical femoral fracture include but not limited to new or unusual thigh, 
hip, or groin pain will be reported.  
 
Dermatologic reactions 
All AEs related to dermatologic reactions include but not limited to dermatitis, eczema, and 
rashes will be reported. 
6.4.1.1.2 Serious Adverse Events 
A SAE is defined as any untoward medical occurrence that at any dose: 
 
Results in death. 
 
Is immediately life-threatening. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
 
Results in persistent or significant disability/incapacity. 
 
Is a congenital anomaly/birth defect. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the outcomes listed 
in the definition above. These should also be considered serious. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasia or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 

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Adverse events associated with hospitalization or prolongation of hospitalization are 
considered as SAEs. Any admission (even if < 24 hours) to a healthcare facility meets these 
criteria. Admission also includes transfer within the hospital to an acute/intensive care unit 
(e.g., from the psychiatric wing to a medical floor, from medical floor to a coronary care unit, 
from neurological floor to a tuberculosis unit). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical AE 
is not in itself an SAE. Examples include the following: 
 
Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or worsening of the pre-existing condition (e.g., for 
work-up of persistent pre-treatment laboratory abnormality) 
 
Social admission (e.g., patient has no place to sleep) 
 
Purely for convenience (e.g., for easier performance of study assessments) 
 
Administrative admission (e.g., for yearly physical examination) 
 
Protocol-specified admission during a study (e.g., for a procedure required by the 
study protocol) 
 
Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery) 
 
Hospitalization for observation without a medical AE 
 
Pre-planned treatments or surgical procedures; these should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient 
 
Hospitalization solely due to disease progression without any other AEs as decided 
by the Investigator 
6.4.1.1.3 Unlisted (Unexpected) Serious Adverse Events 
An unlisted or unexpected SAE is defined as an event of which the nature or severity is not 
consistent with the applicable reference documents (e.g., study drug IB). 
6.4.1.2 Eliciting and Documenting Adverse Events 
Adverse events will be assessed from the date patients signs the ICF until EOS visit, 
regardless of the relationship to the study drug. The condition of the patient will be 

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monitored throughout the study for any signs or symptoms. After the last EOS visit, serious 
adverse drug reactions will be reported to the CELLTRION, Inc. or its designee.  
At every study visit, patient will be asked a standard non-leading question to elicit any 
medically related changes in their wellbeing. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition to patient observations, AEs identified from any study data (e.g., laboratory 
values, physical examination findings, ECG changes) or identified from review of other 
documents that are relevant to patient safety will be documented on the AE page in the eCRF. 
6.4.1.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF 
and source documents. Information to be collected includes drug treatment, dose, event term, 
time of onset, Investigator-specified assessment of severity and relationship to study 
treatment, any required treatment or evaluations, and outcome. 
Adverse events resulting from concurrent condition, reactions to concurrent condition, or 
reactions to concurrent medications must also be reported. All AEs will be followed to 
adequate resolution. Adverse events will be graded for severity according to the CTCAE 
Version 5.0. The Medical Dictionary for Regulatory Activities (MedDRA) will be used to 
code all AEs. 
Any medical condition that is present at the time that the patient is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
The Investigator’s assessment of an AE’s relationship to study treatment is part of the 
documentation process, but it is not a factor in determining what is reported or what is not 
reported in the study. If there is any doubt as to whether a clinical observation is an AE, the 
event will be reported. 
The severity and the relationship or association of the study treatment in causing or 
contributing to the AE will be characterized as defined in Section 6.4.1.6 and Section 6.4.1.7, 
respectively. 

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6.4.1.4 Reporting Serious Adverse Events 
Any AE considered serious by the Investigator or which meets SAE criteria (Section 
6.4.1.1.2) must be reported to 
 
 within 24 hours from the time study center staff first 
learn about the event. The following contact information is to be used for SAE reporting: 
 
  
 
 
 
 
 
Data entry should be completed in the remote data capture system by the Investigator within 
24 hours of awareness of an SAE. In the event that this is not possible (e.g., system failure or 
access problems), the study center should complete an SAE report form and fax it to 
 
PVG within 24 hours of awareness of the event. The remote data capture system should be 
updated as soon as it is available. If the patient is hospitalized during an SAE or because of 
an SAE, a copy of the hospital discharge summary will be faxed to 
 PVG as soon as it 
becomes available. Withdrawal from the study and all therapeutic measures will be at the 
discretion of the Principal Investigator or Sub-Investigator. All SAEs (regardless of 
relationship with the study drug) will be followed up until satisfactory resolution or until the 
Principal Investigator or Sub-Investigator deems the event to be chronic or not clinically 
significant or the patient to be stable. 
The Sponsor or its designee is responsible for reporting relevant SAEs to the competent 
authority, other applicable regulatory authorities, and participating Investigators, in 
accordance with European Clinical Trials Directive (EMA 2001 ), International Council for 
Harmonisation (ICH) guidelines, and/or local regulatory requirements. 
The Sponsor or its designee is responsible for reporting unexpected fatal or life-threatening 
SUSARs (expedited reports) to the regulatory agencies and competent authorities by 
telephone or fax within 7 calendar days after being notified of the event. The Sponsor or its 
designee should report other relevant SAEs associated with the use of the study drug to the 
appropriate competent authorities (according to local guidelines), Investigators, and central 
ethics committees by a written safety report within 15 calendar days of notification. 

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6.4.1.5 Suspected Unexpected Serious Adverse Reactions 
The Sponsor will promptly evaluate all SUSARs against cumulative product experience to 
identify and expeditiously communicate possible new safety findings to Investigators, 
IRBs/IECs, and applicable health authorities based on applicable legislation. 
To determine reporting requirements for single SAE cases, the Sponsor will assess the 
expectedness of these events using the applicable reference documents (e.g., study drug IB). 
Reporting requirements will also be based on the Investigator’s assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
6.4.1.6 Assessment of Severity 
The severity of an AE refers to the extent to which an AE affects the patient’s daily activities. 
The severity of the AE will be graded based on the CTCAE Version 5.0, based on the 
following general guidelines (a semicolon indicates “or” within each description): 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL)1 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting selfcare ADL2 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
1.
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone,
managing money, etc.
2.
Selfcare ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications,
and not bedridden.
The Investigator will assess of the maximum intensity that occurred over the duration of the 
event. If an AE changes from non-serious to serious, a new SAE needs to be reported. 

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Adverse events characterized as intermittent do not require documentation of onset and 
duration of each episode. 
6.4.1.7 Assessment of Causality 
As discussed in Section 6.4.1.3, the Investigator’s assessment of an AE’s relationship to study 
treatment is part of the documentation process, but it is not a factor in determining what is 
reported or what is not reported in the study. If there is any doubt as to whether a clinical 
observation is an AE, the event will be reported. 
The relationship or association of CT-P41 or US-licensed Prolia in causing or contributing to 
the AE will be characterized using the following classification and criteria: 
Unrelated: 
This relationship suggests that there is no association between the study 
drug and the reported event. 
Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed to the AE, e.g., the event follows a reasonable temporal 
sequence from the time of study drug administration or follows a known 
response pattern to the study drug, but could also have been produced by 
other factors. 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known 
pharmacological action of the study drug, known or previously reported 
adverse reactions to the study drug or class of drugs, or judgment based on 
the Investigator’s clinical experience, the association of the event with the 
study drug seems likely. The event disappears or decreases on cessation or 
reduction of the dose of study drug. 
Definite: 
This relationship suggests that a definite causal relationship exists between 
study drug administration and the AE, and other conditions (concurrent 
illness, progression/expression of disease states, or concurrent medication 
reaction) do not appear to explain the event. The event reappears or worsens 
if the study drug is re-administered. 

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6.4.2 Other Safety Assessments 
6.4.2.1 Medical History, Disease History, and Demographic Information 
The medical history (general medical history and medication history), disease history of 
postmenopausal osteoporosis, fracture history, smoking history, and demographic 
information including gender, age, ethnicity, race, and BMI (kg/m2) at Screening will be 
recorded in the patient’s eCRF and the source documents. 
6.4.2.2 Immunogenicity Assessment 
The immunogenicity of CT-P41 and US-licensed Prolia will be assessed by ADA and NAb 
test in a validated immunoassay. Blood samples for immunogenicity assessments will be 
collected at the time points specified in the schedule of assessments (Appendix 11.1). The 
samples at Weeks 0 (Day 1), 26, and 52 will be collected prior to study drug administration. 
For patients who early discontinue study treatment, immunogenicity samples will be 
collected until the next study drug administration scheduled visit and further immunogenicity 
sampling is unnecessary. When a patient discontinues study treatment after administration of 
the study drug at Week 52, the immunogenicity samples will be collected until Week 78 visit. 
If the blood sample is unable to be analyzed or is missing at certain time point, some blood 
samples collected for PK or PD assessments at the same time point can be used for 
immunogenicity assessment after discussion and agreement from CELLTRION, Inc.  
Blood samples for immunogenicity for patients with immune-related AEs will be obtained on 
onset date of immune-related AEs, if possible, or blood sample can be used if it was obtained 
at the same date of study drug administration. 
Analysis will be performed at the central laboratory. 
Details for immunogenicity blood sampling are provided in Section 6.5.3. 
6.4.2.3 Injection Site Reaction Monitoring 
Injection site reactions will be assessed 30 minutes (± 10 minutes) after the end of the study 
drug administration, as specified in the schedule of assessments (Appendix 11.1). 
For patients who early discontinue study treatment, assessment of injection site reaction is 
unnecessary after the discontinuation. 
Details will be recorded in both the source documents and the eCRF. 

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6.4.2.4 Hypersensitivity/Allergic Reaction Monitoring 
Hypersensitivity/allergic reactions monitoring will be assessed before the start of the study 
drug administration (within 15 minutes) and at 1 hour (± 10 minutes) after the end of the 
study drug administration, as specified in the schedule of assessments (Appendix 11.1), by 
additional vital sign measurements including blood pressure, heart and respiratory rates, and 
body temperature. If patients have signs and symptoms of hypersensitivity/allergic reactions 
at home (hives, difficulty breathing, or swelling of face, eyes, lips, or mouth or any 
symptoms of cardiac origin), patients or caregivers should be advised to call the study center 
or get immediate help. 
In addition, hypersensitivity will be monitored by routine continuous clinical monitoring 
including patient-reported signs and symptoms. In case of hypersensitivity, emergency 
medication and equipment, such as adrenaline, antihistamines, corticosteroids, and 
respiratory support including inhalational therapy, oxygen, and artificial ventilation must be 
available and any types of ECG can be performed. 
For patients who experience or develop life-threatening treatment-related 
hypersensitivity/allergic reactions, the study drug must be stopped immediately and the 
patient should be withdrawn from the study. 
For patients who early discontinue study treatment, monitoring of hypersensitivity/allergic 
reactions is unnecessary after the discontinuation. 
Details will be recorded in both the source documents and the eCRF. 
6.4.2.5 Vital Signs, Weight, Height, and Body Mass Index 
Vital signs, weight, height, and BMI measurements will be performed at the time points 
specified in the schedule of assessments (Appendix 11.1). Vital signs (including blood 
pressure, heart and respiratory rates, and body temperature) will be measured after 5 minutes 
of rest (sitting). Body mass index will be calculated by patient’s weight in kg divided by 
patient’s height in m2. All other measurements will be documented at each study center visit. 
Details will be recorded in both the eCRFs and source documents. 
Vital sign measurements will also be monitored before (within 15 minutes) and after the 
study drug administration (1 hour [± 10 minutes]) as part of the hypersensitivity monitoring 
(Section 6.4.2.4). 

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6.4.2.6 Electrocardiogram 
All scheduled 12-lead ECGs will be performed at the study center after the patient has rested 
quietly for at least 5 minutes in a supine position. A 12-lead ECG will be performed at the 
time points specified in the schedule of assessments (Appendix 11.1) and if the patient 
experienced cardiac symptoms during the study drug administration. If following the ECG 
review by the Investigator there are any ECG findings that would indicate cardiac 
insufficiency or QT prolongation, the patient will be referred to a cardiologist to confirm the 
abnormality. The Investigator will then report the event in the eCRF and source documents. 
Regardless of 12-lead ECG result, further evaluation with a cardiologist can be done 
depending on the Investigator’s discretion. In case of hypersensitivity, any type of ECG can 
be performed (Section 6.4.2.4). 
6.4.2.7 New York Heart Association Functional Classification 
At Screening, patients who have history of heart failure will be assessed for the presence of 
congestive heart failure according to the NYHA functional classification (Appendix 11.5). 
Patients with congestive heart failure of class III or IV chronic heart failure, any unstable 
cardiovascular disease, pulmonary disease, autoimmune disease, or electrocardiogram 
abnormalities will be excluded from the study. Results will be recorded in both the eCRF and 
source documents. 
6.4.2.8 Physical Examination 
Investigators should carefully evaluate patients for any indication of injection site reaction, 
hypersensitivity/allergic reactions, infection, hypocalcaemia, ONJ, atypical femoral fracture, 
and dermatologic reactions and treatment should be indicated in accordance with the 
Investigator’s medical judgment. Especially, a thorough oral examination (including mouth, 
gums, teeth, tongue) with appropriate preventive dentistry should be performed prior to 
treatment. Physical examination will be performed at the time points specified in the 
schedule of assessments (Appendix 11.1). 
Information about the physical examination will be recorded by the Investigator or designee 
in the eCRF and source documents. Any abnormalities will be recorded in the source 
documents. Clinically significant findings and illnesses reported after the start of the study 
that meet the definition of an AE will be recorded in the eCRF and source documents. 

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6.4.2.9 Osteonecrosis of the Jaw 
If a patient has an oral AE which is suspected to be ONJ by the Investigator, the patient 
should be examined by a dentist or other qualified oral specialist (e.g., oral surgeon), for 
whom the blind will be maintained until the end of the study, to determine whether it is ONJ 
based on the American Association of Oral and Maxillofacial Surgeons (AAOMS) ONJ case 
definition (Ruggiero et al., 2014). All available information including age, smoking history, 
medical history, prior and concomitant medication, physical examination, oral AE, and 
anatomic location of ONJ lesion will be provided to the dentist or oral specialist. Radiograph 
could be performed by the dentist or oral specialist’s discretion. The Investigator will be 
notified of the adjudication decision by the dentist or oral specialist whether the oral AE is 
meeting or not meeting to the ONJ case definition. If the oral AE is adjudicated positively by 
the dentist or oral specialist, the information including case details (possible inciting event) 
and AAOMS stage should be provided to the Investigator. The treatment and management 
plan for the ONJ should be set up in close collaboration between the Investigator and the 
dentist or oral surgeon. 
6.4.2.10 Atypical Femoral Fracture 
Patients should be advised to report new or unusual thigh, hip, or groin pain. Radiography 
should be performed on patients presenting with such symptoms to evaluate the atypical 
femoral fracture.  
The femoral fracture AE or the adverse event which is suspected to be an atypical femoral 
fracture will be reviewed by a radiologist at the central imaging vendor, for whom the blind 
will be maintained until the end of the study. All available information surrounding the event 
will be provided to the radiologist. The radiologist will review the radiograph(s) or other 
diagnostic image and/or radiology report, surgical report, or discharge summary with 
reference to the American Society for Bone and Mineral Research (ASBMR) Task Force 
2013 Revised Case Definition of atypical femoral fractures (Shane et al., 2014). If the event 
is adjudicated positively for atypical femoral fracture, the Investigator will be notified of the 
adjudication decision. 
6.4.2.11 Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus 
At Screening, hepatitis B will be assessed in all patients. Eligibility for Hepatitis B infection 
will be confirmed according to the Table 6-1.  
A patient with past hepatitis B virus is allowed if resolved. If the patient develops hepatitis B 

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reactivation, the study drug must be stopped. 
If a patient has hepatitis B surface antigen (HBsAg) positive, hepatitis B e antigen (HBeAg) 
and hepatitis B e antibody (HBeAb) tests will be performed at Screening. If HBeAg test 
result is positive, the patient will be excluded from the study. If the patient has HBeAg 
negative and HBeAb positive test results, hepatitis B virus (HBV) DNA test will be 
performed; if the HBV DNA test result is low or absent (undetectable) level, the patient can 
be included in the study. 
If a patient has HBsAg negative, hepatitis B surface antibody (HBsAb) negative or positive, 
and hepatitis B core antibody (HBcAb) (IgM) positive, a HBV DNA test will be performed at 
Screening. If the HBV DNA test result is positive, the patient will be excluded from the 
study; if the HBV DNA test result is negative, the patient can be included in the study. For 
patients who are enrolled based on the HBV DNA test result, testing of HBsAg, HBsAb, 
HBV DNA, AST, ALT, and total bilirubin will be performed at Weeks 26, 52, and 78 (EOS 
visit). 
If a patient has HBsAg negative, HBsAb negative or positive, and HBcAb (IgM) negative, 
the patient can be included in the study. 
Table 6-1 
Eligibility Based on Serologic Markers for Hepatitis B Infection 
Test Results 
Eligibility 
HBsAg 
HBsAb 
HBcAb 
(IgM) 
HBeAg 
HBeAb 
HBV DNA 
+ 
+/- 
+ 
+ 
+/- 
N/A 
Not eligible 
+ 
+/- 
+ 
- 
+ 
+/- 
(low or absent 
[undetectable] 
level) 
Eligible 
- 
+/- 
+ 
N/A 
N/A 
+ 
Not eligible 
- 
+/- 
+ 
N/A 
N/A 
- 
Eligible1 
- 
+/- 
- 
N/A 
N/A 
N/A 
Eligible 
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; DNA, deoxyribonucleic acid; 
EOS, end-of-study; HBcAb, hepatitis B core antibody; HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e 
antigen; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgM, 
immunoglobulin M; N/A, not applicable. 
1 Testing of HBsAg, HBsAb, HBV DNA, AST, ALT, and total bilirubin will be performed at Weeks 26, 52, and 
EOS visit. 
At Screening, hepatitis C antibody will be assessed in all patients. If the hepatitis C antibody 
test result is positive, a hepatitis C virus (HCV) RiboNucleic Acid (RNA) test will be 
performed at Screening. If the HCV RNA test result is positive, the patient will be excluded 

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from the study; If the HCV RNA test result is negative, the patient can be included in the 
study at the Investigator’s discretion. Further evaluation for the patients who are enrolled 
based on HCV RNA test can be done depending on the Investigator’s discretion during the 
study.  
The HIV test will be assessed in all patients at Screening. If the HIV test result is positive, the 
patient will be excluded from the study. 
Hepatitis B, hepatitis C, and HIV analysis will be performed at the central laboratory. 
6.4.2.12 Pregnancy 
Women of child-bearing potential will not be eligible for enrollment in this study. However, 
if a pregnancy is reported from start of the study drug administration through the study 
period, it should be reported to the Sponsor and 
 PVG within 24 hours of the 
Investigator’s knowledge of the event of a pregnancy. The pregnant patient must permanently 
discontinue the study drug immediately. The study center must complete the supplied 
pregnancy form and return it to the Sponsor and 
 PVG within 24 hours after acquisition 
of the consent for the pregnancy form. 
The pregnancy must be followed up to determine outcome (including premature termination). 
The pregnant patient will be followed until the end of the pregnancy (e.g., delivery, stillbirth, 
miscarriage) and the mother and the baby will be followed for 1 year after the birth, provided 
consent is obtained. Any SAE that occurs during pregnancy (e.g., maternal serious 
complications, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, birth defect) 
must be reported within 24 hours in accordance with the procedure for reporting SAEs 
(Section 6.4.1.4). 
6.4.2.13 Clinical Laboratory Analyses 
Blood and urine samples for clinical laboratory assessments will be collected at the time 
points specified in the schedule of assessments (Appendix 11.1). Blood samples do not need 
to be performed in a fasting state unless required in the opinion of the Investigator. Clinical 
laboratory test samples will be analyzed at the central laboratory. 
The following clinical laboratory analyses will be performed. 
Clinical chemistry: 
Albumin, albumin-adjusted total serum calcium, ALP, ALT, AST, 
bicarbonate, blood urea nitrogen, calcium, chloride, total cholesterol, 

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high-density lipoprotein cholesterol, low density lipoprotein 
cholesterol, creatine kinase–myocardial band isoenzyme, creatine 
phosphokinase, creatinine, gamma-glutamyl transferase, glucose, 
lactate dehydrogenase, triglycerides, magnesium, phosphates, 
potassium, sodium, bilirubin (total, direct), total protein, uric acid, 
Troponin I, serum 25-OH vitamin D, thyroid stimulating hormone, 
and intact parathyroid hormone.  
Hematology: 
Hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential count, absolute neutrophil count, lymphocyte count, 
and platelet count. 
Urinalysis: 
Color, pH, specific gravity, glucose, ketones, leukocytes, nitrite, 
protein, bilirubin, urobilinogen, occult blood, and microscopic 
examination (only if urinalysis dipstick results are abnormal). 
Clinical monitoring of albumin-adjusted total serum calcium, serum 25-OH vitamin D, 
mineral levels (magnesium, phosphate), and any sign and symptoms of hypocalcaemia will 
be closely conducted and adequately treated at Investigator’s discretion, if occurred. At 
Weeks 26, and 52, those clinical laboratory tests will be performed to determine the study 
drug administration. Those clinical laboratory tests will be analyzed at the local laboratory 
and test results will be recorded in the eCRF and source documents. If abnormal results are 
reported, patients will be treated accordingly and follow-up actions will be taken at the 
Investigator’s discretion. If needed, those clinical laboratory tests can be occurred at a 
separate site visit within ± 3 days visit window of Week 26 visit or within ± 5 days visit 
window of Week 52 visit, which is followed by the study drug administration occurring 
within the same visit window of each visit. 
Albumin-adjusted total serum calcium level could be calculated using: Corrected calcium 
(mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 − serum albumin [g/dL]), where 4.0 
represents the average albumin level. If the albumin-adjusted total serum calcium level is 
calculated using mg/dL unit, it could be adjusted for SI units as: Corrected calcium (mmol/l) 
= total Ca (mmol/l) + 0.02 (40 – serum albumin [g/l]). 

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6.4.2.14 Patient’s Assessment of Local Site Pain 
All patients will assess local site pain using 100 mm VAS immediately (not exceeding 
15 minutes) after the study drug administration at the time points specified in the schedule of 
assessments (Appendix 11.1). Patient assessment of pain is measured by the patient 
indicating the extent of their pain by marking one line (│) through the 100 mm line 
(Appendix 11.4). 
For patients who early discontinue study treatment, assessment of local site pain is 
unnecessary after the discontinuation. 
6.5 Sample Collections 
The total volume of blood collected for each assessment is discussed in each specific 
laboratory manual. The sample collection tube may be changed during the study and details 
will be provided in the laboratory manual. 
Samples should be stored and shipped as detailed in Section 6.6.2. 
6.5.1 Pharmacokinetic Blood Sampling 
Blood samples for PK assessments will be obtained in accordance with the laboratory manual 
from each patient at the time point specified in the schedule of assessments (Appendix 11.1). 
All samples should be collected as close as possible to the scheduled time point. The actual 
sampling date and time will be recorded in both the eCRF and source documents. 
6.5.2 Pharmacodynamic Blood Sampling 
Blood samples for PD assessments will be obtained in accordance with the laboratory manual 
from each patient at the time point specified in the schedule of assessments (Appendix 11.1). 
All samples should be collected as close as possible to the scheduled time point. The actual 
sampling date and time will be recorded in both the eCRF and source documents. 
6.5.3 Immunogenicity Blood Sampling 
Blood samples for immunogenicity assessments will be obtained in accordance with the 
laboratory manual from each patient at the time point specified in the schedule of 
assessments (Appendix 11.1). All samples should be collected as close as possible to the 
scheduled time point. The actual sampling date and time will be recorded in both the eCRF 
and source documents. 

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6.5.4 Routine Safety Blood Sampling 
Blood samples for routine safety (clinical laboratory testing) will be collected for analysis 
throughout the study at the time points specified in the schedule of assessments (Appendix 
11.1). 
An additional blood sample for hepatitis B, hepatitis C, HIV, and FSH testing will also be 
required at Screening.  
6.6 Labeling, Storage, and Transportation of Samples 
6.6.1 Sample Labeling 
Each sample tube will be clearly labeled with the following information: study number, 
patient number, tube identification, and scheduled sampling time point. 
6.6.2 Sample Storage and Shipment 
During the study, blood samples will be collected for PK, PD, immunogenicity, and safety 
analyses. 
Where appropriate, the serum should be transferred into a sufficient number of transfer tubes 
for transport to assigned testing facilities. Primary and backup samples will be shipped to the 
central laboratory according to the laboratory manual, and primary samples should be 
shipped separately from the backup samples. 
Additionally, backup samples for PK, PD, and immunogenicity should be retained at the 
central laboratory as a backup for up to 5 years after the end of the study in case additional 
analysis is required. If additional analysis for PK, PD, and immunogenicity is not required, 
the sample will be stored at the Sponsor or a designated biobank for a further 5 years (from 
the date the sample is transferred to the biobank) unless a specific authorization is given by 
the Sponsor to destroy the sample. Additional tests can be conducted at the Sponsor or the 
biobank if it is required from a regulatory or medical perspective. Details in storage and 
shipment will be followed according to the laboratory manual. 

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7 
Statistical Analysis Plan 
The statistical analysis will be performed using 
 
 The statistical methods for this study will be 
described in a detailed statistical analysis plan (SAP), which will be finalized before database 
lock. Changes from analyses planned in this protocol will be documented in the SAP. Any 
deviations from the planned analysis as described in the SAP will be justified and recorded in 
the clinical study report (CSR). 
Full details of the statistical methods will be described in the SAP. 
7.1 Primary Endpoint 
The primary efficacy endpoint will be the following: 
•
Percent change from baseline in BMD for lumbar spine (L1 to L4) by DXA at
Week 52
7.2 Secondary Endpoints 
7.2.1 Efficacy Endpoints 
The secondary efficacy endpoints will be the following: 
•
Percent change from baseline in BMD for lumbar spine (L1 to L4), total hip, and
femoral neck by DXA at Weeks 26, 52, and 78
•
The incidences of new vertebral, nonvertebral, and hip fractures during the study
•
Change from baseline in health-related quality of life at Weeks 26, 52, and 78
7.2.2 Pharmacokinetic Endpoints 
The secondary PK endpoints will be the following: 
•
Serum concentration of denosumab (up to Week 78)
•
Maximum serum concentration (Cmax) after the first administration of study drug
(over the initial 6 months [26 weeks])
•
Trough serum concentration (Ctrough) (concentration prior to the next study drug
administration up to Week 78)

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7.2.3 Pharmacodynamic Endpoints 
The secondary PD endpoints will be the following: 
•
Area under the effect curve (AUEC) of serum carboxy-terminal cross-linking
telopeptide of type I collagen (s-CTX) and procollagen type 1 N-terminal propeptide
(P1NP) over the initial 6 months (from Day 1 predose to Week 26 predose)
•
Percent change from baseline of s-CTX and P1NP at Weeks 26, 52, and 78
7.2.4 Safety Endpoints 
Safety assessments will occur throughout the study. The following safety parameters are 
determined as secondary safety endpoints: 
•
Adverse events (including SAEs)
•
Adverse events of special interest (AESI; injection site reaction, drug-related
hypersensitivity/allergic reaction, infection, hypocalcaemia, ONJ, atypical femoral
fracture, and dermatologic reactions)
•
Hypersensitivity/allergic reaction assessments by vital sign monitoring (including
systolic and diastolic blood pressure, heart rate, respiratory rate, and body
temperature)
•
Local site pain using 100 mm VAS
•
Vital sign measurements, weight, height, and BMI
•
Physical examination
•
Clinical laboratory tests
•
12-lead electrocardiogram
•
Prior and concomitant medication
•
Immunogenicity (incidence of ADA and NAb)
Hepatitis B, C, HIV, and FSH testing and NYHA functional classification will be assessed to 
determine patients’ eligibility. 

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7.3 Sample Size Calculation 
A sample size of 440 patients (220 patients in each treatment group of CT-P41 and US-
licensed Prolia) will achieve approximately 90% statistical power for the demonstration of 
similarity of percent change from baseline in BMD for lumbar spine at Week 52, based on 
the two-one sided 5% significance level and an equivalence margin of ± 1.45%. In this 
sample size calculation, the common SD is assumed to be 4.0% and the expected mean 
difference of percent change from baseline to be 0. The dropout rate has been hypothesized 
as 20%. 
7.4 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Intent-to-Treat (ITT) Set: The ITT Set is defined as all patients randomly assigned to 
receive study drug (CT-P41 or US-licensed Prolia), regardless of whether or not any study 
drug was administered. 
ITT – Treatment Period II subset: The ITT – Treatment Period II subset is defined as all 
patients in ITT set who are randomly assigned to receive study drug (CT-P41 or US-licensed 
Prolia) at Week 52 prior to dosing, regardless of whether or not any study drug was 
administered. 
Full Analysis Set (FAS): The FAS is defined as all randomly assigned patients who receive 
at least 1 full dose of study drug (CT-P41 or US-licensed Prolia). 
FAS – Treatment Period II subset: The FAS – Treatment Period II subset is defined as all 
patients in FAS who are randomly assigned at Week 52 prior to dosing and receive 1 full dose 
of study drug (CT-P41 or US-licensed Prolia) at Week 52. 
Per-Protocol Set (PPS): The PPS is defined as all randomly assigned patients who receive 
all 2 doses (full) of study drug (CT-P41 or US-licensed Prolia) at Weeks 0 (Day 1) and 26, 
and have BMD assessments from lumbar spine at baseline and Week 52. Patients with major 
protocol deviation that may affect the interpretation of study results of primary efficacy 
endpoint will be excluded from the PPS. Final determinations of the PPS will be made at the 
blinded data review meeting (DRM) before unblinding. 
Pharmacokinetic Set: The PK Set is defined as all patients who receive at least 1 full dose 
of study drug (CT-P41 or US-licensed Prolia) and have at least 1 post-treatment PK result. 

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PK – Treatment Period II subset: The PK – Treatment Period II subset will consist of all 
patients in PK Set who receive 1 full dose of either of study drug (CT-P41 or US-licensed 
Prolia) at Week 52 and have at least 1 post-treatment PK result at or after Week 52.  
Pharmacodynamic Set: The PD Set is defined as all patients who receive at least 1 full dose 
of study drug (CT-P41 or US-licensed Prolia) and have at least 1 post-treatment PD result.  
PD – Treatment Period II subset: The PD – Treatment Period II subset will consist of all 
patients in PD Set who receive 1 full dose of either of study drug (CT-P41 or US-licensed 
Prolia) at Week 52 and have at least 1 post-treatment PD result at or after Week 52. 
Safety Set: The Safety Set will consist of all patients who receive at least 1 dose (full or 
partial) of study drug (CT-P41 or US-licensed Prolia). 
Safety – Treatment Period II subset: The Safety – Treatment Period II subset will consist 
of all patients in Safety Set who receive 1 dose (full or partial) of study drug (CT-P41 or US-
licensed Prolia) at Week 52. 
Final determination of the major protocol deviations that can affect the data analysis will be 
made at the blinded DRM held in accordance with ICH Technical Requirements for 
Registration of Pharmaceuticals for Human Use harmonised tripartite guideline E9. 
7.5 Description of Subgroups to be Analyzed 
Subgroup analysis by race and age will be performed for primary efficacy endpoint in the 
FAS. Further subgroup analysis could be implemented to reflect medical, regulatory, 
regional, or ethnic consideration, if required. 
7.6 Statistical Analysis Methodology 
7.6.1 General Consideration 
Continuous variables will be summarized by reporting the following descriptive statistics: the 
number of observations (n), mean, SD, median, minimum, and maximum, unless otherwise 
indicated. Categorical variables will be summarized using frequency tables showing the 
number and percentage of patients within a particular category. Data will be listed in data 
listings. 
7.6.2 Demographics, Baseline and Background Characteristics 
The medical history (general medical history and medication history), demographic (e.g., 
gender, age, ethnicity, race, and BMI [kg/m2] at Screening), and baseline characteristics 

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including disease-related medical history, and medication history will be presented in 
summary tables (descriptive statistics for quantitative variables, or frequency for qualitative 
variables). Listings will be provided by treatment group. 
Demographics, baseline and background characteristics for Treatment Period I will be 
summarized using the ITT Set and those for Treatment Period II will be summarized on the 
ITT – Treatment Period II subset, unless otherwise specified. Listings will be provided by 
treatment group on the ITT Set. In addition, a listing of patients whose trial participation is 
impacted by COVID-19 with details of the impact, will be prepared, if applicable. 
7.6.3 Efficacy Analyses 
7.6.3.1 Primary Efficacy Endpoint 
To evaluate the difference between 2 treatment groups in the primary efficacy endpoint, 
percent change from baseline in BMD for lumbar spine (L1 to L4) by DXA at Week 52 will 
be analyzed using an analysis of covariance (ANCOVA) model coupled with multiple 
imputation (MI) assuming the data to be missing at random (MAR). The ANCOVA model 
will include the treatment as a fixed effect and age, baseline BMD T-score at the lumbar 
spine, and prior bisphosphonates therapy (Yes versus No) as covariates. Statistical 
equivalence will be declared if the 90% confidence interval (CI) of the difference in the mean 
of the primary efficacy endpoint between treatment groups falls entirely within an 
equivalence margin, [− 1.45, + 1.45]. The primary analysis will be performed using the FAS. 
A supportive analysis will be performed using the PPS.  
Multiple imputation with the MAR assumption will be applied. The multiple imputed 
datasets will be generated based on regression model with age, baseline BMD T-score at 
lumbar spine, prior bisphosphonates therapy (Yes versus No), and treatment group as 
covariates. Ten imputed datasets will be generated and an ANCOVA for the percent change 
from baseline in BMD for lumbar spine (L1 to L4) by DXA at Week 52 will be performed on 
each of the 10 multiple imputed datasets. The results from each set of imputed datasets will 
then be aggregated for the final statistical inference using Rubin’s method.   
Sensitivity analysis will be conducted in the FAS to examine the impact of missing data on 
primary analysis result by imputing missing data over a range of possible scenarios for the 
treatment effect (Section 7.6.3.1.1). 

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7.6.3.1.1  Sensitivity Analysis of Primary Efficacy Endpoint 
In order to evaluate the impact of missing data of BMD at lumbar spine at Week 52 on the 
primary endpoint results, a tipping point analysis will be conducted for the primary efficacy 
endpoint in the FAS. Missing data for the percent change from baseline in BMD for lumbar 
spine by DXA at Week 52 will be imputed by MI and shifted gradually by treatment groups 
(CT-P41 versus US-licensed Prolia) to assess missing not at random scenarios. 
In addition to the tipping point analysis, imputation under a non-inferiority (NI) null 
hypothesis and non-superiority null hypothesis (Koch , 2008) will be performed as a part of 
sensitivity analysis. The missing data imputed by MI will be further adjusted by the NI or 
non-superiority margin for the CT-P41 treatment group, when testing NI and non-superiority, 
respectively. For this analysis, missing data due to the situation of Ukraine War will not be 
imputed under the corresponding null hypothesis thus remain their initial imputed values, and 
only missing data from outside Ukraine will be adjusted by the margin.  
7.6.3.1.2  Subgroup Analysis by Race and Age 
To assess the consistency of 2 treatment groups in the primary efficacy endpoint by race and 
age, percent change from baseline in BMD for lumbar spine (L1 to L4) by DXA at Week 52 
will be summarized using descriptive statistics including 95% CI for the mean by each 
treatment group and each subgroup in the FAS. 
7.6.3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be summarized using descriptive statistics or 
frequency tables. Data for Treatment Period I will be summarized on the FAS and PPS and 
data for Treatment Period II will be summarized on the FAS – Treatment Period II subset, 
unless otherwise specified. Listing will be provided by treatment group on the ITT set. 
The following secondary efficacy endpoints will be assessed at the time points specified in 
the schedule of assessments (Appendix 11.1). 
•
Percent change from baseline in BMD for lumbar spine (L1 to L4), total hip, and
femoral neck by DXA at Weeks 26, 52, and 78
•
Incidence of new vertebral, nonvertebral, and hip fractures during the study
•
Change from baseline in health-related quality of life at Weeks 26, 52, and 78

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7.6.4 
Pharmacokinetic Analyses 
The serum concentration and PK parameters of Cmax and Ctrough will be summarized using 
descriptive statistics (including geometric mean and coefficient of variation [CV], as 
appropriate). Mean serum concentration time profiles of study drugs will be plotted by 
treatment group on linear and semilogarithmic scales based on scheduled sample times. 
Individual concentrations and scheduled and actual sample times will be presented in data 
listings by treatment group.  
All PK parameters will be estimated using 
 
   
Pharmacokinetic analysis for Treatment Period I will be summarized using the PK Set and 
that for Treatment Period II will be summarized on the PK – Treatment Period II subset, 
unless otherwise specified. Serum concentration of denosumab will be listed by treatment 
group for the Safety Set and all data for the PK parameters will be listed by treatment group 
for the PK Set. 
7.6.5 
Pharmacodynamic Analyses 
The AUEC of s-CTX and P1NP over the initial 6 months (from Day 1 predose to Week 26 
predose) will be assessed and will be estimated 
 
   
Serum concentration and percent change from baseline of s-CTX and P1NP at Weeks 26, 52 
and 78 will also be assessed and summarized using descriptive statistics (including geometric 
mean and CV, as appropriate). Percent change from baseline versus time profiles of s-CTX 
and P1NP will be presented graphically on linear scale by treatment group using scheduled 
sampling times.  
Pharmacodynamic analysis for Treatment Period I will be summarized on the PD Set and that 
for Treatment Period II will be summarized on the PD – Treatment Period II subset, unless 
otherwise specified. Listings will be provided by treatment group on the ITT set. 
7.6.6 
Safety Analyses 
Safety analyses will be performed at the time points specified in the schedule of assessments 
(Appendix 11.1) and will be summarized using descriptive or frequency tables. All safety 
data including immunogenicity for Treatment Period I will be summarized for the Safety Set 

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and that for Treatment Period II will be summarized for the Safety – Treatment Period II 
subset, unless otherwise specified. Listings will be provided by treatment group on Safety 
Set. 
7.6.6.1 Adverse Events 
Adverse events will be coded to system organ class (SOC) and preferred term (PT) according 
to the MedDRA and severity grading of AEs will be recorded according to the CTCAE 
Version 5.0. A TEAE is defined as described in Section 6.4.1.1. The following TEAE 
summaries will be reported by SOC, PT, and treatment group: 
•
Number and percentage of patients reporting at least 1 TEAE
•
Number and percentage of patients reporting at least 1 treatment-emergent SAE
•
Number and percentage of patients discontinuing the study drug due to a TEAE
•
Number and percentage of patients with TEAEs of special interest (injection site
reaction, drug-related hypersensitivity/allergic reaction, infection, hypocalcaemia,
ONJ, atypical femoral fracture, and dermatologic reactions)
Listings will be provided by treatment group showing the details of AEs. 
7.6.6.2 Immunogenicity 
All data will be listed and summarized by treatment group, where appropriate. 
7.6.6.3 Electrocardiograms, Physical Examinations, Vital Signs, Weight, 
Height, and Body Mass Index 
Electrocardiograms, physical examinations, vital signs (systolic and diastolic blood pressure, 
heart rate, respiratory rate, and body temperature) including hypersensitivity monitoring, and 
weight, height, and BMI will be summarized and listed by treatment group for each 
scheduled collection time point. Changes from baseline will also be summarized for all 
scheduled collection times after the first administration of study drug, if applicable. 
7.6.6.4 Clinical Laboratory Analyses 
Clinical laboratory tests (clinical chemistry, hematology, urinalysis, and other) will be 
summarized and listed by treatment group at each scheduled collection time and graded 

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according to the CTCAE v5.0. For continuous parameters, change from baseline will also be 
summarized for all scheduled collection times after the first administration of the study drug. 
7.6.6.5 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO drug dictionary. All prior 
and concomitant medication data will be summarized and listed by treatment group as 
appropriate. 
7.6.6.6 Patient’s Assessment of Local Site Pain 
Local site pain measurements by VAS (Appendix 11.4) will only be assessed by immediately 
after the administration of the study drug at each scheduled collection time point and will be 
summarized and listed by treatment group. 
7.6.6.7 Other Safety Analyses 
All other safety data will be summarized and listed by treatment group as appropriate. 
7.7 Interim Analysis 
No interim analyses are planned for this study. 
7.8 Data Quality Assurance 
This study will be conducted according to the ICH E6(R2) risk and quality processes 
described in the applicable procedural documents. The quality management approach to be 
implemented in this study will be documented and will comply with the current ICH Good 
Clinical Practice (GCP) guidelines on quality and risk management. 
Step to be taken to ensure the accuracy and reliability of data includes the selection of 
qualified Investigators and appropriate study centers, review of protocol procedures with the 
Investigator and associated staff prior to the study, periodic monitoring visits by the Sponsor 
or its designee, and direct transmission of clinical laboratory data from a central laboratory 
into the clinical database. The data will be collected via Electronic Data Capture (EDC) using 
eCRFs. The study center will be responsible for data entry into the EDC system. The eCRF 
will be reviewed for accuracy and completeness by the monitor during on-site or remote 
monitoring visits and after their return to the Sponsor or its designee. In the event of 
discrepant data, the Sponsor will request data clarification from the study centers, which the 
study centers will resolve electronically in the EDC system. The Sponsor will be responsible 
for the data management of this study, including quality checking of the data. 

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Quality assurance staff from the Sponsor or its designee may visit the study center to carry 
out an audit of the study in compliance with regulatory guidelines and company policy. Such 
audits will require access to all study records, including source documents, for inspection and 
comparison with the eCRF. Patient privacy must, however, be respected. Sufficient prior 
notice will be provided to allow the Investigator to prepare properly for the audit. 
Similar auditing procedures may also be conducted by agents of any regulatory body 
reviewing the results of this study in support of a licensing application. The Investigator 
should immediately notify the Sponsor or its designee if he or she has been contacted by a 
regulatory agency concerning an upcoming inspection. 

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8 
Investigator’s Obligations 
The following administrative items are meant to guide the Investigator in the conduct of the 
study but may be subject to change based on industry and government standard operation 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendment. 
8.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the patient (or the patient’s legal guardian), except as necessary for monitoring 
and auditing by the Sponsor, its designee, the regulatory authorities, or the IRB/IEC. 
The Investigator, all employees, and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
8.2 Independent Ethics Committee or Institutional Review Board 
Regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
before participation of human patients in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study patients, and any 
other written information regarding this study to be provided to the patient or the patient’s 
legal guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals 
and of the IRB/IEC compliance with ICH harmonised tripartite guideline E6(R2): GCP will 
be maintained by the study center and will be available for review by the Sponsor or its 
designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the data approval or a favorable opinion was granted. 
The Investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
Investigator must promptly supply the Sponsor or its designee, the IRB/IEC, and, where 

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applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing risk to patients. 
8.3 Patient Information and Consent 
A written informed consent in compliance with the ICH E6(R2) guidelines shall be obtained 
from each patient before entering the study or performing any unusual or non-routine 
procedure that involves risk to the patient. An informed consent template may be provided by 
the Sponsor to the study centers. If any institution-specific modifications to study-related 
procedures are proposed or made by the study center, the consent should be reviewed by the 
Sponsor or its designee or both before IRB/IEC submission. Once reviewed, the consent will 
be submitted by the Investigator to his or her IRB/IEC for review and approval before the 
start of the study. If the ICF is revised during the course of the study, all active participating 
patients must sign the revised form in case new information becomes available that may be 
relevant to the subject’s willingness to continue participation in the clinical study. 
Before recruitment and enrollment, each prospective patient or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the 
Investigator is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to 
participate tin the study by signing the ICF. 
In addition to the standard requirements that physicians are currently obliged to observe 
when providing information, the following points must also be covered: 
 
A description of the objectives of the study and how it will be organized 
 
The type of treatment 
 
Any potential negative effects attributable to the study drug 
 
The freedom to ask for further information at any time 
 
The patient’s right to withdraw from the clinical study at any time without giving 
reason and without jeopardizing the patient’s further course of medical treatment 
 
The existence of patient insurance coverage and a summary of what is included in 
this coverage 
 
Adequate time and opportunity to satisfy questions will be given to the patients. 

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The Investigator will be supplied with an adequate number of ICFs to be used. The forms 
will be signed and dated by both the Investigator or Sub-Investigator and the patient’s legal 
representatives (according to the local regulations) before the beginning of the study. The 
Investigator shall retain the signed original ICF(s) and give a copy of the signed original form 
to the patient or legal guardian. 
To ensure medical confidentiality and data protection, the signed ICFs will be stored in the 
Investigator’s study file. The Investigator will allow inspection of the forms by authorized 
representatives of the Sponsor, IRB/IEC members, and regulatory authorities. The 
Investigator will confirm, by signing and dating the eCRFs, that informed consent has been 
obtained. 
8.4 Study Reporting Requirements 
By participating in this study, the Principal Investigator or Sub-Investigator agrees to submit 
reports of SAEs according to the timeline and method outlined in Section 6.4.1.4. In addition, 
the Principal Investigator or Sub-Investigator agrees to submit annual report to his or her 
IRB/IEC as appropriate. 
8.5 Financial Disclosure and Obligations 
CELLTRION, Inc. is the Sponsor of the study and is funding the study. All financial details 
are provided in the separate contracts between the institution, Investigator, and CRO. The 
Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws. The Sponsor will indemnify all Investigators 
participating in this study against future claims by study patients; the terms of this will be 
detailed within a separate letter of indemnification. The indemnity will only apply where all 
study procedures have been carried out according to this protocol. 
The Investigator is required to take out liability insurance for all patients included in the 
study as required by local law and/or regulations and/or ICH guideline for GCP, whichever is 
applicable. 
The Investigator and the Sponsor will sign a clinical study agreement before the start of the 
study. The agreement will outline overall Sponsor and Investigator responsibilities in relation 
to the study. Financial remuneration will cover the costs based on the calculated expenses of 
performing the study assessments in accordance with the protocol and the specified terms of 
payment will be described in the contract. 

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Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements per regional 
requirements. In addition, the Investigator must provide to the Sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the Sponsor nor its designee is financially responsible for further testing or treatment 
or any medical condition that may be detected during the Screening process. In addition, in 
the absence of specific arrangements, neither the Sponsor nor its designee is financially 
responsible for further treatment of the patient’s pre-existing disease prior to study 
participation (Screening). 
The Sponsor undertakes to compensate the patient for injuries which are considered, on the 
balance of probabilities, to have arisen as a result of their participation in the trial. 
8.6 Investigator Documentation 
Before beginning the study, the Investigator will be asked to comply with ICH E6(R2) 8.2 
and Title 21 of the Code of Federal Regulation (CFR) by providing the following essential 
documents, including but not limited to: 
 
Independent Ethics Committee/IRB approval 
 
Original Investigator-signed Investigator agreement page of the protocol 
 
Curriculum vitae for the Principal Investigator and each Sub-Investigator. Current 
licensure must be noted in the curriculum vitae. The curriculum vitae will be signed 
and dated by the Principal Investigators and Sub-Investigators at the study start-up, 
indicating that they are accurate and current 
 
Financial disclosure information to allow the Sponsor to submit complete and 
accurate certification or disclosure statements. In addition, the Investigators must 
provide to the Sponsor a commitment to promptly update this information if any 
relevant changes occur during the course of the investigation and for 1 year after the 
completion of the study 
 
Independent Ethics Committee/IRB-approved informed consent, samples of study 
center advertisements for recruitment for this study, and any other written 
information regarding this study that is to be provided to the patient or legal 
guardian, and 

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 
Laboratory certifications and normal ranges for any local laboratories used by the 
study center. 
8.7 Study Conduct 
The Investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The Investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations.  
8.8 Data Collection 
8.8.1 Electronic Case Report Forms and Source Documents 
It is the intent of this study to acquire study data via electronic format. As part of the 
responsibilities assumed by participating in the study, the Principal Investigator or Sub-
Investigator agrees to maintain adequate case histories for the patients treated as part of the 
research under this protocol. The Principal Investigator or Sub-Investigator agrees to 
maintain source documentation (e.g., laboratory reports), enter patient data into the eCRF as 
accurately as possible, and respond to any reported discrepancies rapidly. These source 
documents may include diaries, laboratory reports, ECG strips, etc. For data collected using 
CRO electronic clinical outcome assessment system, data in this system itself will be 
considered as source document. 
The analysis data sets will be combination of these data and data from other sources (e.g., 
laboratory data). 
The eCRF are accessed through the appropriate system, which allows for on-site data entry 
and data management. Study center users can read from and write to the Sponsor’s database 
where the clinical data are collected. This provides immediate, direct data transfer to the 
database, as well as immediate detection of discrepancies, enabling study center coordinators 
to resolve and manage discrepancies in a timely manner. 
Each study center staff involved with the study at each study center will have an individual 
logon account and password that allow for record traceability. Thus, the system, and 
subsequently any investigative reviews, can identify coordinators, Investigators and 
individuals who have entered or modified records. 

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8.9 Adherence to Protocol 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
8.10 Adverse Events and Study Report Requirements 
By participating in this study, the Investigator agrees to submit reports of SAEs to the 
Sponsor and/or IRB/IEC according to the timeline and method outlined in Section 6.4.1.4. In 
addition, the Investigator agrees to submit annual reports to the study center IRB/IEC as 
appropriate. 
8.11 Investigator’s Final Report 
Upon completion of the study, the Investigator, where applicable, should inform the 
institution; the Investigator/institution should provide IRB/IEC with a summary of the 
study’s outcome and the Sponsor and regulatory authority(ies) with any reports required. 
8.12 Record Retention 
All correspondence (e.g., with Sponsor, IRB/IEC, or Clinical Research Associates) relating to 
this clinical study will be kept in appropriate file folders. Records of patients, source 
documents, eCRFs, and drug inventory sheets pertaining to the study must kept on file. 
Essential documents should be retained until at least 15 years after the date on which the 
results of the study are submitted to the regulatory authorities in support of an allocation for a 
research or marketing permit, or completion date for study by approval or disapproval of any 
application, whichever is later. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. It is the responsibility of the Sponsor to inform the Investigator/institution as to 
when these documents no longer need to be retained. 
If an Investigator moves, withdraws from an investigation, or retires, the responsibility for 
maintaining the records may be transferred to another person, who will accept the 
responsibility. Notice of transfer must be made to and agreed upon by the Sponsor. 
8.13 Patients Identification Register 
The Investigator agrees to complete a patient identification register, which will be used for 
the purpose of long-term follow-up, if needed. This form will be treated as confidential and 

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will be filed by the Investigator in the Study Center Master File. Otherwise, all reports and 
communications relating to the study will identify patients by assigned number only. 
8.14 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the Sponsor will be 
responsible for these activities and will work with the Investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The Sponsor has final approval authority over all 
such issues. 
Data are the property of the Sponsor and cannot be published without prior authorization 
from the Sponsor, but data publication thereof will not be unduly withheld. 

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9 
Study Management 
9.1 Sponsor 
CELLTRION, Inc. 
23, Academy-ro, Yeonsu-gu, Incheon, 
22014, Republic of Korea 
Phone:  + 82 32 850 5000 
Fax: + 82 32 850 5050 
E-mail: contact@celltrion.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

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9.3 Central Analytical Facilities 
Any analytical facilities and procedures utilized for this study must be Good Laboratory 
Practice compliant. Details of analytical facilities will be provided in the ICF.  
9.4 Monitoring 
9.4.1 Data Safety Monitoring Board 
This study will be monitored by an independent DSMB consisting of a PK specialist, 
statistician, chairing physician, and an independent physician. The DSMB will review and 
evaluate accumulating safety data to ensure the safety of study patients and also review study 
results. 
Further details will be provided in the independent DSMB charter. 
9.4.2 Monitoring of the Study 
The clinical monitor, as a representative of the Sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the Investigator and study center at periodic 
intervals, in addition to maintaining necessary telephone and letter contact. The monitor will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
Investigator and staff. In case where a monitoring visit cannot be made because of the 
pandemic situation of COVID-19, the monitor will discuss with the Sponsor, CRO, and the 
Investigator for further plan, which will be specified in the Appendix 11.6. 
All aspects of the study will be carefully monitored, by the Sponsor or its designee, for 
compliance with applicable government regulation with respect to current ICH E6(R2) and 
SOPs. 
9.4.3 Inspection of Records 
Investigators and institutions involved in the study will permit study related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the Investigator agrees to allow the Sponsor, representatives 
of the Sponsor, or a regulatory agency access to all study records. 
The Investigator should promptly notify the Sponsor and CRO of any audits scheduled by 
any regulatory authorities. 

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9.5 Management of Protocol Amendments and Deviations 
9.5.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the patient, must be reviewed and approved by the Sponsor or its 
designee. Substantial amendments to the protocol must be submitted in writing to the 
applicable IRB/IEC and regulatory authority for approval before patients are enrolled under 
an amended protocol. This will be fully documented. 
The Investigator must not implement any deviation from or change to the protocol without 
discussion and agreement from the Sponsor or its designee, and prior review, documented 
approval, and favorable opinion of the amendment from the relevant IRB/IEC and/or 
regulatory authorities, except where it is necessary to eliminate an immediate hazard to 
patients or where the changes involve only logistical or administrative aspects of the clinical 
study. The eCRF and source documents will describe any departure from the protocol and the 
circumstances requiring it. 
Protocol amendments will be submitted to the appropriate authorities as required by the 
applicable regulatory requirements. 
9.5.2 Protocol Deviations 
The Investigator or designee must document and explain in the patient’s source 
documentation any deviation from the approved protocol. The Investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
patients without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the Sponsor for agreement 
and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the Sponsor and the IRB/IEC and agreed to by the 
Investigator. A significant deviation occurs when there is non-adherence to the protocol by 
the patient or Investigator that results in a significant and additional risk to the patient’s right, 
safety and wellbeing. Significant deviations can include non-adherence to inclusion or 
exclusion criteria, or non-adherence to regulations or ICH GCP guidelines, and will lead to 
the patient being withdrawn from the study (Section 4.2). 

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Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Deviations will be defined before unblinding. Principal Investigators will 
be notified in writing by the monitor of deviations. The IRB/IEC should be notified of all 
protocol deviations in a timely manner. 
9.6 Study Termination 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
The completion of the study is defined as the date of final database lock with no further 
database change for the final CSR. 
9.7 Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
CSR is prepared and provided to the regulatory agency(ies) as required by the applicable 
regulatory requirement(s). The Sponsor will also ensure that the CSR in marketing 
applications meets the standards of the ICH harmonised tripartite guideline E3: Structure and 
content of CSRs. 
CELLTRION, Inc. plans to prepare 1 CSR, including but not limited to the following. 
 
All data after completion of the study (up to Week 78) 
But additional CSRs will be generated upon requirements for regulatory or academic 
purposes (including all data after completion of the Treatment Period I [Week 52]). 

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11 Appendices 
11.1 Schedule of Assessments  
 
Screening 
Treatment Period I 
Treatment Period II 
EOS1 
Week 
(Month) 
− 28 to − 1 
W0  
(M0) 
W1 
W2 
W4 
W8 
W12 
(M3) 
W26 
(M6) 
W27 
W39 
(M9) 
W52 
(M12) 
W53 
W60 
W68 
W78 
(M18) 
Day 
1 
3 
10 
15 
29 
57 
85 
183 
190 
274 
365 
372 
421 
477 
547 
Visit Window2 
 
- 
±1 day 
±3 days 
±5 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C and HIV3 
X 
 
 
 
 
 
 
 
(X) 
 
 
(X) 
 
 
 
(X) 
NYHA Functional Classification4 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follicle-stimulating hormone 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization6 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Efficacy assessment – Predose, if study drug is administered on the same visit 
DXA scan7 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Lateral spine X-rays (Lumbar and 
thoracic)8 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
QoL assessment (OPAQ-SV, EQ-5D-5L) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Safety/Laboratory Test – Predose, if study drug is administered on the same visit 
Vital Signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG10 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Height, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
Physical examination11 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
Urinalysis12 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
Hematology, Clinical chemistry13 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Serum 25-OH vitamin D,  
Albumin-adjusted total serum calcium 
(total Ca and serum albumin),  
Phosphate, Magnesium (local)14 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Immunogenicity/PK/PD Sampling – Predose, if study drug is administered on the same visit 
Immunogenicity Sampling15 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
X 
  
X 
X 
X 
Pharmacokinetic Sampling16 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 

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Screening 
Treatment Period I 
Treatment Period II 
EOS1 
Week 
(Month) 
− 28 to − 1 
W0  
(M0) 
W1 
W2 
W4 
W8 
W12 
(M3) 
W26 
(M6) 
W27 
W39 
(M9) 
W52 
(M12) 
W53 
W60 
W68 
W78 
(M18) 
Day 
1 
3 
10 
15 
29 
57 
85 
183 
190 
274 
365 
372 
421 
477 
547 
Visit Window2 
 
- 
±1 day 
±3 days 
±5 days 
Pharmacodynamic Sampling17 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
Study drug administration 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Hypersensitivity/allergic reaction 
Monitoring18 and injection site reaction19 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Local site pain by VAS20 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Vitamin D and Ca supplements 
Treatment21 
 
X 
Radiography22 
 
As required 
Prior/Concomitant Medications23 
X 
X 
AE Monitoring24 
X 
X 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMD, bone mineral density; BMI; body mass index; Ca, calcium; DNA, deoxyribonucleic acid; DXA, dual-
energy X-ray absorptiometry; ECG, electrocardiogram; eCRF, electronic case report form; EOS, end-of-study; EQ-5D-5L, EuroQoL-5 Dimensions-5 Levels Health Survey; HBcAb, hepatitis B core antibody; 
HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human 
immunodeficiency virus; ICF, informed consent form; IgM, immunoglobulin M; NYHA, New York Heart Association; OPAQ-SV, osteoporosis assessment questionnaire-short version; RNA, ribonucleic acid; 
QoL, quality of life; VAS, visual analog scale. 
Note: For patients who early discontinue study treatment or initiated different osteoporosis medication (including those prohibited by the protocol), every effort should be made to complete regularly scheduled 
study visits, and PK, PD, and immunogenicity samples will be collected until the next study drug administration scheduled visit. When a patient discontinues study treatment after administration of the study drug at 
Week 52, the PK, PD, and immunogenicity samples will be collected until Week 78 visit. Especially, if a patient discontinues the study treatment prior to Week 52, the patient should return to the study center at 
Week 52 for the primary efficacy assessment. If a patient cannot or is unwilling to attend any visit(s), a safety follow-up (e.g., adverse events, concomitant medications) will be conducted by telephone according to 
the study visit schedule.  
1. 
An EOS visit will occur at the Week 78 visit for all patients who completed or discontinued study treatment.  
2. 
A dosing visit window of ± 3 days is allowed for Week 26 visit and that of ± 5 days is allowed for Week 52 visit. If any study visit has to be rescheduled, subsequent visits should follow the original visit date 
scheduled. 
3. 
At Screening, hepatitis B will be assessed in all patients. A patient with past hepatitis B virus is allowed if resolved. If the patient develops hepatitis B reactivation, the study drug must be stopped. Further 
eligibility for hepatitis B infection will be confirmed according to the Table 6-1. At Screening, hepatitis C antibody will be assessed in all patients. If hepatitis C antibody test result is positive, a HCV RNA 
test will be performed at Screening. If the HCV RNA test result is positive, the patient will be excluded from the study; If the HCV RNA test result is negative, the patient can be included in the study at the 
Investigator’s discretion. Further evaluation for the patients who are enrolled based on HCV RNA test can be done depending on the Investigator’s discretion during the study. HIV test will be assessed in all 
patients at Screening. If the HIV test result is positive, the patient will be excluded from the study. Hepatitis B, hepatitis C, and HIV analysis will be performed at the central laboratory. 
4. 
At Screening, patients who have history of heart failure will be assessed for the presence of congestive heart failure according to the NYHA functional classification. 
5. 
The inclusion and exclusion criteria need to be confirmed by screening results prior to the randomization on Day 1.  
6. 
Patients will be randomly assigned to one of two treatment groups (either CT-P41 or US-licensed Prolia) on Day 1 prior to the study drug administration. Second randomization will be performed prior to the 
study drug administration on Week 52. Patients who are initially randomized to CT-P41 in Treatment Period I will continue to receive CT-P41. Patients who are initially randomized to US-licensed Prolia in 
Treatment Period I, will be re-randomized in a ratio of 1:1 to switching arm (CT-P41) or non-switching arm (US-licensed Prolia). 
7. 
Bone mineral density will be assessed by DXA at Screening and at Weeks 26, 52 and 78 (EOS visit). Assessment of lumbar spine, total hip, and femoral neck BMD will be performed at a central imaging 

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vendor. If needed, Week 26 DXA scan can be occurred at a separate site visit within ± 3 days visit window of Week 26 visit, which is followed by the study drug administration occurring within the same 
visit window of Week 26 visit. At Week 52 visit, the DXA scan will be analyzed by both the central imaging vendor and the study center. If needed, Week 52 DXA scan can be occurred at a separate site visit 
within ± 5 days visit window of Week 52 visit, which is followed by the study drug administration occurring within the same visit window of Week 52 visit. A BMD assessor for the local reading will be 
assigned to each study center. If possible, it is recommended that the local reading will be performed by the same person at each study center throughout the study period. The local reading result at Week 52 
will be used for the stratification factor of the second randomization.  
8. 
Lateral spine X-ray will be performed at Screening, Weeks 26, 52, and 78 (EOS visit), and also could be performed as required for confirmation of suspected vertebral fractures. If needed, the lateral spine X-
ray at Week 26 or Week 52 can be occurred at a separate site visit within ± 3 days or ± 5 days visit window of Week 26 or Week 52 visit respectively, which is followed by the study drug administration 
occurring within the same visit window of Week 26 or Week 52 visit. 
9. 
Vital signs (including systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature) will be measured after 5 minutes of rest (sitting). 
10. All scheduled 12-lead ECG will be performed at the study center after the patients have rested in a supine position for at least 5 minutes prior to recording of 12-lead ECG. Regardless of the 12-lead ECG 
result, further cardiological evaluation can be conducted at the Investigator’s discretion. 
11. Physical examination including oral examination (including mouth, gums, teeth, tongue). 
12. Urinalysis analysis will be performed at the central laboratory. 
Urinalysis 
Color, pH, specific gravity, ketones, protein, glucose, bilirubin, leukocytes, nitrite, urobilinogen, occult blood, and microscopic examination (if urinalysis dipstick results are 
abnormal).  
13. Hematology, clinical chemistry, and other test samples will be analyzed at the central laboratory. Clinical monitoring of albumin-adjusted total serum calcium, serum 25-OH vitamin D, and mineral levels 
(magnesium, phosphate), and any sign and symptoms of hypocalcaemia should be closely conducted and adequately treated at the Investigator’s discretion, if occurred. 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential count, absolute neutrophil count, lymphocyte count, and platelets count 
Clinical chemistry 
Albumin, albumin-adjusted total serum calcium, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen, 
calcium, chloride, total cholesterol, high-density lipoprotein cholesterol, low density lipoprotein cholesterol, creatine kinase-myocardial band isoenzyme, creatine phosphokinase, 
creatinine, gamma-glutamyl transferase, glucose, lactate dehydrogenase, triglycerides, magnesium, phosphate, potassium, sodium, total bilirubin, direct bilirubin, total protein, uric 
acid, Troponin I, serum 25-OH vitamin D, thyroid stimulating hormone, and intact parathyroid hormone 
14. Clinical laboratory results including serum 25-OH vitamin D, albumin-adjusted total serum calcium, phosphate, and magnesium will be obtained to determine the study drug administration at Weeks 26 and 
52. The clinical laboratory tests will be monitored for hypocalcaemia and will be analyzed at the local laboratory. If abnormal results are reported, patients will be treated accordingly and follow-up actions 
will be taken at the Investigator’s discretion. If needed, the tests can be occurred at a separate site visit within ± 3 days visit window of Week 26 visit or within ± 5 days visit window of Week 52 visit, which 
is followed by the study drug administration occurring within the same visit window of each visit. Albumin-adjusted total serum calcium level will be calculated using: Corrected calcium (mg/dL) = measured 
total Ca (mg/dL) + 0.8 (4.0 − serum albumin [g/dL]), where 4.0 represents the average albumin level. If the albumin-adjusted total serum calcium level is calculated using mg/dL unit, it could be adjusted for 
SI units as: Corrected calcium (mmol/l) = total Ca (mmol/l) + 0.02 (40 – serum albumin [g/l]). 
15. Samples for immunogenicity testing will be collected prior to dosing of the study drug if study drug is administered on the same visit. Other samples could be taken at any time of the scheduled visit. 
Additional immunogenicity will be assessed when immune-related AEs occur. Analysis will be performed at the central laboratory. For patients who early discontinue study treatment, immunogenicity 
samples will be collected until the next study drug administration scheduled visit and further immunogenicity sampling is unnecessary. When a patient discontinues study treatment after administration of the 
study drug at Week 52, the immunogenicity samples will be collected until Week 78 visit. 
16. Samples for pharmacokinetic testing should be collected up to 30 minutes prior to dosing of the study drug if study drug is administered on the same visit. Other samples could be taken at any time of the 
scheduled visit. Analysis will be performed at the central laboratory. For patients who early discontinue study treatment, pharmacokinetic samples will be collected until the next scheduled study drug 
administration visit and further pharmacokinetic sampling is unnecessary. When a patient discontinues study treatment after administration of the study drug at Week 52, pharmacokinetic samples will be 
collected until Week 78 visit. 
17. Samples for pharmacodynamic testing should be taken in the morning after fasting overnight for 8 hours prior to assessment, and the patients have to refrain from intense exercise the day prior to PD 
assessment. Analysis will be performed at the central laboratory. For patients who early discontinue study treatment, pharmacodynamic samples will be collected until the next study drug administration 
scheduled visit and further pharmacodynamic sampling is unnecessary. When a patient discontinues study treatment after administration of the study drug at Week 52, pharmacodynamic samples will be 

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collected until Week 78 visit. 
18. Vital signs including systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature (before the start of the study drug administration [within 15 minutes] and at 1 hour [± 10 minutes] 
after the end of the study drug administration) will be assessed to monitor for possible hypersensitivity reactions. In addition, hypersensitivity will be monitored by routine continuous clinical monitoring 
including patient-reported signs and symptoms. In case of hypersensitivity, emergency medication and equipment, such as adrenaline, antihistamines, corticosteroids and respiratory support including 
inhalational therapy, oxygen and artificial ventilation must be available and any types of ECG can be performed. For patients who early discontinue study treatment, monitoring of hypersensitivity/allergic 
reactions is unnecessary after the discontinuation. 
19. Injection site reaction will be assessed 30 minutes (± 10 minutes) after the end of administration of the study drug. For patients who early discontinue study treatment, assessment of injection site reaction is 
unnecessary after the discontinuation. 
20. Patients will assess local site pain using 100 mm VAS immediately (not exceeding 15 minutes) after the end of administration of the study drug. For patients who early discontinue study treatment, assessment 
of local site pain is unnecessary after the discontinuation. 
21. All patients will also receive daily supplementation containing at least 1,000 mg of elemental calcium and at least 400 IU vitamin D from randomization to EOS visit. The information about calcium and 
vitamin D administration will be collected via patient’s diary and will be also recorded in both the source documents and eCRF. 
22. Radiography will be performed as required for confirmation of suspected fractures. Radiography will be analyzed at a central imaging vendor. 
23. Use of all prior and concomitant medication from the 30 days prior to the signed date of ICF until the EOS will be recorded. Use of all prior and concomitant medications for the treatment of osteoporosis, 
from the diagnosis of disease until the EOS visit, will be recorded. For eligibility check, relevant medication history will be also recorded. 
24. Adverse events will be assessed from the signed date of ICF until EOS visit, regardless of the relationship to the study drug. The condition of the patient will be monitored throughout the study for any signs 
or symptoms. After the last EOS visit, serious adverse drug reactions will be reported to CELLTRION, Inc. or its designee. 
 
 

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11.2 Osteoporosis Assessment Questionnaire Short Version (OPAQ-SV) 
Please answer the following questions about your health. Most questions ask about your 
health during the past two weeks. There are no right or wrong answers to the questions.  
 
All 
days 
Most 
days 
Some 
days 
Few 
days 
No 
days 
 
▼ 
▼ 
▼ 
▼ 
▼ 
1. 
How often were you able to do 
daily shopping or errands? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
2. 
How often were you in a bed or 
chair for most of the day? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
3. 
How often were you able to do 
sports and games that you would 
like to do? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
4. 
How often were you able to walk as 
much as you needed to? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
5. 
How often did you have trouble 
bending, lifting or stooping? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
6. 
How often did you have trouble 
walking a block or climbing one 
flight of stairs? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
7. 
How often did you need to use a 
cane, crutches, walker, or 
companion while walking? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
8. 
Could you easily put on or take off 
a pair of stockings and/or 
underwear? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
9. 
Could you easily comb, brush, or 
style your hair? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
10. Could you easily reach shelves that 
were above your head? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
 
Always 
 
Very 
Often 
Sometimes 
 
Almost 
Never 
Never 
 
 
▼ 
▼ 
▼ 
▼ 
▼ 
11. Have you had to change the way 
you bathe yourself? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
12. Have you had to change the types 
of clothes you wear because of 
difficulty in dressing? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
13. How often were you able to do 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 

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light housework such as cooking 
without help? 
14. How often were you able to do 
heavy housework such as 
vacuuming without help? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
15. How often were you able to do 
your daily work, either at home, as 
a volunteer, at school, or at a paid 
job? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
 
All 
days 
Most 
days 
Some 
days 
Few 
days 
No 
days 
 
▼ 
▼ 
▼ 
▼ 
▼ 
16. How often do you have trouble 
getting in or out of bed? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
17. How often do you have trouble 
getting in or out of a chair? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
18. How often do you have trouble 
getting on or off the toilet? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
19. How often do you have trouble 
getting in or out of cars or public 
transportation? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
 
Always 
 
Very 
Often 
Sometimes 
 
Almost 
Never 
Never 
 
 
▼ 
▼ 
▼ 
▼ 
▼ 
20. How often were you afraid that you 
would fall? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
21. How often were you afraid that you 
would accidentally break or 
fracture a bone? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
22. How often did you feel that you 
were losing balance? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
23. How often did you use a handrail or 
other support when walking up or 
down stairs? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
24. How often did your fear of falling 
keep you from doing what you 
want to do? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
 
All 
days 
Most 
days 
Some 
days 
Few 
days 
No 
days 
 
▼ 
▼ 
▼ 
▼ 
▼ 

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25. How often did you have any back 
ache or pain?  
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
 
Severe 
 
Moderate 
 
Mild 
 
Very 
Mild 
None 
 
 
▼ 
▼ 
▼ 
▼ 
▼ 
26. How would you describe the back 
ache or pain you usually have? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
 
All 
days 
Most 
days 
Some 
days 
Few 
days 
No 
days 
 
▼ 
▼ 
▼ 
▼ 
▼ 
27. How often did your back feel stiff 
for more than one hour from the 
time you woke up? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
28. How often did back ache or pain 
keep you from doing what you 
wanted to do? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
 
Always 
 
Very 
Often 
Sometimes 
 
Almost 
Never 
Never 
 
 
▼ 
▼ 
▼ 
▼ 
▼ 
29. How often were you aware of the 
changes in your body when trying 
on clothes? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
30. How often were you bothered by 
the way your back looks? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
31. How often were you concerned by 
changes in the way your body 
looks? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
32. How often did you feel confident 
you could live on your own without 
assistance? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
33. How often did you have to rely on 
others for assistance with daily 
activities? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
34. How often were you worried that 
you might not be able to take care 
of yourself in the future? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
 
 

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11.3 EuroQoL-5D-5L (EQ-5D-5L) 
Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems in walking about 
 
I have slight problems in walking about 
 
I have moderate problems in walking about 
 
I have severe problems in walking about 
 
I am unable to walk about 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g., work, study, housework, family or leisure 
activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 
 

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 
We would like to know how good or bad your health is TODAY. 
 
This scale is numbered from 0 to 100. 
 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 
Please mark an X on the scale to indicate how your health is TODAY. 
 
Now, write the number you marked on the scale in the box below. 
10
0 
20
30
40
50
60
80
70
90
100 
5 
15
25
35
45
55
75
65
85
95
The best health 
you can imagine 
YOUR HEALTH TODAY = 

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11.4 Visual Analog Scale (VAS) Local Site Pain 
Patient assessment of local site pain is measured by the patient indicating the extent of their 
pain by making one line (│) through the 100 mm line (0 mm equals no pain and 100 mm 
equals most severe pain). The length of the line is measured from the left (in mm) and the 
value (in mm) recorded in the patient’s eCRF. 
No pain  
   Most severe pain 
Value:
(mm) 

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11.5 New York Heart Association Functional Classification 
As defined in Zhang et al., 2018, the New York Heart Association (NYHA) classification 
is used in patients with heart failure. 
Class 
Symptoms 
I 
(Mild) 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath).  
II 
(Mild) 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea. 
IV 
(Severe) 
Unable to carry on any physical activity without discomfort. Symptoms of 
heart failure at rest. If any physical activity is undertaken, discomfort 
increases. 

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11.6 Risk Assessment and Mitigation Plan due to COVID-19 
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially 
identified during an outbreak of atypical viral pneumonia cases of unknown cause in the 
People’s Republic of China in December 2019 and the disease caused by SARS-CoV-2 has 
been designated as COVID-19. On 11 March 2020, the World Health Organization (WHO) 
declared the SARS-CoV-2 infection outbreak a global pandemic and to date in excess of 
1.6 million deaths have been reported globally (WHO COVID-19 Dashboard 2020). 
Due to the global impact of the COVID-19 pandemic, the Sponsor is taking proactive 
measures to guarantee that all site staff and patients involved in the trial are secure and the 
patients remain in the study until their last visit, with continuation of treatment during the 
study period. 
1.
Benefit and Risk Assessment on Study Population
Considering the most common symptoms of COVID-19 are fever, dry cough, and tiredness 
(WHO Q&A on COVID-19) and the irrelevance between cause of COVID-19 and 
osteoporosis disease itself, osteoporosis symptoms and disease itself have a low chance to 
deteriorate directly due to COVID-19. Furthermore, no high risk was seen for COVID-19 
complications in women older than 50 years for postmenopausal or aromatase inhibitor-
induced osteoporosis, and the patients are recommended to maintain the denosumab 
treatment for the management of osteoporosis during the COVID-19 outbreak (Gittoes et al., 
2020). However, the irrelevance cannot be concluded since no studies have been conducted 
and there were a few research studies reporting the increased risk for respiratory infections 
following denosumab treatment (Formenti et al., 2020).  
Moreover, it has yet to be concluded that calcium and vitamin D, which is a protocol defined 
co-administration, may have beneficial effects to treat COVID-19. To date, it has been shown 
that the patients with osteoporosis may be protected from SARS-CoV-2 by vitamin D 
independently of the pharmacologic antiosteoporotic treatments (Bilezikian et al., 2020). 
Basically, the quarantine of COVID-19 should be carried out based on the SOP of each site 
and local regulatory guidelines. Taking all these facts into consideration, the risks of COVID-
19 infection for each patient are not expected to increase by participating in this study. Yet 
due to the possibility of increasing the safety risk by being involved in the study, a systematic 
risk assessment will be conducted during the study by the Sponsor through a sufficient 
discussion with the Investigators and DSMB. 

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2.
Mitigation Plans
Investigational Product Management 
To cope better with the sudden imposition of movement restriction and/or increased shipment 
lead time due to frequent flight cancellation and limited staff at customs, sufficient IP will be 
supplied to cover patient visits for longer periods. Inter-country IP transfer using regional 
airways will be considered in case intercontinental flights are repeatedly cancelled. In 
addition, the Sponsor will prepare site-to-site transfer of IP from nearby clinical sites in case 
an agile resupply is required (e.g., more patients are enrolled at a site than anticipated but 
additional supplied IP is not sufficient to meet demand). 
Rescheduling of Visit and Study Drug Administration Schedule of Patients 
The COVID-19 screening tests will be performed locally based on each site and/or local 
regulatory guidelines upon the Investigator’s discretion throughout the study period. If 
COVID-19 is confirmed positive during the Screening period, the patient should not be 
enrolled in this study until confirmation of complete recovery from COVID-19 as per site 
and/or local regulatory guidelines. Although patients can be rescreened only once under 
normal circumstances as specified in Section 4.3, additional rescreening can be performed 
only in limited cases considering COVID-19. If COVID-19 is confirmed after randomization, 
the Investigators will discuss on a case-by-case basis regarding the specific case of the 
patient with the Sponsor. In the case of a patient who has contact with COVID-19 patients 
within 14 days from Screening, the patient should not be enrolled in the study. If the patient 
has contact with COVID-19 patients within 14 days following any site visit, the Investigator 
will re-assess the visit schedule following the site and/or local regulatory guidelines. 
Investigators will promptly notify the Sponsor if any unfavorable situation has occurred in 
relation to local COVID-19 status (e.g., site shut down, lock down of city, cohort isolation, 
etc.). For sites where the patients are unable to travel or use public transportation, the 
Sponsor will support the patients with alternative transportation or reimbursement for travel 
to ensure the visits can be made within the window or the visit can be proceeded at the 
earliest possible opportunity. Pre-approval is required for reimbursement. 
The patients require face-to-face interactions for study drug administration. Therefore, in the 
event patients cannot visit the study center on the scheduled day for injection, the treatment 
schedule will be adjusted following Section 5.8. However, if study drug administration 
cannot be carried out within an allowed visit window or a missed dose is expected, whether 

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to continue with the subsequent study treatment will be discussed with the Sponsor, ensuring 
the compliance with the trial protocol to such an extent that an ongoing benefit-risk 
assessment for the clinical trial and patients is still possible. 
Even if a study visit cannot be made, possible data will be continuously collected via a 
telephone call and during the next visit, if applicable. The Investigator will keep following up 
with patients regarding any safety issues (AEs, concomitant medication) by telephone call 
before the patients visit the site. 
Although the COVID-19 pandemic situation is likely to introduce more protocol deviations 
than under normal circumstances, protocol deviations will be managed in accordance with 
the standard procedures. The number and type of deviations will be monitored periodically to 
assess whether a protocol amendment or other modifications are needed.   
DXA scan and X-ray assessments 
For BMD assessment, only Hologic or Lunar bone densitometers will be allowed during the 
study, and the same DXA instrument should be used for all study procedures for each patient 
during the study. However, in COVID-19 pandemic situation, if the patients are restricted in 
their ability to travel to the sites and/or the sites ae locked down, the alternative imaging 
centers can be considered to acquire the DXA scans. The alternative center should follow the 
central imaging provider’s guidance on selecting an appropriate replacement scanner and a 
phantom scanning process to quantify any calibration differences. All DXA scans will be 
submitted to and analyzed by the central imaging vendor. 
For vertebral fractures, the lateral spine X-ray will be performed throughout the study, and 
may be performed in the alternative imaging centers in COVID-19 pandemic situation (site 
shut down, lock down of city etc.). The lateral spine X-ray for vertebral fracture as well as 
copies of other diagnostic image and related source documents should be submitted to the 
central imaging vendor for confirmation of fracture. And, if X-ray is necessary to support the 
patient’s medical care, the X-rays also could be read locally.  
The nonvertebral fractures may be assessed by alternative imaging centers in COVID-19 
pandemic situation. The information about new nonvertebral fractures (e.g., details regarding 
the type of fracture and other pertinent data) and level of trauma causing the fracture will be 
recorded from the alternative centers. A copy of other diagnostic image and/or radiology 
report, surgical report, or discharge summary will also be included in the patient’s individual 
source documents and should be submitted to the central imaging vendor for confirmation of 

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fracture. For further details on the source documents for nonvertebral fractures, see Section 
6.1.2.2. 
Site Monitoring and Audit 
In cases where a monitoring visit cannot be performed because of the prevailing COVID-19 
situation, centralized monitoring will be performed by the Sponsor and/or CRO as 
alternatives particularly, for the sites where the first patient is randomized but the first 
monitoring visit is not performed. Manual data review on the eCRF will be performed and if 
any mistakes or deviations are observed, proper guidance will be provided to prevent them 
happening in the future. Sponsor and/or CRO will review the data entered in the eCRF 
continuously and ensure queries are raised and support the sites as necessary. If necessary, 
the Sponsor will create and review a report based on the eCRF data to check whether visits, 
assessments and administrations of study treatment are in progress according to protocol and 
the same will be shared with CRO for site management. 
Audits are required to ensure quality assurance throughout the study period in order to 
evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable 
regulatory requirements. In cases where an audit cannot be performed due to the COVID-19 
pandemic situation, the Sponsor will postpone audits or consider performing remote audits 
after careful consideration of the COVID-19 pandemic situation according to Guidance on 
the management of clinical trials during the COVID-19 (coronavirus) Pandemic (European 
Medicines Agency (2020)). Audits will be conducted only when permitted under national, 
local and/or organizational social distancing restrictions. 
Handling of Missing Data 
To assess any possible risks on data collection, data will be routinely reviewed according to 
Centralized monitoring plan and Risk based monitoring plan. After data collection, missing 
data on the primary efficacy analysis due to COVID-19 will be analyzed as specified in 
Section 7.6.3.1.1 with other missing cases. However, if a different approach is required for 
missing data due to COVID-19, it will be discussed at the blinded data review meeting on a 
case-by-case basis and the procedure for handling missing data in the statistical analysis will 
be specified in the SAP.