Clinical trial NCT04664959
Conditions: Postmenopausal Osteoporosis
Sponsor: Samsung Bioepis Co., Ltd.
Start date: 2020-11-26; Completion date: 2023-01-03
Enrollment: 457 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomised, double-blind, multicentre study to evaluate the efficacy, safety, PK, PD, and immunogenicity of SB16 compared to Prolia® in postmenopausal women with osteoporosis.

Detailed description:
Subjects will be randomised in a 1:1 ratio to receive either SB16 or Prolia®. At Month 12, subjects in Prolia® treatment group will be randomised again in a 1:1 ratio to either continue on Prolia® treatment or be transitioned to SB16 treatment. Investigational product (60 mg in 1 mL of SB16 or Prolia®) will be given subcutaneously every 6 months up to Month 12, and the last assessment will be done at Month 18.

Arms: arm 1: Subjects randomised into SB16 group will receive SB16 (60 mg in 1 mL) subcutaneously every 6 months. arm 2: Subjects randomised into Prolia® group will receive Prolia® (60 mg in 1 mL) subcutaneously every 6 months.

At Month 12, subjects in Prolia® treatment group will be re-randomised in a 1:1 ratio to either continue on Prolia® treatment or be transitioned to SB16 treatment. After re-randomisation, subjects transited to SB16 group will receive SB16, and subjects remaining in Prolia® group will continue to receive Prolia® at Month 12.
Interventions: intervention 1: SB16 (Proposed Denosumab Biosimilar) intervention 2: Prolia® (Denosumab)
Intervention descriptions: intervention 1: Subjects randomised into SB16 group will receive SB16 (60 mg in 1 mL) subcutaneously every 6 months.

At Month 12, subjects transited from Prolia® group to SB16 group will receive SB16 (60 mg in 1 mL) subcutaneously. intervention 2: Subjects randomised into Prolia® group will receive Prolia® (60 mg in 1 mL) subcutaneously every 6 months.

Protocol documents:
Prot_000.pdf: 
SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 1 of 90 
Clinical Study Protocol 
A Phase III, Randomised, Double-blind, Multicentre Clinical Study to 
Compare the Efficacy, Safety, Pharmacokinetics, Pharmacodynamics, and 
Immunogenicity between SB16 (proposed denosumab biosimilar) and 
Prolia® in Postmenopausal Women with Osteoporosis 
Product 
SB16 (proposed denosumab biosimilar) 
EudraCT Number 
2020-001479-34 
US IND Number (if applicable) 
N/A 
Protocol Number 
SB16-3001 
Study Phase 
Phase III 
Version and Effective Date 
Version 2.0 
May 03, 2021 
Version 1.0 
Apr 06, 2020 
Sponsor 
Samsung Bioepis Co., Ltd. 
76, Songdogyoyuk-ro, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
This document contains confidential information belonging to Samsung Bioepis Co., Ltd. Your acceptance or 
review of this document constitutes agreement that you will not copy or disclose the information contained 
herein to others or use it for unauthorised purposes without written authorisation from the Sponsor. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 2 of 90 
SYNOPSIS 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
Title of Study: 
A Phase III, Randomised, Double-blind, Multicentre Clinical Study to Compare the Efficacy, Safety, 
Pharmacokinetics, Pharmacodynamics, and Immunogenicity between SB16 (proposed denosumab biosimilar) 
and Prolia® in Postmenopausal Women with Osteoporosis 
Protocol No: 
SB16-3001 
Phase: 
III 
Investigator Sites: 
Approximately 44 investigator sites globally 
Planned Study 
Period: 

Screening period: 28 days after signing the informed consent form (ICF)
-
Additional 28 days will be allowed to subjects who are not eligible only
due to vitamin D deficiency, for vitamin D repletion and repeat of serum
vitamin D test.

Main period: Approximately 12 months after Randomisation

Transition period: Approximately 6 months after Month 12
Objectives: 
Primary objective 
The primary objective of this study is to demonstrate the equivalence of SB16 to Prolia®, in terms of percent 
change from baseline in lumbar spine bone mineral density (BMD) at Month 12 in subjects with 
postmenopausal osteoporosis (PMO). 
Secondary objectives 
The secondary objectives are: 

To evaluate the efficacy of SB16 compared to Prolia® by
-
Percentage change from baseline in lumbar spine BMD
-
Percentage change from baseline in total hip BMD
-
Percentage change from baseline in femoral neck BMD

To evaluate the safety and tolerability of SB16 compared to Prolia®


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 3 of 90 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
 
To evaluate the pharmacokinetic (PK) profile of SB16 compared to Prolia® 
 
To evaluate the pharmacodynamic (PD) profile of SB16 compared to Prolia® 
 
To evaluate the immunogenicity of SB16 compared to Prolia® 
 
To evaluate the safety, tolerability, immunogenicity, PK, PD, and efficacy in subjects with PMO who 
transitioned to SB16 from Prolia® compared to subjects who maintained Prolia® from the Main period 
Study Design: 
For the Main period 
This is a Phase III, randomised, double-blind, parallel group, multicentre, equivalence study to evaluate the 
efficacy, safety, PK, PD, and immunogenicity of SB16 compared to Prolia® in PMO. Subjects will be 
randomised in a 1:1 ratio to receive either SB16 or Prolia® subcutaneously at Months 0 and 6. Study visits will 
occur at Months 0, 0.5, 1, 3, 6, 9, and 12. 
BMD assessment will be done at Months 6 and 12. Blood sampling for safety, PK, PD, and immunogenicity 
will be done at Months 0, 0.5, 1, 3, 6, 9, and 12. 
For the Transition period 
This is a Phase III, randomised, double-blind, multicentre, transition study to investigate the safety, tolerability, 
immunogenicity, PK, PD, and efficacy of SB16 in subjects with PMO who transitioned from the Prolia® arm, 
compared with subjects who maintained Prolia® treatment after Month 12 from the Main period of the SB16-
3001 study. 
The Transition period is up to 6 months after Month 12 of the Main period of the SB16-3001 study. Subjects 
will receive either SB16 or Prolia® subcutaneously at Month 12. 
At Month 12, subjects receiving Prolia® from the Main period of the SB16-3001 study will be randomised 
again in a 1:1 ratio to either continue on Prolia® (Prolia®/Prolia®) or be transitioned to SB16 (Prolia®/SB16) up 
to Month 18. Subjects receiving SB16 from the Main period of the SB16-3001 study will continue to receive 
extended treatment of SB16 up to Month 18 but they will also follow the randomisation procedure to maintain 
blinding. 
BMD assessment and blood sampling for safety, PK, PD, and immunogenicity will be done at Month 18. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 4 of 90 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
Number of Subjects: 
Approximately 432 subjects will be randomised in the study. 
Target Population: 
Postmenopausal women with osteoporosis 
Main Eligibility Criteria: 
Inclusion criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1.
Postmenopausal women (defined as lack of menstrual period for at least 12 months prior to Screening,
for which there is no other pathological or physiological cause) who are 55 to 80 years of age at
Screening

Serum follicle stimulating hormone (FSH) test can be done at Screening in case of uncertainty.
2.
Ambulatory and visually unimpaired to participate in the study at Screening, in the opinion of the
Investigator
3.
Absolute BMD consistent with T-score at the total hip or lumbar spine of ≥ ‒4 and ≤ ‒2.5, determined
by central imaging centre at Screening
4.
At least three evaluable vertebrae within L1 to L4, one evaluable femoral neck, and one evaluable hip
joint for BMD measurement, determined by central imaging centre at Screening
5.
Biologic (defined as any therapeutic monoclonal antibody or fusion receptor protein, including
denosumab, denosumab biosimilars, or romosozumab) naïve at Screening
6.
Body weight of ≥ 50 kg and ≤ 90 kg at Screening
7.
Has provided informed consent voluntarily and must be able to, in the opinion of the Investigator,
understand the implications of taking part in the study, be willing to follow the study requirements,
and complete the study
Subjects must meet the following criteria to be enrolled in the Transition period: 
1.
Have been enrolled and completed the scheduled Month 12 of the Main period of the SB16-3001
study


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 5 of 90 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for the study: 
1.
One severe or more than two moderate vertebral fractures on spinal X-ray according to Genant
classification, determined by central imaging centre at Screening
2.
History of hip fracture or bilateral hip replacement at Screening
3.
Uncorrected vitamin D deficiency (defined as serum 25-hydroxyvitamin D level < 20 ng/mL [50
nmol/L]) at Screening
4.
Hypercalcemia or hypocalcaemia (defined as albumin-adjusted serum calcium for hypocalcaemia <
2.1 mmol/L [8.4 mg/dL] or for hypercalcemia > 2.62 mmol/L [10.5 mg/dL]) at Screening
5.
Inadequate haematological function at Screening defined as the following:
a.
White blood cell count < 3.5 × 103 cells/μL (< 3.5 × 109 cells/L)
b.
Haemoglobin < 9 g/dL
c.
Platelet count < 100,000/mm3 (< 100 × 109/L)
6.
Inadequate renal or hepatic function at Screening defined as the following:
a.
Estimated glomerular filtration rate (eGFR) < 45 mL/min by the Modification of Diet in Renal
Disease (MDRD) formula or under dialysis
b.
Serum alanine transaminase and aspartate transaminase ≥ 2 × upper limit of reference range
7.
Known allergic reactions, hypersensitivity, or intolerance to denosumab or to any ingredients of the
investigational product (IP), including latex allergy or hereditary problems of fructose intolerance at
Screening
8.
May not tolerate long-term calcium or vitamin D supplementation or subject with malabsorption of
calcium or vitamin D supplements, in the opinion of the Investigator, at Screening
9.
Use of any of the below medications that can affect BMD:
a.
Oral bisphosphonate at any dose for osteoporosis treatment:
-
Used for > 3 years cumulatively at Screening
-
Used for ≤ 3 years cumulatively and passed < 1 year since the last dose at Screening


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 6 of 90 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
b. 
Intravenous bisphosphonate at any dose within 5 years prior to Screening 
c. 
Parathyroid hormone (PTH) or PTH analogues at any dose within 2 years prior to Screening 
d. 
Systemic hormone replacement therapy (oral or transdermal oestrogen), selective oestrogen 
receptor modulators (SERMs), tibolone, aromatase inhibitors, or androgens at any dose within 1 
year prior to Screening 
 
Exceptionally, non-systemic vaginal oestrogen treatment is permitted. 
e. 
Calcitonin or its derivatives, calcimimetics (such as cinacalcet or etelcalcetide), or calcitriol at 
any dose within 3 months prior to Screening 
f. 
Systemic glucocorticoids (≥ 5 mg prednisone equivalent per day or cumulative dose ≥ 50 mg) 
for more than 10 days within 3 months prior to Screening 
g. 
Fluoride or strontium intended for osteoporosis treatment at any dose at any time at Screening 
h. 
Any non-biologic IP for osteoporosis treatment that mechanism of action is not within excluded 
medications in exclusion criteria number 9-a to 9-g at any dose within 5 years prior to Screening 
i. 
Other bone active drugs at any dose within 3 months prior to Screening 
10. Use of any non-biologic IP that is not indicated for osteoporosis from another study at any dose 
within five half-lives of that product prior to Randomisation or use of an investigational device at 
Screening 
11. Non-osteoporosis medical conditions that can affect BMD at Screening: 
a. 
History of hyperparathyroidism or hypoparathyroidism, or current hyperparathyroidism or 
hypoparathyroidism 
b. 
Current uncontrolled hyperthyroidism or hypothyroidism 
c. 
History of bone disease such as osteomalacia, osteogenesis imperfecta, osteopetrosis, 
achondroplasia, or Paget’s disease of the bone 
d. 
History of chronic inflammatory diseases, obvious sclerosis, osteophytosis, severe scoliosis, or 
other degenerative changes due to other co-morbidities that may interfere with the interpretation 
of dual-energy X-ray absorptiometry (DXA) imaging results 
e. 
History of metabolic or other endocrinologic diseases such as malabsorption syndrome 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 7 of 90 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
(including celiac disease), Cushing disease, acromegaly, or hyperprolactinemia 
12. History of osteonecrosis of jaw, osteonecrosis of external auditory canal, or atypical femoral fracture
at Screening or related-risk based on the physical examination including oral at Screening
13. History of active periodontal disease or invasive dental procedure within 6 months prior to Screening
or plan to do invasive dental procedures (e.g., tooth extraction, dental implants, or oral surgery)
during the study period
14. Fracture (except atypical femoral fracture and hip fracture) which has been in active healing within
12 months prior to Screening at the discretion of the Investigator
15. History of clinically significant active infection within 2 weeks prior to Randomisation, and for
cellulitis, erysipelas, or infections that requires hospitalisation or intravenous antibiotics, within 8
weeks prior to Randomisation
16. Known history for hepatitis B or hepatitis C or human immunodeficiency virus infection, or positive
testing for hepatitis B (hepatitis B virus surface antigen [HBsAg]) or hepatitis C (hepatitis C virus
antibody [HCV Ab]) virology at Screening
17. History of acute or chronic pancreatitis at Screening
18. History of acute myocardial infarction or New York Heart Association (NYHA) III/IV congestive
heart failure within 1 year prior to Randomisation
19. History of cardiac arrythmia or long QT syndrome or electrocardiogram (ECG) abnormalities (e.g.,
that required hospitalisation, emergency cardioversion, or defibrillation) indicating safety risk at
Screening
20. Malignancy not cured within 5 years prior to Randomisation

Exceptionally, completely excised and cured basal cell carcinoma or cervical carcinoma in situ
can be permitted.
21. History of organ transplantation at Screening
22. History of alcohol or substance-abuse within 12 months prior to Screening
23. Any clinically significant disease or disorder or laboratory abnormality which, in the opinion of the
Investigator, would prevent the subject from completing the study or the interpretation of the study
results at Screening and Randomisation


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 8 of 90 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
Subjects meeting the following criteria must not be enrolled in the Transition period: 
1. 
Found to be of increased risk to continue enrolment, in the opinion of the Investigator 
Investigational Products: 
 
Name: SB16 (proposed denosumab biosimilar) or European Union (EU) sourced Prolia® 
 
Formulation: Pre-filled syringe (PFS) of 1 mL contains 60 mg of denosumab (60 mg/mL) 
 
Route of administration: Subcutaneous injection 
 
Dose regimen: 60 mg every 6 months 
Non-investigational Products: 
 
Elemental calcium (at least 1 g per day) 
 
Vitamin D (at least 800 IU per day) 
Above dose of daily calcium and vitamin D will be given from Randomisation to end of study (EOS)/early 
termination (ET). During the screening period, subjects will receive calcium and vitamin D at the discretion of 
the Investigator. 
Main Criteria for Evaluation: 
Primary endpoint 
 
Percent change from baseline in lumbar spine BMD at Month 12 
Secondary endpoints for the Main period 
Efficacy endpoints 
 
Percent change from baseline in lumbar spine BMD at Month 6 
 
Percent change from baseline in total hip BMD at Months 6 and 12 
 
Percent change from baseline in femoral neck BMD at Months 6 and 12 
Safety endpoints 
 
Incidence of adverse events (AEs) 
 
Incidence of serious AEs (SAEs) 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 9 of 90 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
PK endpoint 
 
Serum drug concentration at Months 0, 0.5, 1, 3, 6, 9, and 12 
PD endpoints 
 
Serum C-telopeptide of type I collagen (CTX) concentration at Months 0, 0.5, 1, 3, 6, 9, and 12 
 
Area under the effect curve from time zero to Month 6 (AUEC0-M6) of percent change from baseline 
in serum CTX 
 
Serum procollagen type I N-terminal propeptide (P1NP) concentration at Months 0, 0.5, 1, 3, 6, 9, 
and 12 
Immunogenicity endpoint 
 
Incidence of anti-drug antibodies (ADAs) at Months 0, 0.5, 1, 3, 6, 9, and 12 
 
Incidence of neutralising antibodies (NAbs) at Months 0, 0.5, 1, 3, 6, 9, and 12 
Secondary endpoints for the Transition period 
Safety endpoints 
 
Incidence of AEs 
 
Incidence of SAEs 
Immunogenicity endpoint 
 
Incidence of ADAs at Month 18 
 
Incidence of NAbs at Month 18 
Efficacy endpoints 
 
Percent change from baseline in lumbar spine BMD at Month 18 
 
Percent change from baseline in total hip BMD at Month 18 
 
Percent change from baseline in femoral neck BMD at Month 18 
PK endpoint 
 
Serum drug concentration at Month 18 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 10 of 90 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
PD endpoints 
 
Serum CTX concentration at Month 18 
 
Serum P1NP concentration at Month 18 
Statistical Methods: 
Analysis sets for efficacy analyses 
Full Analysis Set (FAS) consists of all randomised subjects. Following the intent-to-treat principle, subjects 
will be analysed according to the treatment group they are assigned at Randomisation. However, subjects who 
do not have any lumbar spine BMD assessment result after Randomisation by accident and do not receive any 
IP during the study period will be excluded from FAS. 
Per-Protocol Set (PPS) consists of all FAS subjects who have lumbar spine BMD assessment results at baseline 
and Month 12 without any major protocol deviations that have impact on the lumbar spine BMD assessment 
results. Major protocol deviations may include deviations from inclusion/exclusion criteria, withdrawal criteria, 
IP compliance, concomitant medication, and study procedure. Major protocol deviations that will lead to 
exclusion from this set will be pre-defined using the final version of merged protocol deviation list prior to 
unblinding the treatment group assignment for analyses. 
Efficacy analyses 
For the European Medicines Agency (EMA), Korea Ministry of Food and Drug Safety (MFDS), and other 
regulatory submissions, the primary efficacy analysis will be performed for the PPS using an analysis of 
covariance with the baseline value of lumbar spine BMD as a covariate and treatment group as a factor. The 
equivalence will be declared if the two-sided 95% confidence interval (CI) of the mean difference in percent 
change from baseline in lumbar spine BMD at Month 12 between SB16 and Prolia® lies within the pre-defined 
equivalence margin of [−2.0%, 2.0%]. To conduct the sensitivity analysis for the FAS, missing data will be 
imputed using multiple imputation method for subjects who drop out for the study prior to the primary analysis 
time point under the assumption of missing at random. Available case analysis will also be performed for the 
FAS. 
For the United States of America (US) Food and Drug Administration (FDA) submission, the primary efficacy 
analysis will be performed for the FAS using an analysis of covariance with the baseline value of lumbar spine 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 11 of 90 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
BMD as a covariate and treatment group as a factor. The equivalence will be declared if the two-sided 90% CI 
of the mean difference in percent change from baseline in lumbar spine BMD at Month 12 between SB16 and 
Prolia® lies within the pre-defined equivalence margin of [−1.45%, 1.45%]. Missing data will be imputed using 
multiple imputation method for subjects who drop out for the study prior to the primary analysis time point. 
For sensitivity analysis, available case analysis will be performed for the FAS and the same analysis will be 
repeated for the PPS. 
As the secondary efficacy endpoints, percent change from baseline in BMD (lumbar spine, total hip, and 
femoral neck) will be analysed similarly to the primary endpoint. 
Safety analyses 
Safety analyses will be performed for the Safety Set (SAF1) and Safety Set for the Transition period (SAF2). 
All reported terms for AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA®). 
All AE data will be summarised by count and percentage of subjects experiencing events by system organ class, 
preferred term, and treatment group. SAEs leading to IP discontinuation and treatment emergent AEs (TEAEs) 
by causality and severity will be summarised similarly. 
Changes in vital signs and clinical laboratory parameters will be summarised descriptively by treatment group 
and visit. Other safety variables will be summarised unless otherwise specified. 
PK and PD analyses 
PK analyses will be performed for the PK Analysis Set (PKS). Serum drug concentration will be summarised 
descriptively by treatment group and visit. 
PD analyses will be performed for the PD Analysis Set (PDS). Serum CTX and P1NP concentrations will be 
summarised descriptively by treatment group and visit. In addition, the AUEC0-M6 of percent change from 
baseline in serum CTX will be analysed using an analysis of variance model. 
Immunogenicity analyses 
Immunogenicity analyses will be performed for the SAF1 and SAF2. ADA and NAb results will be summarised 
with frequency and percentage by treatment group and visit. The incidence of overall ADA will be summarised 
by treatment group. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 12 of 90 
 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB16 (proposed denosumab biosimilar) 
Name of Active Ingredient: 
Denosumab 
Sample size calculation 
The equivalence margin for the mean difference of percent change from baseline in lumbar spine BMD at 
Month 12 is derived from 3 historical studies with Prolia®. In denosumab Phase II study, mean (standard error) 
percent change from baseline in lumbar spine BMD at Month 12 is 4.55% (0.47) and −0.81% (0.48) for 
denosumab and placebo arms, respectively. [1] FREEDOM study reported the mean percent change from 
baseline as 5.5% and 0.0%, [2] and in Bone study, mean percent change from baseline is 4.4% and −0.5% for 
denosumab and placebo arms, respectively. [3] 
A meta-analysis estimates 5.35% of mean percent change from baseline in lumbar spine BMD at Month 12 
with 95% CI of [4.83%, 5.87%]. For the EMA submission, 40% of lower limit of 95% CI was 2.0%, which 
implies that approximately 60% treatment effect is obtained to preserve the treatment effect over placebo, and 
this margin is corresponds to the EMA’s recommendation. For the US FDA submission, 1.45% which is 30% 
of lower limit of 95% CI was chosen to preserve approximately 70% of the treatment effect over placebo per 
the US FDA’s recommendation. 
With the given equivalence margin of [−2.0%, 2.0%] for the EMA submission, 140 subjects per treatment group 
was calculated with the assumptions of no mean difference, common standard deviation of 5.13 at the overall 
5% significance level. Assuming a 15% loss from randomised subjects after 12 months, a sample size of 165 
subjects per treatment group (overall sample size of 330) will give 140 completers per treatment group after 12 
months, which is estimated to give 80% power to detect the equivalence within the margin of [−2.0%, 2.0%]. 
With the given equivalence margin of [−1.45%, 1.45%] for the US FDA submission, 216 subjects per treatment 
group was calculated with the assumptions of no mean difference, common standard deviation of 5.13 at the 
overall 10% significance level. Overall sample size of 432 is estimated to give 80% power to detect the 
equivalence within the margin of [−1.45%, 1.45%]. 
Therefore, the sample size of 432 allows enough power to detect the equivalence in both situations. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 13 of 90 
 
GRAPHICAL STUDY DESIGN AND SCHEDULE OF ACTIVITIES 
ICF = informed consent form; ® = Randomisation; n = number of subjects; IP = investigational product; BMD = bone mineral density; PK = pharmacokinetic; PD = pharmacodynamic; EOS = 
end of study 
1 Informed consent should be obtained prior to any study related procedures. 
2 At Month 12, subjects receiving Prolia® will be randomised in a 1:1 ratio to either continue to receive Prolia® or be transitioned to SB16. Subjects receiving SB16 will continue to receive SB16 
up to Month 18 but they will also follow the randomisation procedure to maintain blinding. 
Figure 1. Graphical Study Design 






SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 16 of 90 
 
16.  Randomisation must proceed after all screening procedures including eligibility confirmation. 
17.  At Month 12, subjects receiving Prolia® will be re-randomised in a 1:1 ratio to either continue to receive Prolia® or be transitioned to SB16. Subjects receiving SB16 will continue to receive 
SB16 up to Month 18 but they will also follow the randomisation procedure to maintain blinding. 
18.  Blood sample for PK assessment will be collected prior to dosing at Months 0, 6, and 12, Months 0.5, 1, 3, and 9, and EOS/ET. 
19.  Blood sample for immunogenicity assessment will be collected prior to dosing at Months 0, 6, and 12, Months 0.5, 1, 3, and 9, and EOS/ET. 
20.  Blood sample for PD assessment will be collected prior to dosing at Months 0, 6, and 12, Months 0.5, 1, 3, and 9, and EOS/ET. 
21.  Blood sample for CTX and P1NP should be collected in the morning hours after fasting for at least 8 hours. 
22.  On the day of baseline PD assessment (Month 0), calcium should not be given before the PD blood sampling. 
23.  SB16 and Prolia® will be subcutaneously administered 60 mg every 6 months. 
24.  Monitoring for injection site reaction will be done after IP administration at Months 0, 6, and 12. 
25.  Daily elemental calcium (≥ 1 g) and vitamin D (≥ 800 IU) will be given to the subjects from Randomisation to EOS/ET. Instruction for non-IP supplementation will be done at Months 0, 0.5, 
1, 3, 6, 9, and 12. 
26.  Previous and concomitant medication within 5 years prior to Screening and concomitant medication thereafter. Also, previous oral bisphosphonate history in a lifetime will be collected. 
27.  AEs will be collected from the time of signing the ICF until the EOS/ET. SAEs will be collected until 6 months after the last IP dose or EOS/ET, whichever longer. If the subject would 
withdraw before receiving the first dose of IP, AEs and SAEs should be collected up until the time the subject withdraws. 
28.  Subjects who withdraw from the study before EOS will be asked to return to the investigational site for the ET procedures to be performed at 6 months from the last IP dose. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 17 of 90 
 
LIST OF ABBREVIATIONS 
 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AUEC0-M6 
Area under the effect curve from time zero to Month 6 
BMD 
Bone mineral density 
CHO 
Chinese Hamster Ovary 
CI 
Confidence interval 
CRO 
Contract Research Organisation 
CSR 
Clinical study report 
CTX 
C-telopeptide of type I collagen 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOS 
End of study 
ET 
Early termination 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GIOP 
Glucocorticoid-induced osteoporosis 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B virus surface antigen 
HCV Ab 
Hepatitis C virus antibody 
ICF 
Informed consent form 
ICH 
International Council of Harmonisation 
IEC 
Independent Ethics Committee 
IP 
Investigational product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MDRD 
Modification of Diet in Renal Disease 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 18 of 90 
 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MFDS 
Ministry of Food and Drug Safety 
NAb 
Neutralising antibody 
NYHA 
New York Heart Association 
OPG 
Osteoprotegerin 
P1NP 
Procollagen type I N-terminal propeptide 
PD 
Pharmacodynamic(s) 
PDS 
Pharmacodynamic Analysis Set 
PFS 
Pre-filled syringe 
PK 
Pharmacokinetic(s) 
PKS 
Pharmacokinetic Analysis Set 
PMO 
Postmenopausal osteoporosis 
PPS 
Per-Protocol Set 
PTH 
Parathyroid hormone 
RAN 
Randomised Set 
RANK 
Receptor activator of nuclear factor kappa B 
RANKL 
Receptor activator of nuclear factor kappa-Β ligand 
SAE 
Serious adverse event 
SAF1 
Safety Set 
SAF2 
Safety Set for the Transition period 
SAP 
Statistical analysis plan 
SERM 
Selective oestrogen receptor modulator 
SOP 
Standard operating procedure 
TEAE 
Treatment emergent adverse event 
TSH 
Thyroid stimulating hormone 
US 
United States of America 
WHO 
World Health Organisation 
 
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 19 of 90 
 
TABLE OF CONTENTS 
SYNOPSIS ............................................................................................................................................. 2 
GRAPHICAL STUDY DESIGN AND SCHEDULE OF ACTIVITIES ........................................ 13 
LIST OF ABBREVIATIONS ............................................................................................................ 17 
TABLE OF CONTENTS ................................................................................................................... 19 
LIST OF TABLES .............................................................................................................................. 24 
LIST OF FIGURES ............................................................................................................................ 24 
LIST OF STUDY STAFF ................................................................................................................... 25 
1. INTRODUCTION ........................................................................................................................... 26 
 Background ................................................................................................................................ 26 
 Overview of SB16 ...................................................................................................................... 26 
1.2.1. Non-clinical Studies of SB16 .............................................................................................. 27 
 Comparator Investigational Product: Prolia® ............................................................................. 27 
1.3.1. Non-clinical Data of Reference Product .............................................................................. 27 
1.3.2. Clinical Data of Reference Product in Postmenopausal Osteoporosis ................................ 27 
 Study Rationale .......................................................................................................................... 28 
 Risk and Benefit Assessment ..................................................................................................... 28 
1.5.1. Known Potential Risks ........................................................................................................ 28 
1.5.2. Known Potential Benefits .................................................................................................... 29 
1.5.3. Assessment of Potential Risks and Benefits ........................................................................ 29 
2. STUDY OBJECTIVES AND ENDPOINTS ................................................................................. 30 
 Study Objectives......................................................................................................................... 30 
2.1.1. Primary Objective ................................................................................................................ 30 
2.1.2. Secondary Objectives .......................................................................................................... 30 
 Study Endpoints ......................................................................................................................... 30 
2.2.1. Primary Endpoint ................................................................................................................. 30 
2.2.2. Secondary Endpoints for the Main Period ........................................................................... 30 
2.2.3. Secondary Endpoints for the Transition Period ................................................................... 31 
3. STUDY DESIGN ............................................................................................................................. 32 
 Overview of Study Design ......................................................................................................... 32 
 Rationale for Study Design ........................................................................................................ 32 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 20 of 90 
 
3.2.1. Scientific Rationale for Study Design ................................................................................. 32 
3.2.2. Rationale for Pharmacokinetic Assessments ....................................................................... 32 
3.2.3. Rationale for Pharmacodynamic Assessments .................................................................... 33 
3.2.4. Rationale for Immunogenicity Assessments ........................................................................ 33 
 Duration of Study Participation .................................................................................................. 33 
 Number of Subjects .................................................................................................................... 33 
 End of Study Definition ............................................................................................................. 33 
4. STUDY POPULATION .................................................................................................................. 34 
 Overview .................................................................................................................................... 34 
 Inclusion Criteria ........................................................................................................................ 34 
 Exclusion Criteria ....................................................................................................................... 34 
 Lifestyle Considerations ............................................................................................................. 37 
 Screen Failure, Re-test, and Re-screening .................................................................................. 37 
4.5.1. Screen Failure ...................................................................................................................... 37 
4.5.2. Re-test .................................................................................................................................. 37 
4.5.3. Re-screening ........................................................................................................................ 37 
5. TREATMENT AND INVESTIGATIONAL PRODUCT ............................................................ 38 
 Treatment of the Subjects ........................................................................................................... 38 
5.1.1. Dosing and Treatment Schedule .......................................................................................... 38 
5.1.2. Assignment of Subjects to Treatment Group ....................................................................... 38 
5.1.3. Blinding ............................................................................................................................... 38 
 Investigational Product ............................................................................................................... 38 
5.2.1. Identity of Investigational Product ...................................................................................... 38 
5.2.2. Formulation, Packaging, and Labelling ............................................................................... 39 
5.2.3. Product Storage and Stability .............................................................................................. 39 
5.2.4. Preparation and Administration of Investigational Products ............................................... 39 
5.2.5. Treatment Compliance and Investigational Product Accountability.................................... 39 
 Non-investigational Product ....................................................................................................... 40 
 Permitted and Prohibited Concomitant Medication or Treatment .............................................. 41 
5.4.1. Permitted Concomitant Medications or Treatment .............................................................. 41 
5.4.2. Prohibited Concomitant Medications, Procedures or Treatments ........................................ 41 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 21 of 90 
 
6. STUDY ASSESSMENT .................................................................................................................. 41 
 Efficacy Assessment ................................................................................................................... 41 
6.1.1. Bone Mineral Density ............................................................................................................. 41 
 Safety Assessment ...................................................................................................................... 42 
6.2.1. Adverse Events .................................................................................................................... 42 
6.2.2. Clinical Laboratory Evaluations .......................................................................................... 42 
6.2.3. Physical Examination .......................................................................................................... 43 
6.2.4. 12-lead Electrocardiogram ................................................................................................... 43 
6.2.5. Vital Signs ............................................................................................................................ 44 
 Pharmacodynamic Assessment ................................................................................................... 44 
 Other Assessments ...................................................................................................................... 44 
6.4.1. Pharmacokinetic Assessment ............................................................................................... 44 
6.4.2. Immunogenicity Assessment ............................................................................................... 44 
6.4.3. Spine X-ray .......................................................................................................................... 45 
7. STUDY PROCEDURES ................................................................................................................. 45 
 Study Flow and Visit Schedule ................................................................................................... 45 
7.1.1. Screening (Day ‒28 to Day ‒1) ........................................................................................... 45 
7.1.2. Treatment Period .................................................................................................................. 46 
7.1.2.1. Visit 1 (Month 0)............................................................................................................... 46 
7.1.2.2. Visit 2 (Month 0.5 ± 3 Days) ............................................................................................ 47 
7.1.2.3. Visit 3 (Month 1 ± 3 Days) ............................................................................................... 47 
7.1.2.4. Visit 4 (Month 3 ± 7 Days) ............................................................................................... 48 
7.1.2.5. Visit 5 (Month 6 ± 7 Days) ............................................................................................... 48 
7.1.2.6. Visit 6 (Month 9 ± 7 Days) ............................................................................................... 49 
7.1.2.7. Visit 7 (Month 12 ± 7 Days) ............................................................................................. 50 
7.1.3. End of Study Visit (Month 18 ± 7 Days) ............................................................................. 51 
7.1.4. Early Termination Visit (6 Months from the Last Investigational Product Dosing ± 7 Days)
 ....................................................................................................................................................... 51 
7.1.5. Unscheduled Visit ................................................................................................................ 52 
 Discontinuation .......................................................................................................................... 52 
7.2.1. Discontinuation of Subjects ................................................................................................. 52 
7.2.2. Discontinuation of Study Sites ............................................................................................ 53 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 22 of 90 
 
7.2.3. Discontinuation of the Study ............................................................................................... 53 
8. SAFETY MONITORING AND REPORTING ............................................................................ 53 
 Adverse Events ........................................................................................................................... 53 
8.1.1. Definition of Adverse Event ................................................................................................ 53 
8.1.2. Period of Observation for Adverse Events .......................................................................... 54 
8.1.3. Reporting Adverse Events ................................................................................................... 54 
8.1.4. Severity Assessment ............................................................................................................ 54 
8.1.5. Causality Assessment ........................................................................................................... 55 
8.1.6. Expectedness Assessment .................................................................................................... 55 
8.1.7. Withdrawal due to Adverse Events ...................................................................................... 55 
 Serious Adverse Events .............................................................................................................. 55 
8.2.1. Definition of Serious Adverse Event ................................................................................... 55 
8.2.2. Reporting Serious Adverse Events ...................................................................................... 56 
 Adverse Events of Special Interest ............................................................................................. 57 
8.3.1. Hypocalcaemia .................................................................................................................... 57 
8.3.2. Hypersensitivity ................................................................................................................... 57 
8.3.3. Osteonecrosis of the Jaw ..................................................................................................... 57 
8.3.4. Atypical Femoral Fractures .................................................................................................. 57 
8.3.5. Skin infections ..................................................................................................................... 58 
 Unblinding of Assigned Treatment ............................................................................................. 58 
 Independent Data and Safety Monitoring Board ........................................................................ 58 
9. STATISTICAL METHODS AND DATA ANALYSIS .................................................................. 58 
 Statistical Hypotheses................................................................................................................. 59 
 Analysis Sets .............................................................................................................................. 59 
 Subject Demographic and Baseline Characteristics ................................................................... 60 
 Analysis of the Primary Objective .............................................................................................. 60 
 Analysis of the Secondary Objectives ........................................................................................ 60 
9.5.1. Efficacy Analyses ................................................................................................................ 60 
9.5.2. Safety Analyses .................................................................................................................... 60 
9.5.3. Pharmacokinetic and Pharmacodynamic Analyses .............................................................. 61 
9.5.4. Immunogenicity Analyses ................................................................................................... 61 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 23 of 90 
 
 Sample Size Calculations ........................................................................................................... 61 
10. DATA COLLECTION AND MANAGEMENT ......................................................................... 62 
 Data Confidentiality ................................................................................................................. 62 
 Monitoring ................................................................................................................................ 62 
 Data Handling and Record Keeping ......................................................................................... 62 
 Future Use of Stored Specimens and Data ............................................................................... 63 
 Database Management and Coding .......................................................................................... 63 
 Quality Control and Quality Assurance .................................................................................... 63 
 Protocol Deviation .................................................................................................................... 64 
11. ETHICS CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES .......................... 64 
 Institutional Review Boards and Independent Ethics Committees ........................................... 64 
 Ethical Conduct of the Study .................................................................................................... 64 
 Subject Information and Informed Consent ............................................................................. 64 
 Investigator Information ........................................................................................................... 65 
11.4.1. Investigator Obligations ..................................................................................................... 65 
11.4.2. Training of Investigator Site Personnel .............................................................................. 65 
11.4.3. Protocol Signatures ............................................................................................................ 65 
11.4.4. Coordinating Investigator .................................................................................................. 65 
11.4.5. Financing and Insurance .................................................................................................... 65 
12. PUBLICATION POLICY ............................................................................................................ 65 
13. REFERENCES .............................................................................................................................. 67 
PROTOCOL SIGNATURE PAGES.................................................................................................. 69 
CHANGE HISTORY OF PROTOCOL AMENDMENT ................................................................ 71 
Version 2.0, May 03, 2021 ................................................................................................................ 71 
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 24 of 90 
 
LIST OF TABLES 
Table 1. Schedule of Activities ............................................................................................................. 14 
Table 2. World Health Organisation Categories of Bone Density ......................................................... 42 
Table 3. Parameters for Clinical Laboratory Tests ................................................................................ 42 
 
LIST OF FIGURES 
Figure 1. Graphical Study Design ......................................................................................................... 13 
 
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 25 of 90 
 
LIST OF STUDY STAFF 
 
SPONSOR: 
Samsung Bioepis Co., Ltd. 
76, Songdogyoyuk-ro, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
 
 
Clinical Project Manager 
 
 
 
Clinical Development 
Lead 
 
 
 
Clinical Research 
Scientist 
 
 
 
Statistician 
 
 
 
Safety Physician 
 
 
 
Project Safety Lead 
 
 
 
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 26 of 90 
 
1. Introduction 
 Background 
Osteoporosis is defined as a systemic skeletal disease characterised by low bone mass and 
microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and 
susceptibility to fracture. [4] Fractures resulting from osteoporosis become increasingly common in 
women after age 55 years and men after age 65 years, resulting in substantial bone-associated 
morbidities, and increased mortality and health-care costs. [5] An estimated 2.7 million hip fractures 
occurred in 2010 worldwide, of which 1,364,717 (51%) were calculated to be potentially preventable 
(264,162 in men, and 1,100,555 in women), if osteoporosis (defined as a femoral neck T-score of –2.5 
standard deviation or less) could be avoided. [6] 
Several chemical entities with original modes of action have been approved for the treatment of 
postmenopausal osteoporosis (PMO) after demonstration of an anti-fracture efficacy at the level of the 
axial skeleton (spine) or appendicular skeleton (all non-vertebral, major non-vertebral, or hip). [7] These 
products include bisphosphonates with daily or intermittent dosing formulations, selective oestrogen 
receptor modulators (SERMs), calcitonin, active vitamin D metabolites, teriparatide, and strontium 
ranelate. Some of them have also been approved for the treatment of osteoporosis in men. 
Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa B 
ligand (RANKL) that blocks its binding to receptor activator of nuclear factor kappa B (RANK), 
inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone 
density. Denosumab showed effectiveness in the treatment of osteoporosis in postmenopausal women 
and in men at increased risk of fractures, and treatment to increase bone mass in men with osteoporosis 
at high risk for fracture and is approved as Prolia®. [8; 9] Also it showed effectiveness in the treatment 
of giant cell tumour and prevention of skeletal-related events in patients with bone metastases, and is 
approved as Xgeva®. [10; 11] The recommended dose of Prolia® is 60 mg every 6 months as a 
subcutaneous injection and that of Xgeva® is 120 mg every 4 weeks as a subcutaneous injection. 
A biosimilar is a biological medicine highly similar to another already approved biological medicine 
(the 'reference medicine') and is expected to increase accessibility of biologics to a wider patient 
population. 
 Overview of SB16 
SB16 has been developed as a similar biological medicinal product to Prolia® and Xgeva® having 
denosumab as the active substance. Prolia® is currently indicated for osteoporosis in postmenopausal 
women and in men, glucocorticoid-induced osteoporosis (GIOP), and bone loss associated with 
hormone ablation therapy in prostate cancer patients by both European Medicines Agency (EMA) and 
the United States of America (US) Food and Drug Administration (FDA). In addition, US FDA 
approved Prolia® for the treatment of bone loss associated with adjuvant aromatase inhibitor therapy 
for breast cancer. [8; 9] Xgeva® is currently indicated for the prevention of skeletal-related events in 
patients with advanced malignancies involving bone and the treatment of giant cell tumour of bone that 
is unresectable or where surgical resection is likely to result in severe morbidity by both EMA and US 
FDA. In addition, US FDA approved Xgeva® for the treatment of hypercalcemia of malignancy 
refractory to bisphosphonate therapy. [10; 11] 
SB16 is manufactured with Chinese Hamster Ovary (CHO) mammalian cell expression system in 
suspension culture by recombinant deoxyribonucleic acid (DNA) technology and purified by various 
affinity and ion exchange chromatography. 
According to the guideline International Council of Harmonisation (ICH) Q6B, characterisation of a 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 27 of 90 
 
biological therapeutic must involve its physicochemical properties, biological activities, purity, 
impurities, and quantity. The characterisation study will employ the ‘state-of-the-art’ analytical methods 
in order to investigate the primary, secondary, higher-order structures, and the post-translational 
modifications associated the structural heterogeneity, the charge variants, the purity, and the biological 
activities. 
1.2.1. Non-clinical Studies of SB16 
As outlined in the “Guideline on similar biological medicinal products containing biotechnology-
derived proteins as active substance: non-clinical and clinical issues”, [12] a risk-based approach was 
taken to the non-clinical evaluation of SB16. A series of in vitro biologic activity studies is to be 
performed in order to demonstrate non-clinical similarity between SB16, Prolia®, and Xgeva®. In line 
with the guideline, if similarity is to be demonstrated in quality and in vitro comparisons to provide 
non-clinical evidence of similarity between SB16, Prolia®, and Xgeva®, in vivo studies will not be 
performed. Moreover, in vitro studies are considered to be the more sensitive measurement than with in 
vivo studies. Also, non-clinical safety pharmacology, reproductive and developmental toxicity, and 
carcinogenicity studies were not performed, as they are not required for non-clinical testing of 
biosimilars as outlined in the guideline. [12] 
 Comparator Investigational Product: Prolia® 
1.3.1. Non-clinical Data of Reference Product 
In ovariectomised monkeys, once-monthly treatment with Prolia® suppressed bone turnover and 
increased BMD and strength of cancellous and cortical bone at doses 50-fold higher than the 
recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg). 
Bone tissue was normal with no evidence of mineralisation defects, accumulation of osteoid, or woven 
bone. 
Because the biological activity of Prolia® in animals is specific to nonhuman primates, evaluation of 
genetically engineered (‘knockout’) mice or use of other biological inhibitors of the RANK/RANKL 
pathway, namely osteoprotegerin (OPG)-Fc, provided additional information on the pharmacodynamic 
(PD) properties of Prolia®. RANK/RANKL knockout mice exhibited absence of lymph node formation, 
as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland 
development during pregnancy). Neonatal RANK/RANKL knockout mice exhibited reduced bone 
growth and lack of tooth eruption. A corroborative study in 2-week-old rats given the RANKL inhibitor 
OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These 
changes were partially reversible in this model when dosing with the RANKL inhibitors was 
discontinued. 
The carcinogenic potential of Prolia® has not been evaluated in long-term animal studies. 
The genotoxic potential of Prolia® has not been evaluated. 
Prolia® had no effect on female fertility or male reproductive organs in monkeys at doses that were 13-
to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 
6 months, based on body weight (mg/kg). [8; 9] 
1.3.2. Clinical Data of Reference Product in Postmenopausal Osteoporosis 
The efficacy and safety of Prolia® in the treatment of PMO was demonstrated in a 3-year, randomised, 
double-blind, placebo-controlled trial. Enrolled women had a baseline BMD T-score between ‒2.5 and 
‒4.0 at either the lumbar spine or total hip. Women with other diseases (such as rheumatoid arthritis, 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 28 of 90 
 
osteogenesis imperfecta, and Paget’s disease) or on therapies that affect bone were excluded from this 
study. The 7,808 enrolled women were aged 60 to 91 years with a mean age of 72 years. Overall, the 
mean baseline lumbar spine BMD T-score was ‒2.8, and 23% of women had a vertebral fracture at 
baseline. Women were randomised to receive subcutaneous injections of either placebo (n = 3,906) or 
Prolia® 60 mg (n = 3,902) once every 6 months. All women received at least 1 g calcium and 400 IU 
vitamin D supplementation daily. 
The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) 
vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine radiographs (T4 
to L4) using a semiquantitative scoring method. Secondary efficacy variables included the incidence of 
hip fracture and nonvertebral fracture, assessed at 3 years. 
Prolia® significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years 
(p < 0.0001). The incidence of new vertebral fractures at 3 years was 7.2% in the placebo-treated women 
compared to 2.3% for the Prolia®-treated women. The absolute risk reduction was 4.8% and relative 
risk reduction was 68% for new morphometric vertebral fractures at 3 years. 
Prolia® was effective in reducing the risk for new morphometric vertebral fractures regardless of age, 
baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a drug for 
osteoporosis. 
The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for Prolia®-
treated women at year 3. The age-adjusted absolute risk reduction of hip fractures was 0.3% with a 
relative risk reduction of 40% at 3 years (p = 0.004). 
Treatment with Prolia® significantly increased BMD at all anatomic sites measured at 3 years. The 
treatment differences in BMD at 3 years were 8.8% at the lumbar spine, 6.4% at the total hip, and 5.2% 
at the femoral neck. Consistent effects on BMD were observed at the lumbar spine, regardless of 
baseline age, race, weight/body mass index, baseline BMD, and level of bone turnover. 
After Prolia® discontinuation, BMD returned to approximately baseline levels within 12 months. [2; 8; 
9] 
 Study Rationale 
A biosimilar is a biological medicinal product that is highly similar to an already authorised original 
biological medicinal product (reference medicinal product) in terms of quality, tolerability, and efficacy 
based on a comprehensive comparability exercise. [12; 13] EMA and US FDA have developed specific 
guidelines for a biologic drug to be approved as a biosimilar. [13; 14] These guidelines recommend a 
stepwise approach in developing a biosimilar starting with extensive physicochemical and biological 
characterisation before initiating clinical studies for the comparison of the efficacy, tolerability, 
pharmacokinetic (PK) properties, and immunogenicity of the biosimilar. The purpose of this study is to 
demonstrate the equivalence in efficacy of SB16 compared to Prolia® and to evaluate the safety and 
immunogenicity in subjects with PMO. In addition, systemic exposure and the PD profiles of SB16 to 
Prolia® will also be evaluated. 
 Risk and Benefit Assessment 
1.5.1. Known Potential Risks 
According to Prolia® Prescribing Information and Summary of Product Characteristics, there are 
potential risks such as hypersensitivity, hypocalcaemia, disturbances of mineral metabolism, 
osteonecrosis of the jaw, atypical subtrochanteric, diaphyseal femoral fractures, serious infection, 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 29 of 90 
 
dermatologic adverse reactions, and musculoskeletal pain. Also, as this is a therapeutic protein, there is 
a potential for immunogenicity with investigational products (IPs; SB16 or Prolia®). [8; 9] 
In order to ensure the safety of subjects who participate in the study, safety will be monitored during 
the whole study period based on the vital signs, laboratory safety assessments, physical examination 
including the evaluation of injection site, and reported AEs. 
Subject should be instructed to report any symptoms, especially symptoms related to AE of special 
interests (AESIs) in Section 8.3 without delay and should be managed appropriately. Following 
discontinuation of Prolia® treatment, fracture risk increases, including the risk of multiple vertebral 
fractures. Thus, next treatment will be discussed at early termination (ET)/end of study (EOS) to prevent 
loss of bone mass and/or fractures. 
Participation in clinical study requires frequent visits than usual medical practice, thus, additional risk 
under the Coronavirus Disease 2019 should be considered. The Sponsor will consider whether to start, 
continue, temporarily halt, or close the study at some or all study sites based on the risk assessment 
based on relevant parties’ input on an ongoing basis. 
This study will take place at multicentre with accessible medical facilities which will allow immediate 
treatment of medical emergencies. All study related procedures will be conducted by medical staffs with 
appropriate level of training and expertise and an understanding of the IPs, its target, and mechanism 
of action. An independent Data and Safety Monitoring Board (DSMB) will convene at pre-specified 
intervals to conduct interim monitoring of accumulating safety data. Following each data review, the 
DSMB will make recommendations regarding the conduct of the study, including continuation of the 
study without modifications, modification of the protocol, pausing of subject enrolment until the 
resolution of an issue, or termination of the study for safety reasons. 
1.5.2. Known Potential Benefits 
Prolia® binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and 
survival of osteoclasts, the cells responsible for bone resorption. Prolia® prevents RANKL from 
activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the 
RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing 
bone resorption and increasing bone mass and strength in both cortical and trabecular bone. 
Prolia® reduces fracture risk and increases BMD in PMO. A meta-analysis that compared denosumab 
with placebo showed a 68% reduction in the risk of vertebral fractures (hazard ratio, 0.32; 95% 
confidence interval [CI], 0.26 to 0.40), a 39% reduction in the risk of hip fractures (hazard ratio, 0.61; 
95% CI, 0.37 to 0.98), and a 19% reduction in the risk of nonvertebral fractures (hazard ratio, 0.81; 95% 
CI, 0.69 to 0.95). [8; 9] 
Although clinical data is currently unavailable for SB16, SB16 is expected to have similar clinical 
outcome to Prolia® based on the physicochemical and biological similarity. 
1.5.3. Assessment of Potential Risks and Benefits 
If left untreated, osteoporosis can progress painlessly until bone break. These broken bones, also known 
as fractures, occur typically in the hip, spine, and wrist; hip and spinal fractures in particular can have 
serious consequences. Thus, benefit of Prolia® treatment including reducing fracture risk and increase 
in BMD outweigh the potential risks. 
The available data demonstrate a high degree of physicochemical and biological similarity of SB16 
with the reference medicinal product (Prolia®). The suitability of the methodology employed to evaluate 
the similarity of SB16 and Prolia® in a pharmaceutical setting were confirmed by EMA and the US 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 30 of 90 
 
FDA. The known and potential risks of receiving SB16 are expected to be similar to those seen with 
Prolia®. In conclusion, sufficient evidence supports the administration of SB16, as a similar biological 
medicinal product of Prolia®, to subjects with PMO. 
Risk assessment for the Coronavirus Disease 2019 will be documented on an ongoing basis in relevant 
documents. The risk assessment and associated mitigation measures based on inputs from relevant 
stakeholders will be prioritised to consider the rights, safety, and wellbeing of the study subjects. 
2. Study Objectives and Endpoints 
 Study Objectives 
2.1.1. Primary Objective 
The primary objective of this study is to demonstrate the equivalence of SB16 to Prolia®, in terms of 
percent change from baseline in lumbar spine BMD at Month 12 in PMO. 
2.1.2. Secondary Objectives 
The secondary objectives are: 
 
To evaluate the efficacy of SB16 compared to Prolia® by 
- 
Percentage change from baseline in lumbar spine BMD 
- 
Percentage change from baseline in total hip BMD 
- 
Percentage change from baseline in femoral neck BMD 
 
To evaluate the safety and tolerability of SB16 compared to Prolia® 
 
To evaluate the PK profile of SB16 compared to Prolia® 
 
To evaluate the PD profile of SB16 compared to Prolia® 
 
To evaluate the immunogenicity of SB16 compared to Prolia® 
 
To evaluate the safety, tolerability, immunogenicity, PK, PD, and efficacy in subjects with 
PMO who transitioned to SB16 from Prolia® compared to subjects who maintained Prolia® 
from the Main period 
 Study Endpoints 
2.2.1. Primary Endpoint 
 
Percent change from baseline in lumbar spine BMD at Month 12 
2.2.2. Secondary Endpoints for the Main Period 
Efficacy endpoints 
 
Percent change from baseline in lumbar spine BMD at Month 6 
 
Percent change from baseline in total hip BMD at Months 6 and 12 
 
Percent change from baseline in femoral neck BMD at Months 6 and 12 
Safety endpoints 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 31 of 90 
 
 
Incidence of AEs 
 
Incidence of serious AEs (SAEs) 
PK endpoint 
 
Serum drug concentration at Months 0, 0.5, 1, 3, 6, 9, and 12 
PD endpoints 
 
Serum C-telopeptide of type I collagen (CTX) concentration at Months 0, 0.5, 1, 3, 6, 9, and 
12 
 
Area under the effect curve from time zero to Month 6 (AUEC0-M6) of percent change from 
baseline in serum CTX 
 
Serum procollagen type I N-terminal propeptide (P1NP) concentration at Months 0, 0.5, 1, 3, 
6, 9, and 12 
Immunogenicity endpoint 
 
Incidence of anti-drug antibodies (ADAs) at Months 0, 0.5, 1, 3, 6, 9, and 12 
 
Incidence of neutralising antibodies (NAbs) at Months 0, 0.5, 1, 3, 6, 9, and 12 
2.2.3. Secondary Endpoints for the Transition Period 
Safety endpoints 
 
Incidence of AEs 
 
Incidence of SAEs 
Immunogenicity endpoint 
 
Incidence of ADAs at Month 18 
 
Incidence of NAbs at Month 18 
Efficacy endpoints 
 
Percent change from baseline in lumbar spine BMD at Month 18 
 
Percent change from baseline in total hip BMD at Month 18 
 
Percent change from baseline in femoral neck BMD at Month 18 
PK endpoint 
 
Serum drug concentration at Month 18 
PD endpoints 
 
Serum CTX concentration at Month 18 
 
Serum P1NP concentration at Month 18 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 32 of 90 
 
3. Study Design 
 Overview of Study Design 
For the Main period 
This is a Phase III, randomised, double-blind, parallel group, multicentre, equivalence study to evaluate 
the efficacy, safety, PK, PD, and immunogenicity of SB16 compared to Prolia® in PMO. Subjects will 
be randomised in a 1:1 ratio to receive either SB16 or Prolia® subcutaneously at Months 0 and 6. Study 
visits will occur at Months 0, 0.5, 1, 3, 6, 9, and 12. 
For the Transition period 
This is a Phase III, randomised, double-blind, multicentre, transition study to investigate the safety, 
tolerability, immunogenicity, PK, PD, and efficacy of SB16 in subjects with PMO who transitioned 
from the Prolia® arm, compared with subjects who maintained Prolia® treatment after Month 12 from 
the Main period of the SB16-3001 study. 
Subjects will be enrolled in the Transition period for up to 6 months after Month 12 of the Main period 
of the SB16-3001 study. Subjects will receive either SB16 or Prolia® subcutaneously at Month 12. 
At Month 12, subjects receiving Prolia® from the Main period of the SB16-3001 study will be 
randomised again in a 1:1 ratio to either continue on Prolia® (Prolia®/Prolia®) or be transitioned to SB16 
(Prolia®/SB16) up to Month 18. Subjects receiving SB16 from the Main period of the SB16-3001 study 
will continue to receive extended treatment of SB16 up to Month 18 but they will also follow the 
randomisation procedure to maintain blinding. 
 Rationale for Study Design 
3.2.1. Scientific Rationale for Study Design 
The purpose of this study is to demonstrate the equivalence in clinical efficacy of SB16 and European 
Union (EU) sourced Prolia® in subjects with PMO. 
According to EMA and US FDA guideline, the endpoints and study populations should be clinically 
relevant and sensitive in detecting clinically meaningful differences in safety and effectiveness between 
the proposed biosimilar product and reference product. [15; 13] Among the approved indications by 
both EMA and US FDA, PMO population is considered the most appropriate population to assess 
clinical similarity between SB16 and Prolia®. 
As the most sensitive clinical endpoint in PMO, percent change of BMD at Month 12 will be compared 
between SB16 and Prolia® to demonstrate the clinical similarity. BMD is a validated biomarker for the 
evaluation of the treatment effect and risk of fracture, and BMD change after denosumab treatment was 
shown in the several studies. [1; 2; 3] 
This study is a randomised, double-blind, multicentre study for 18 months. And transition will be 
performed at Month 12 to investigate the clinical impact (safety and immunogenicity) of switching. 
3.2.2. Rationale for Pharmacokinetic Assessments 
A randomised, three-arm, parallel, single-dose comparative PK study will be conducted in healthy male 
subjects to demonstrate similarity in PK profiles of SB16 and EU sourced Prolia® and US sourced 
Prolia®. However, since target-mediated clearance of denosumab can be more accurately investigated 
in PMO patients, additional PK assessments will be performed in this comparative efficacy study to 
provide supportive evidence to PK similarity. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 33 of 90 
 
3.2.3. Rationale for Pharmacodynamic Assessments 
In pivotal trials of Prolia®, denosumab treatment rapidly reduced the rate of bone turnover, reaching a 
nadir for the bone resorption marker serum CTX (85% reduction) by 3 days, with reductions maintained 
over the dosing interval. At the end of each dosing interval, CTX reductions were partially attenuated 
from maximal reduction of ≥ 87% to approximately ≥ 45% (range 45-80%), reflecting the reversibility 
of denosumab’s effects on bone remodelling once serum levels diminish. These effects were sustained 
with continued treatment. Bone turnover markers generally reached pre-treatment levels within 9 
months after the last dose. Upon re-initiation, reductions in CTX by denosumab were similar to those 
observed in patients initiating primary denosumab treatment. [8; 9] 
Thus, together with BMD which is a primary endpoint of SB16 Phase III study as a strong predictor of 
fracture in denosumab, PD markers such as serum P1NP and CTX will be measured and compared. 
CTX was also selected for the Phase I trial because this proximal PD marker is more sensitive than 
other bone turnover markers. 
Instead of true clinical outcomes such as fracture, SB16 will compare the change of BMD to Prolia® 
for demonstration of biosimilarity. Also, PD markers such as serum P1NP and CTX will be measured 
and compared. 
3.2.4. Rationale for Immunogenicity Assessments 
Biological/biotechnology-derived proteins can induce an unwanted immune response that is triggered 
by more than a single factor and the consequence of immunogenicity may vary considerably, ranging 
from irrelevant to therapy to serious and life-threatening. Immune responses may affect both safety and 
effectiveness such as altering PK, inducing anaphylaxis, or promoting development of NAbs that 
neutralise the product as well as its endogenous protein counterpart. 
In clinical studies of Prolia®, NAbs have not been observed for denosumab. Using a sensitive 
immunoassay < 1% of patients treated with denosumab for up to 5 years tested positive for non-NAbs 
with no evidence of altered pharmacokinetics, toxicity, or clinical response. [8; 9] 
For subjects’ safety and for demonstrating biosimilarity, immunogenicity will be assessed in this study 
according to the recommended guideline. 
 Duration of Study Participation 
The duration of study participation will be 28 days of screening period, 12 months of Main period, and 
6 months of Transition period. 
In subjects who are not eligible only due to vitamin D deficiency, additional 28 days of screening period 
(a total of 56 days) will be allowed for vitamin D repletion and re-test. 
 Number of Subjects 
Approximately 432 subjects are planned to be randomised from approximately 44 sites for study 
duration. 
 End of Study Definition 
A subject is considered to have completed the study if she has completed the last scheduled visit or the 
last scheduled procedure shown in the Schedule of Activities (Table 1). EOS is defined as completion 
of the last scheduled visit (Month 18) shown in the Table 1. The end of this clinical study is defined as 
completion of the last subject’s EOS/ET. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 34 of 90 
 
4. Study Population 
 Overview 
The study population for this study is subjects with PMO. Eligibility for participation in this study will 
be based on the inclusion/exclusion criteria. 
 Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Postmenopausal women (defined as lack of menstrual period for at least 12 months prior to 
Screening, for which there is no other pathological or physiological cause) who are 55 to 80 
years of age at Screening 
 
Serum follicle stimulating hormone (FSH) test can be done at Screening in case of 
uncertainty. 
2. Ambulatory and visually unimpaired to participate in the study at Screening, in the opinion of 
the Investigator 
3. Absolute BMD consistent with T-score at the total hip or lumbar spine of ≥ ‒4 and ≤ ‒2.5, 
determined by central imaging centre at Screening 
4. At least three evaluable vertebrae within L1 to L4, one evaluable femoral neck, and one 
evaluable hip joint for BMD measurement, determined by central imaging centre at Screening 
5. Biologic (defined as any therapeutic monoclonal antibody or fusion receptor protein, including 
denosumab, denosumab biosimilars, or romosozumab) naïve at Screening 
6. Body weight of ≥ 50 kg and ≤ 90 kg at Screening 
7. Has provided informed consent voluntarily and must be able to, in the opinion of the 
Investigator, understand the implications of taking part in the study, be willing to follow the 
study requirements, and complete the study 
Subjects must meet the following criteria to be enrolled in the Transition period: 
1. Have been enrolled and completed the scheduled Month 12 of the Main period of the SB16-
3001 study 
 Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for the study: 
1. One severe or more than two moderate vertebral fractures on spinal X-ray according to Genant 
classification, determined by central imaging centre at Screening 
2. History of hip fracture or bilateral hip replacement at Screening 
3. Uncorrected vitamin D deficiency (defined as serum 25-hydroxyvitamin D level < 20 ng/mL 
[50 nmol/L]) at Screening 
4. Hypercalcemia or hypocalcaemia (defined as albumin-adjusted serum calcium for 
hypocalcaemia < 2.1 mmol/L [8.4 mg/dL] or for hypercalcemia > 2.62 mmol/L [10.5 mg/dL]) 
at Screening 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 35 of 90 
 
5. Inadequate haematological function at Screening defined as the following: 
a. 
White blood cell count < 3.5 × 103 cells/μL (< 3.5 × 109 cells/L) 
b. Haemoglobin < 9 g/dL 
c. 
Platelet count < 100,000/mm3 (< 100 × 109/L) 
6. Inadequate renal or hepatic function at Screening defined as the following: 
a. 
Estimated glomerular filtration rate (eGFR) < 45 mL/min by the Modification of Diet in 
Renal Disease (MDRD) formula or under dialysis 
b. Serum alanine transaminase and aspartate transaminase ≥ 2 × upper limit of reference 
range 
7. Known allergic reactions, hypersensitivity, or intolerance to denosumab or to any ingredients 
of the IP, including latex allergy or hereditary problems of fructose intolerance at Screening 
8. May not tolerate long-term calcium or vitamin D supplementation or subject with 
malabsorption of calcium or vitamin D supplements, in the opinion of the Investigator, at 
Screening 
9. Use of any of the below medications that can affect BMD: 
a. 
Oral bisphosphonate at any dose for osteoporosis treatment: 
- 
Used for > 3 years cumulatively at Screening 
- 
Used for ≤ 3 years cumulatively and passed < 1 year since the last dose at Screening 
b. Intravenous bisphosphonate at any dose within 5 years prior to Screening 
c. 
Parathyroid hormone (PTH) or PTH analogues at any dose within 2 years prior to 
Screening 
d. Systemic hormone replacement therapy (oral or transdermal oestrogen), SERMs, tibolone, 
aromatase inhibitors, or androgens at any dose within 1 year prior to Screening 
 
Exceptionally, non-systemic vaginal oestrogen treatment is permitted. 
e. 
Calcitonin or its derivatives, calcimimetics (such as cinacalcet or etelcalcetide), or 
calcitriol at any dose within 3 months prior to Screening 
f. 
Systemic glucocorticoids (≥ 5 mg prednisone equivalent per day or cumulative dose ≥ 50 
mg) for more than 10 days within 3 months prior to Screening 
g. Fluoride or strontium intended for osteoporosis treatment at any dose at any time at 
Screening 
h. Any non-biologic IP for osteoporosis treatment that mechanism of action is not within 
excluded medications in exclusion criteria number 9-a to 9-g at any dose within 5 years 
prior to Screening 
i. 
Other bone active drugs at any dose within 3 months prior to Screening 
10. Use of any non-biologic IP that is not indicated for osteoporosis from another study at any 
dose within five half-lives of that product prior to Randomisation or use of an investigational 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 36 of 90 
 
device at Screening 
11. Non-osteoporosis medical conditions that can affect BMD at Screening: 
a. 
History of hyperparathyroidism or hypoparathyroidism, or current hyperparathyroidism or 
hypoparathyroidism 
b. 
Current uncontrolled hyperthyroidism or hypothyroidism 
c. 
History of bone disease such as osteomalacia, osteogenesis imperfecta, osteopetrosis, 
achondroplasia, or Paget’s disease of the bone 
d. 
History of chronic inflammatory diseases, obvious sclerosis, osteophytosis, severe 
scoliosis, or other degenerative changes due to other co-morbidities that may interfere with 
the interpretation of dual-energy X-ray absorptiometry (DXA) imaging results 
e. 
History of metabolic or other endocrinologic diseases such as malabsorption syndrome 
(including celiac disease), Cushing disease, acromegaly, or hyperprolactinemia 
12. History of osteonecrosis of jaw, osteonecrosis of external auditory canal, or atypical femoral 
fracture at Screening or related-risk based on the physical examination including oral at 
Screening 
13. History of active periodontal disease or invasive dental procedure within 6 months prior to 
Screening or plan to do invasive dental procedures (e.g., tooth extraction, dental implants, or 
oral surgery) during the study period 
14. Fracture (except atypical femoral fracture and hip fracture) which has been in active healing 
within 12 months prior to Screening at the discretion of the Investigator 
15. History of clinically significant active infection within 2 weeks prior to Randomisation, and 
for cellulitis, erysipelas, or infections that requires hospitalisation or intravenous antibiotics, 
within 8 weeks prior to Randomisation 
16. Known history for hepatitis B or hepatitis C or human immunodeficiency virus infection, or 
positive testing for hepatitis B (hepatitis B virus surface antigen [HBsAg]) or hepatitis C 
(hepatitis C virus antibody [HCV Ab]) virology at Screening 
17. History of acute or chronic pancreatitis at Screening 
18. History of acute myocardial infarction or New York Heart Association (NYHA) III/IV 
congestive heart failure within 1 year prior to Randomisation 
19. History of cardiac arrythmia or long QT syndrome or electrocardiogram (ECG) abnormalities 
(e.g., that required hospitalisation, emergency cardioversion, or defibrillation) indicating 
safety risk at Screening 
20. Malignancy not cured within 5 years prior to Randomisation 
 
Exceptionally, completely excised and cured basal cell carcinoma or cervical carcinoma in 
situ can be permitted. 
21. History of organ transplantation at Screening 
22. History of alcohol or substance-abuse within 12 months prior to Screening 
23. Any clinically significant disease or disorder or laboratory abnormality which, in the opinion 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 37 of 90 
 
of the Investigator, would prevent the subject from completing the study or the interpretation 
of the study results at Screening and Randomisation 
Subjects meeting the following criteria must not be enrolled in the Transition period: 
1. Found to be of increased risk to continue enrolment, in the opinion of the Investigator 
 Lifestyle Considerations 
Before the day of PD assessment (bone turnover markers [serum CTX and P1NP]), subjects should fast 
at least 8 hours before blood sampling. PD blood sampling should be performed in the morning hours. 
On the day of baseline PD assessment (Month 0), calcium should not be given before the PD blood 
sampling. 
All subjects should be encouraged to maintain good oral hygiene and receive routine dental check-ups 
(see Section 8.3). 
 Screen Failure, Re-test, and Re-screening 
4.5.1. Screen Failure 
Screen failures are defined as subjects who consent to participate in the clinical trial but do not meet 
one or more criteria required for participation in the trial during the screening procedures. 
If the subject is not randomised within 28 days after signing the informed consent form (ICF), the 
subject must be screen failed. 
Exceptionally, if the subject is not eligible only due to vitamin D deficiency, additional 28 days of 
screening period is allowed. In this case if the subject is not randomised within 56 days after signing 
the ICF, the subject must be screen failed. 
4.5.2. Re-test 
Clinical laboratory test for eligibility review will not be allowed for re-test unless any technical error 
(e.g., missing value due to sample mishandling) was found. 
Exceptionally, in subjects who are not eligible only due to vitamin D deficiency, serum vitamin D can 
be re-tested only once after vitamin D repletion and re-test result will be used for eligibility review. 
Additional 28 days of screening period will be allowed to those subjects. Vitamin D repletion method 
will be determined by the Investigator considering subject’s serum vitamin D level. To avoid repetition 
of unnecessary procedures, screening procedures previously performed other than vitamin D re-test will 
not be repeated in this case. 
Re-scanning of DXA or lateral spine X-ray during the study period is not allowed except for cases where 
it has been confirmed that the image is not evaluable by the central imaging centre due to quality issue. 
4.5.3. Re-screening 
Re-screening is allowed for administrative reason only, i.e. not medical issues. Subjects who did not 
meet eligibility criteria at Screening cannot be re-screened. Each case of re-screening must be discussed 
and agreed with the Sponsor on a case-by-case basis. Subject can be re-screened only once; new subject 
number will be assigned for the re-screened subject and all the screening procedures will be done after 
signing ICF. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 38 of 90 
5. Treatment and Investigational Product
Treatment of the Subjects
5.1.1. Dosing and Treatment Schedule 
Subjects will be administered SB16 or Prolia® 60 mg pre-filled syringe (PFS) as a single subcutaneous 
injection at Months 0 and 6 in the Main period and Month 12 in the Transition period. 
All subjects should receive at least of elemental calcium 1 g daily and at least 800 IU vitamin D daily. 
Dosing visits will involve a window period of ± 7 days from the scheduled dosing date except Month 
0. No visit windows are allowed for the Month 0 and first IP administration is performed during this
visit.
Dose modifications of IP are not allowed. 
5.1.2. Assignment of Subjects to Treatment Group 
A unique subject number will be assigned to the subject by the Interactive Web Response System (IWRS) 
at Screening. 
Subjects who meet all criteria for enrolment will be randomised in a ratio of 1:1 to receive either SB16 
or Prolia® at Month 0. 
A unique randomisation number will be assigned to the subject number by the IWRS at Randomisation 
to ensure that treatment group assignment is unbiased and concealed from subjects, Investigators, and 
other study personnel. The randomisation number is linked to the treatment group assignment, which 
in turn is linked to IP kit number. 
The assigned subject number(s) and randomisation number(s) will not be re-used. 
For the Transition period, the same subject number used in the randomised, double-blind period will be 
conveyed to register the subject using the IWRS. At Month 12, subjects receiving Prolia® from the Main 
period of the SB16-3001 study will be randomised again in a 1:1 ratio to either continue on 
(Prolia®/Prolia®) or be transitioned to SB16 (Prolia®/SB16) up to Month 18. Subjects receiving SB16 
from the Main period of the SB16-3001 study will continue to receive extended treatment of SB16 up 
to Month 18 but they will also follow the randomisation procedure to maintain blinding. 
5.1.3. Blinding 
This study is double-blinded in order to eliminate observer or performance bias. Subjects, Investigators, 
and other study personnel will be unaware of the treatment group assignments throughout the study 
period. Unblinding is referred to Section 8.4. 
To ensure the blinding of the treatment group assignment, blinding cap will be applied to IP PFS (SB16 
or Prolia®). 
The IP (SB16 and Prolia®) PFS will be packaged and labelled identically, to ensure the blinding of the 
treatment group assignment. 
 Investigational Product 
5.2.1. Identity of Investigational Product 

Name: SB16 (proposed denosumab biosimilar) or EU sourced Prolia®


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 39 of 90 
 
 
Formulation: PFS of 1 mL contains 60 mg of denosumab (60 mg/mL) 
 
Route of administration: Subcutaneous injection 
 
Dose regimen: 60 mg every 6 months 
5.2.2. Formulation, Packaging, and Labelling 
These IP PFSs will be packed and labelled in a double-blinded manner for clinical use. The labels for 
carton and PFS will contain the protocol number, unique identifier, Sponsor company name, expiry or 
re-test date, storage condition, and other details according to the Good Manufacturing Practice (GMP) 
and other relevant local laws and/or regulations. 
The temperature will be monitored properly during the study period. The IP should be stored in a secure 
area and clearly labelled and stored away from other IP or medication to prevent confusion (e.g., in a 
clearly marked box on a separate shelf of the refrigerator). 
A detailed guideline for IP preparation, administration, storage, and destruction will be provided in the 
pharmacy manual. 
5.2.3. Product Storage and Stability 
IPs should be stored at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from 
light. The temperature will be monitored properly during the study period. If continuous monitoring is 
not available then manual temperature logs should be generated and recorded to ensure proper storage 
conditions. If a temperature deviation occurred, responsible person should contact the Sponsor to 
determine if the IP is still appropriate for use. 
Do not freeze IPs. The IPs must not be used beyond the expiration date. Once removed from the 
refrigerator, IPs must not be exposed to temperatures above 25°C/77°F and must be used within 14 days. 
If not used within the 14 days, IPs should be discarded. Protect IPs from direct light and heat. Avoid 
vigorous shaking of IPs. 
5.2.4. Preparation and Administration of Investigational Products 
IPs should be inspected visually prior to administration. IPs are clear, colourless to pale yellow solution 
that may contain trace amounts of translucent to white proteinaceous particles. If particulates, 
cloudiness, or discoloration are visible, the IPs must not be used. 
Prior to administration, IPs may be removed from the refrigerator and brought to room temperature (up 
to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Refrain from 
warming IPs in any other way. 
IPs will be administered as a single subcutaneous injection in the upper arm, the upper thigh, or the 
abdomen. Only the Investigator or trained designee with an appropriate qualification (per local 
regulation) can perform and monitor the administration of IPs. In this study, IPs must be administered 
only on an on-site basis. 
5.2.5. Treatment Compliance and Investigational Product Accountability 
All IP injections will be given by the Investigator or designee to ensure compliance. The exact date and 
time of IP injection must be recorded in the source documentation and the electronic case report form 
(eCRF). 
The Investigator and/or designee should maintain the documents of IP accountability and record the IP 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 40 of 90 
kit number administered to subjects. IP accountability and dispensing records must be kept current and 
contain the following information: 

The identification of the subjects to whom the drug was dispensed

The date(s) and quantity of the drug dispensed to the subject

The dispensing and inventory logs must be available for inspection by the study monitor
The Investigator and/or designee is responsible for accounting all unused IP and all used IP containers. 
The Investigator uses this information to maintain an accurate and complete dispensing and inventory 
record. 
IP supplies are shipped to the investigational site as needed. The monitor will review drug accounting 
during routine monitoring visits with the documents containing relevant information. At the completion 
or termination of the study, a final drug accountability review and reconciliation must be completed; 
any discrepancies must be investigated and their resolution must be documented. 
The used IP should be disposed and/or destructed after use according to the local regulation. In case 
that the IP is disposed after use, the Investigator is responsible for accounting other materials of used 
IP such as IP container. The Investigator uses this information to maintain an accurate and complete 
dispensing and inventory record provided by the Sponsor. 
All unused IPs should be returned to the Sponsor or designated vendor unless local destruction is 
approved by the Sponsor. If destruction is authorised at the investigational site, the Investigator must 
ensure that the materials are destroyed in compliance with all applicable environmental regulations, 
institutional policies, and any instructions provided by the Sponsor. Destruction of the IPs must be 
adequately documented. 
 Non-investigational Product 

Elemental calcium (at least 1 g per day)

Vitamin D (at least 800 IU per day)
Above dose of daily calcium and vitamin D will be given from Randomisation to EOS/ET. During the 
screening period, subject may receive the calcium and vitamin D at the discretion of the Investigator. 
If hypocalcaemia or hypercalcemia occurs, the Investigator can modify dietary intake of calcium and 
adjust the calcium and/or vitamin D dosage if needed. In such cases, the change should be reported in 
the eCRF and hypocalcaemia or hypercalcemia reported as an AE if clinically significant. 
Intolerance to the non-IP can occur, especially for calcium. Calcium intolerance can manifest as bloating 
or constipation. The formulation and/or dose frequency (e.g., dose divided two times a day) can be 
changed to reduce intolerance and increase compliance by the Investigator’s discretion. 
If intolerance continues after lowering the dose, temporarily discontinuation can be considered. 
Permanent discontinuation of calcium and/or vitamin D should be discussed with the Sponsor. 
Investigator should document in source data. 
On the day of baseline PD measurement (Month 0), calcium intake is not allowed before the PD blood 
sampling. 
Vitamin D and calcium supplements will be made available at the investigational sites. The Sponsor 
will not provide these supplementations, but they will be reimbursed if required. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 41 of 90 
 Permitted and Prohibited Concomitant Medication or Treatment 
5.4.1. Permitted Concomitant Medications or Treatment 
Any other procedures or medications except for prohibited concomitant medications or treatments that 
are considered necessary for the subject’s welfare, and that are not expected to interfere with the 
evaluation of the IP may be given at the Investigator’s discretion. 
5.4.2. Prohibited Concomitant Medications, Procedures or Treatments 
The following medications will be prohibited during the study period. 

Xgeva®

Drugs used for osteoporosis: Including but not limited to romosozumab, bisphosphonates,
SERM, hormone replacement therapy, tibolone, PTH and its analogues, calcitonin, fluoride,
and strontium
-
During the study period, non-systemic vaginal oestrogen treatment is permitted at the
Investigator’s discretion if clinically needed for the treatment.

Drugs that affect bone metabolism: Including but not limited to androgens, aromatase
inhibitors, calcitriol, adrenocorticotropic hormone, growth hormone-releasing hormone,
gonadotropin-releasing hormone, corticosteroids, calcimimetics (cinacalcet and etelcalcetide),
aluminium, lithium, heparin (including unfractionated heparin and low molecular weight
heparins), warfarin, phenytoin, primidone, carbamazepine, phenobarbital, valproate,
oxcarbazepine, topiramate, barbiturate, protease inhibitors, methotrexate, chemotherapeutic
agents, cyclosporine, tacrolimus, and prescribed vitamin K
-
During the study period, inhaled or topical glucocorticoid is permitted at the Investigator’s
discretion if clinically needed for the treatment.

Any kind of monoclonal antibodies or fusion receptor protein
Planned invasive dental procedures (e.g., dental implants or oral surgery) and major surgeries or bone 
surgeries (unless required for AE/SAE management) are prohibited during the study period. 
6. Study Assessment
Efficacy Assessment
6.1.1. Bone Mineral Density 
BMD of lumbar spine (L1 to L4), total hip, and femoral neck will be measured at Screening, prior to 
dosing at Months 6, 12, and EOS/ET. BMD will be measured only by either GE Lunar or Hologic 
machines. 
Site staffs who will perform BMD measurement in this study must read and understand the image 
acquisition guideline before performing study procedure. Only DXA devices certified by the central 
reading centre are allowed to be used in this study. If one or more DXA devices are certified in an 
investigational site, a subject is strongly recommended to be scanned on the same DXA machine at all 
follow up timepoints and not switch between scanners. If a scanner switch (e.g., due to breakdown) or 
repair (hardware or software) should occur due to unforeseen reasons the imaging vendor needs to be 
immediately notified prior to the change or as soon as possible. The replacement machine should be 
from the same manufacturer consistently from Screening to EOS/ET. Scanning of subjects on DXA 






SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 44 of 90 
 
The Investigator should assess all 12-ECG and any clinically significant abnormality must be recorded 
on the eCRF as either medical history or AE as appropriate (see Section 8). 
6.2.5. Vital Signs 
Vital signs include blood pressure, heart rate, and body temperature. Vital signs will be assessed at 
Screening, and prior to dosing at Months 0, 6, and 12, Months 0.5, 1, 3, and 9, and EOS/ET. 
The Investigator should assess all vital signs and any clinically significant abnormalities must be 
recorded on the eCRF as either medical history or AE as appropriate (see Section 8). 
 Pharmacodynamic Assessment 
Blood sample for PD assessment will be taken at prior to dosing at Months 0, 6, and 12. Also, blood 
samples will be taken at Months 0.5, 1, 3, and 9, and EOS/ET. 
Blood sample for CTX and P1NP assessment should be collected after fasting for at least 8 hours and 
during the morning hours. 
In all cases, the exact date and time of the PD sampling and IP administration must be carefully recorded 
in the source documents and eCRF. Detail instructions of handling, storage, and shipment for PD 
samples are described in the laboratory manual. 
The Sponsor or its designated representative will store PD samples after the end of the clinical study 
for the maximum 10 years in order to have the possibility to repeat the assay already performed (e.g., 
re-analysis requested by regulatory authorities or failure of first analysis). Subjects’ samples may be 
used for method validation and/or investigation, only for this study. 
 Other Assessments 
6.4.1. Pharmacokinetic Assessment 
Blood sample for PK assessment will be taken in all randomised subjects at prior to dosing at Months 
0, 6, and 12. Also, blood samples will be taken at Months 0.5, 1, 3, and 9, and EOS/ET. 
In all cases, the exact date and time of the PK sampling and IP administration must be carefully recorded 
in the source documents and eCRF. Detail instructions of handling, storage, and shipment for PK 
samples are described in the laboratory manual. 
The Sponsor or its designated representative will store PK samples after the end of the clinical study 
for the maximum 10 years in order to have the possibility to repeat the assay already performed (e.g., 
re-analysis requested by regulatory authorities or failure of first analysis). Subjects’ samples may be 
used for method validation and/or investigation, only for this study. 
6.4.2. Immunogenicity Assessment 
Blood sample for immunogenicity assessment will be taken in all randomised subjects at prior to dosing 
at Months 0, 6, and 12. Also, blood samples will be taken at Months 0.5, 1, 3, and 9, and EOS/ET. 
In all cases, the exact date and time of the immunogenicity sampling and IP administration must be 
carefully recorded in the source documents and eCRF. Detail instructions of handling, storage, and 
shipment for immunogenicity samples are described in the laboratory manual. 
The Sponsor or its designated representative will store immunogenicity samples after the end of the 
clinical study for the maximum 10 years in order to have the possibility to repeat the assay already 
performed (e.g., re-analysis requested by regulatory authorities or failure of first analysis). Subjects’ 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 45 of 90 
 
samples may be used for method validation and/or investigation, only for this study. 
6.4.3. Spine X-ray 
Lateral thoracic and lumbar spine X-rays assessment will be done at Screening to determine any 
potential exclusions due to vertebral fractures as determined by Genant scoring. A detailed instruction 
for spine X-ray assessment will be provided in the image acquisition guideline. 
7. Study Procedures 
 Study Flow and Visit Schedule 
During this study, all procedures and assessments will be performed at time points specified in the 
Schedule of Activities (Table 1). Detail instructions of collecting, processing, storing, and shipping for 
blood and urine samples are described in the laboratory manual. All results should be recorded in the 
source documents along with the date and time the procedures were performed. 
7.1.1. Screening (Day ‒28 to Day ‒1) 
Screening shall be performed within 28 days before Randomisation (i.e. excluding the day of 
Randomisation). 
All subjects must provide written informed consent prior to any study related procedures being 
performed. 
 
Written informed consent 
The following procedures should be performed: 
 
Demographic information 
 
Medical and surgical history 
 
12-lead ECG 
- 
12-lead ECG should be measured prior to both the vital sign assessment and the blood 
sampling 
 
Vital signs 
- 
Vital sign should be measured prior to the blood sampling being performed. 
 
Physical examination 
 
Height and weight 
 
Serum FSH (optional), PTH, TSH, and virology markers (Hepatitis B and C virology [HBsAg 
and HCV Ab]) 
 
Haematology, biochemistry tests, and urinalysis (dipstick) 
 
Lateral spine X-ray (lumbar and thoracic) 
 
BMD (lumbar, total hip, and femoral neck) 
 
Serum vitamin D (25-hydroxyvitamin D) 
 
Previous and concomitant medications 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 46 of 90 
 
 
AEs 
 
Eligibility assessment 
If the subject is not randomised within 28 days after signing the ICF, the subject must be screen failed. 
Clinical laboratory test for eligibility review will not be allowed for re-test unless any technical error 
(e.g., missing value due to sample mishandling) was found. 
Exceptionally, in subjects who are not eligible only due to vitamin D deficiency, serum vitamin D can 
be re-tested only once after vitamin D repletion and re-test result will be used for eligibility review. 
Additional 28 days will be allowed to those subjects. In this case if the subject is not randomised within 
56 days after signing the ICF, the subject must be screen failed. To avoid repetition of unnecessary 
procedures, screening procedures previously performed other than vitamin D re-test will not be repeated 
in this case. 
During the screening period, subject may receive the calcium and vitamin D at the discretion of the 
Investigator. 
Re-scanning of DXA or lateral spine X-ray during the study period is not allowed except for cases where 
it has been confirmed that the image is not evaluable by the central imaging centre due to quality issue. 
Once the subject is confirmed eligible for the study, the subject will be reminded in particular of the 
study restrictions such as prohibited medications and other study requirements. The Investigator shall 
pay attention to each subject’s particular needs in order to provide the necessary training and advice 
and foster protocol compliance. 
7.1.2. Treatment Period 
7.1.2.1. Visit 1 (Month 0) 
The following procedures should be performed: 
✓ Eligibility assessment 
✓ Randomisation 
 
Randomisation must proceed after all screening procedures and eligibility confirmation. 
✓ Prior to dosing 
 
Vital signs 
- 
Vital sign should be measured prior to the blood sampling being performed. 
 
Physical examination 
 
Weight 
 
Haematology, biochemistry tests, and urinalysis (dipstick) 
 
Blood sampling for PK assessment 
 
Blood sampling for immunogenicity assessment 
 
Blood sampling for PD assessment 
- 
Blood sample for CTX and P1NP should be collected in the morning hours after fasting 
for at least 8 hours. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 47 of 90 
 
- 
On the day of baseline PD measurement (Month 0), calcium should not be given before 
the PD blood sampling. 
✓ IP administration 
 
SB16 and Prolia® will be subcutaneously administered 
✓ Post dosing 
 
Monitoring for injection site reaction 
✓ Any time regardless of IP dosing 
 
Concomitant medications 
 
AEs 
 
Instruction for non-IP supplementation 
7.1.2.2. Visit 2 (Month 0.5 ± 3 Days) 
Month 0.5 is 15 days after Month 0. 
The following procedures should be performed: 
 
Vital signs 
- 
Vital sign should be measured prior to the blood sampling being performed. 
 
Physical examination 
 
Weight 
 
Haematology, biochemistry tests, and urinalysis (dipstick) 
 
Blood sampling for PK assessment 
 
Blood sampling for immunogenicity assessment 
 
Blood sampling for PD assessment 
- 
Blood sample for CTX and P1NP should be collected in the morning hours after fasting 
for at least 8 hours. 
 
Concomitant medications 
 
AEs 
 
Instruction for non-IP supplementation 
7.1.2.3. Visit 3 (Month 1 ± 3 Days) 
Month 1 is 30 days after Month 0. 
The following procedures should be performed: 
 
Vital signs 
- 
Vital sign should be measured prior to the blood sampling being performed. 
 
Physical examination 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 48 of 90 

Weight

Haematology, biochemistry tests, and urinalysis (dipstick)

Blood sampling for PK assessment

Blood sampling for immunogenicity assessment

Blood sampling for PD assessment
-
Blood sample for CTX and P1NP should be collected in the morning hours after fasting
for at least 8 hours.

Concomitant medications

AEs

Instruction for non-IP supplementation
7.1.2.4. Visit 4 (Month 3 ± 7 Days) 
Month 3 is 91 days after Month 0. 
The following procedures should be performed: 

Vital signs
-
Vital sign should be measured prior to the blood sampling being performed.

Physical examination

Weight

Haematology, biochemistry tests, and urinalysis (dipstick)

Blood sampling for PK assessment

Blood sampling for immunogenicity assessment

Blood sampling for PD assessment
-
Blood sample for CTX and P1NP should be collected in the morning hours after fasting
for at least 8 hours.

Concomitant medications

AEs

Instruction for non-IP supplementation
7.1.2.5. Visit 5 (Month 6 ± 7 Days) 
Month 6 is 182 days after Month 0. 
The following procedures should be performed: 
✓
Prior to dosing

Vital signs
-
Vital sign should be measured prior to the blood sampling being performed.


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 49 of 90 
 
 
Physical examination 
 
Weight 
 
Haematology, biochemistry tests, and urinalysis (dipstick) 
 
BMD (lumbar, total hip, and femoral neck) 
 
Serum vitamin D (25-hydroxyvitamin D) 
 
Blood sampling for PK assessment 
 
Blood sampling for immunogenicity assessment 
 
Blood sampling for PD assessment 
- 
Blood sample for CTX and P1NP should be collected in the morning hours after fasting 
for at least 8 hours. 
✓ IP administration 
 
SB16 and Prolia® will be subcutaneously administered 
✓ Post dosing 
 
Monitoring for injection site reaction 
✓ Any time regardless of IP dosing 
 
Concomitant medications 
 
AEs 
 
Instruction for non-IP supplementation 
7.1.2.6. Visit 6 (Month 9 ± 7 Days) 
Month 9 is 273 days after Month 0. 
The following procedures should be performed: 
 
Vital signs 
- 
Vital sign should be measured prior to the blood sampling being performed. 
 
Physical examination 
 
Weight 
 
Haematology, biochemistry tests, and urinalysis (dipstick) 
 
Blood sampling for PK assessment 
 
Blood sampling for immunogenicity assessment 
 
Blood sampling for PD assessment 
- 
Blood sample for CTX and P1NP should be collected in the morning hours after fasting 
for at least 8 hours. 
 
Concomitant medications 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 50 of 90 
 
 
AEs 
 
Instruction for non-IP supplementation 
7.1.2.7. Visit 7 (Month 12 ± 7 Days) 
Month 12 is 364 days after Month 0. 
The following procedures should be performed: 
✓ Prior to dosing 
 
Vital signs 
- 
Vital sign should be measured prior to the blood sampling being performed. 
 
Physical examination 
 
Weight 
 
Haematology, biochemistry tests, and urinalysis (dipstick) 
 
BMD (lumbar, total hip, and femoral neck) 
 
Serum vitamin D (25-hydroxyvitamin D) 
 
Blood sampling for PK assessment 
 
Blood sampling for immunogenicity assessment 
 
Blood sampling for PD assessment 
- 
Blood sample for CTX and P1NP should be collected in the morning hours after fasting 
for at least 8 hours. 
 
Eligibility assessment 
✓ Randomisation 
 
Subjects receiving Prolia® will be re-randomised in a 1:1 ratio to either continue to receive 
Prolia® or be transitioned to SB16. Subjects receiving SB16 will continue to receive SB16 up 
to Month 18 but they will also follow the randomisation procedure to maintain blinding. 
✓ IP administration 
 
SB16 and Prolia® will be subcutaneously administered 
✓ Post dosing 
 
Monitoring for injection site reaction 
✓ Any time regardless of IP dosing 
 
Concomitant medications 
 
AEs 
 
Instruction for non-IP supplementation 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 51 of 90 
 
7.1.3. End of Study Visit (Month 18 ± 7 Days) 
EOS (Month 18) is 546 days after Month 0. 
Following discontinuation of IP administration, increased fracture risk can be expected, including the 
risk of multiple vertebral fractures. This risk should be informed to the subject and next treatment will 
be decided at EOS at the Investigator discretion to prevent loss of bone mass and/or risk of fractures. 
The following procedures should be performed: 
 
Vital signs 
- 
Vital sign should be measured prior to the blood sampling being performed. 
 
Physical examination 
 
Weight 
 
Haematology, biochemistry tests, and urinalysis (dipstick) 
 
BMD (lumbar, total hip, and femoral neck) 
 
Blood sampling for PK assessment 
 
Blood sampling for immunogenicity assessment 
 
Blood sampling for PD assessment 
- 
Blood sample for CTX and P1NP should be collected in the morning hours after fasting 
for at least 8 hours. 
 
Concomitant medications 
 
AEs 
7.1.4. Early Termination Visit (6 Months from the Last Investigational Product Dosing ± 7 Days) 
Subjects who withdraw from the study before EOS will be asked to return to the investigational site for 
the ET procedures to be performed at 6 months from the last IP dose. Following discontinuation of IP 
administration, increased fracture risk can be expected, including the risk of multiple vertebral fractures. 
This risk should be informed to the subject and next treatment will be decided at ET at the Investigator 
discretion to prevent loss of bone mass and/or risk of fractures. 
The following procedures should be performed: 
 
Vital signs 
- 
Vital sign should be measured prior to the blood sampling being performed. 
 
Physical examination 
 
Weight 
 
Haematology, biochemistry tests, and urinalysis (dipstick) 
 
BMD (lumbar, total hip, and femoral neck) 
 
Blood sampling for PK assessment 
 
Blood sampling for immunogenicity assessment 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 52 of 90 
 
 
Blood sampling for PD assessment 
- 
Blood sample for CTX and P1NP should be collected in the morning hours after fasting 
for at least 8 hours. 
 
Concomitant medications 
 
AEs 
7.1.5. Unscheduled Visit 
Unscheduled visit is allowed during study period at the discretion of the Investigator, if deemed 
clinically necessary for the subject’s safety. Any tests, procedures, or assessments performed at the 
unscheduled visits must be recorded in the source documents and be entered in the eCRF if entry is 
available. If a subject is discontinued from the study during unscheduled visit and subject refused ET 
visit, it should be recorded in the eCRF. 
 Discontinuation 
7.2.1. Discontinuation of Subjects 
Subject must be discontinued from the study permanently in the event of any of the following: 
 
Consent withdrawal by subject 
- 
If a subject withdraws her consent, the Investigator must inquire the reasons for consent 
withdrawal as to whether it is related to the study (e.g., AE); however, the subject could 
refuse to provide such reason 
- 
If the main reason for consent withdrawal is considered related to the study, the Investigator 
may select appropriate reason among the reasons listed below other than consent 
withdrawal 
 
Death 
 
Unacceptable toxicity that makes subject study participation impossible, agreed by the 
Investigator (e.g., osteonecrosis of jaw or serious hypersensitivity reactions to denosumab) 
 
Protocol deviations that may affect the subject’s safety seriously and/or integrity of data 
(including ineligibility) agreed by the Investigator (e.g., IP dosing out of visit window or using 
prohibited medication during the study period) 
 
Lack of efficacy or disease progression (e.g., decrease of BMD or osteoporotic fracture) that 
requires change of osteoporosis drug, agreed by the Investigator 
 
Lost to follow-up 
 
Unblinding of treatment arm to subject or investigator 
 
The Investigator’s discretion for any other reason 
If a subject is prematurely discontinued from IP after the first IP dose, the subject will complete the ET 
procedures. 
If the subject refused ET visit, it should be recorded in the eCRF. In all cases, the reason for IP 
discontinuation must be recorded in the eCRF and in the subject’s medical record. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 53 of 90 
 
7.2.2. Discontinuation of Study Sites 
Study site participation may be discontinued if Sponsor, the Investigator, or the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) of the study site judges it necessary for any reason. 
Health authorities and IRB/IEC will be informed about the discontinuation of the study in accordance 
with applicable regulations. 
7.2.3. Discontinuation of the Study 
The Sponsor may terminate this study prematurely, for reasonable cause provided that written notice is 
submitted in advance of the intended termination: 
 
Poor enrolment of subjects making completion of the study within acceptable time frame 
 
Discontinuation of development of the study drug 
 
The decision by the Sponsor to terminate the study based on medical/ethical, business decision, 
or study conduct-related reasons 
If the study is terminated or discontinued prematurely, the Sponsor will promptly notify to the 
Investigator. Investigator may be informed of additional procedures to be followed in order to assure 
that adequate consideration is given to the protection of the subject’s interests. 
Health authorities and IRB/IEC will be informed about the discontinuation of the study in accordance 
with applicable regulations. 
8. Safety Monitoring and Reporting 
 Adverse Events 
8.1.1. Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered 
the medicinal (investigational) product or other protocol-imposed intervention and which does not 
necessarily have to have a causal relationship with this treatment or intervention. An AE can therefore 
be an unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of any dose of a medicinal (investigational) product or other 
protocol-imposed intervention regardless of attribution. 
All AEs during the period of observation (as specified in Section 8.1.2) including the events that 
occurred prior to administration of an IP should be reported as an AE in the AE section of the eCRF. 
Pre-existing conditions which worsen (i.e., increase in severity) that meet the definition of an AE during 
the study are to be reported as AEs. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should be 
reported if it meets the definition of an AE. For example, an acute appendicitis that begins during the 
AE reporting period should be reported as an AE and the resulting appendectomy should be recorded 
as treatment of the AE. 
The AEs that emerge during treatment with an IP (i.e. treatment-emergent AE [TEAE]) will be analysed 
for the purposes of safety analyses. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 54 of 90 
 
8.1.1.1. Clinically Significant Abnormality 
If there are any abnormalities discovered during the laboratory test, physical examination, vital signs, 
and/or other safety assessments and the abnormality is assessed clinically significant by the 
Investigator, it should be reported as an AE. This does not apply to pre-existing conditions which 
have been documented at Screening or if the abnormality is consistent with a current diagnosis 
(underlying disease or other AEs). If it is not specified or defined elsewhere in the protocol, clinically 
significant abnormality may include the events that led to an intervention, including withdrawal of 
the IP treatment, dose reduction, significant additional concomitant medication, and others evaluated 
as clinically significant by the Investigator. 
If a clinically significant clinical laboratory or other abnormality from safety assessment is not a sign 
of a disease or syndrome, the abnormality itself should be reported as an AE in the eCRF. If the 
abnormality can be characterised by a precise clinical term, the clinical term should be reported as the 
AE. For example, an elevated serum potassium level of 7.0 mEq/L should be reported as 
‘hyperkalaemia’. 
Observations of the same clinically significant abnormality from visit to visit should not be repeatedly 
reported as AEs in the eCRF, unless their severity, seriousness, or aetiology changes. 
8.1.2. Period of Observation for Adverse Events 
AEs will be collected from the time of signing the written informed consent until the EOS/ET. SAEs 
will be collected until 6 months after the last IP dose or EOS/ET, whichever longer.  
If the subject would withdraw before receiving the first dose of IP, AEs and SAEs should be collected 
up until the time the subject withdraws. 
Unresolved AEs should be followed until AE resolution or stabilisation, or until the EOS/ET, 
whichever comes first. 
If the subject has an unresolved SAE or AESI at the EOS/ET, these cases will be followed until event 
resolution or stabilisation (see Section 8.2.2). 
8.1.3. Reporting Adverse Events 
AEs are to be reported in the eCRF and reviewed by the Investigator. When reporting an AE, a 
diagnosis (when possible and appropriate) rather than each individual sign and symptom should be 
reported. 
Each AE is to be assessed to determine if it meets the criteria of an SAE (see Section 8.2.1 for SAE 
definition). If an AE is classified as an SAE, it must be reported to Sponsor, or its designated 
representative, promptly according to the timeline specified in Section 8.2.2. For an SAE, a diagnosis 
with a description of signs and symptoms as well as other supporting information that led to the 
diagnosis should be described in the SAE form provided to the Sponsor, or its designated representative 
(see Section 8.2.2.). 
8.1.4. Severity Assessment 
The Investigator is responsible for assessing and reporting the severity of AEs. 
Following classifications should be used to classify AEs: 
 
Mild events are usually transient and do not interfere with the subject’s daily activities, 
 
Moderate events introduce a low level of inconvenience or concern to the subject and may 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 55 of 90 
 
interfere with daily activities, 
 
Severe events interrupt the subject’s usual daily activities. 
8.1.5. Causality Assessment 
The Investigator is responsible for assigning a causal relationship to each AE. The causal relationship 
between the IP and/or non-IP and the AE should be defined as not related (no) or related (yes). 
Events should be classified as ‘related’ if there is a reasonable possibility that the IP and/or non-IP 
caused the AE. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
Events should be classified as ’not related’ if there is no reasonable possibility that the IP and/or non-
IP caused the AE. 
8.1.6. Expectedness Assessment 
Expectedness of AEs will be assessed by referring to the safety information in the Investigator’s 
brochure of the relevant safety section, if deemed necessary. More detailed information on 
expectedness assessment will be explained in the Investigator’s brochure. 
8.1.7. Withdrawal due to Adverse Events 
Subject withdrawal from the study due to an AE should be distinguished from withdrawal due to 
personal reasons and recorded on the appropriate eCRF section. Subjects withdrawn due to an AE 
should be followed up until the time point specified in the Section 8.1.2. When a subject withdraws 
from the study due to an SAE, the SAE must be reported and followed in accordance with the 
requirements outlined in Section 8.2.2. 
Subjects who discontinue the administration of IPs because of serious or significant safety issues 
should be followed closely until the events are fully and permanently resolved or stabilised. 
 Serious Adverse Events 
8.2.1. Definition of Serious Adverse Event 
An SAE is any untoward medical occurrence at any dose that: 
 
Results in death, 
 
Is life-threatening, 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, 
 
Results in persistent or significant disability/incapacity, 
 
Results in congenital anomaly/birth defects, 
 
Is medically important. 
Medical and scientific judgement 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 hospitalisation. However, if it is determined that the event may 
jeopardise the subject and may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021
Samsung Bioepis – Confidential and Proprietary Information 
Page 56 of 90 
or convulsions that do not result in hospitalisation or development of drug dependency or drug abuse. 
The term ‘severe’ is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as ‘serious’, which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to a subject’s 
life or functioning. 
8.2.1.1. Life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
8.2.1.2. Hospitalisation 
AEs reported from clinical studies associated with inpatient hospitalisation or prolongations of 
hospitalisation are considered serious. Staying at an observation unit in the emergency room for more 
than 24 hours qualifies for hospitalisation. Any events leading to subsequent emergency room visit 
for less than 24 hours should be in the discretion of Investigator to assess serious as medically 
important. 
Hospitalisation or prolongation of hospitalisation in the absence of a precipitating clinical AE is not 
in itself an SAE. Examples include: 

Admission for treatment of a pre-existing condition (prior to ICF signed) not associated with
the development of a new AE or with a worsening of the pre-existing condition (e.g., for work-
up of persistent pre-treatment lab abnormality),

Social admission for convenience (e.g., admission of a subject who does not have a carer),

Administrative admission (e.g., for a yearly physical exam),

Protocol-specified admission during a clinical 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).
Pre-planned treatments or surgical procedures should be noted in the screening documentation for the 
individual subject. 
8.2.2. Reporting Serious Adverse Events 
All SAEs must be reported to the Sponsor or its designated representative via eCRF SAE report form 
at least within 24 hours of the Investigator becoming aware of the event. A paper SAE form can be 
used as backup in every case when the eCRF would not be available. 
In particular, if the SAE is fatal or life-threatening, Sponsor must be notified immediately, irrespective 
of the extent of available AE information. This timeframe also applies to additional (follow-up) 
information that becomes available on previously forwarded SAE reports. Sponsor will then follow 
expedited reporting procedures according to local and international regulations as appropriate. 
The Investigator is obligated to pursue and provide information to Sponsor on all SAEs in accordance 
with the timeframes for reporting specified above. In addition, an Investigator may be requested by 
Sponsor to obtain specific additional follow-up information in an expedited fashion. This information 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 57 of 90 
 
may be more detailed than that captured on eCRF. In general, this will include a description of the 
SAE, which should be provided in sufficient detail so as to allow for a complete medical assessment 
of the case and independent determination of possible causality. Information on other possible causes 
of the event, such as concomitant medications and illnesses must be provided. In the case of a subject 
death, a summary of available autopsy findings must be submitted as soon as possible to Sponsor or 
its designated representative. 
All unresolved SAEs will be followed until event resolution or stabilisation (for chronic events), if 
possible, even when a subject is withdrawn from treatment. For chronic events that do not fully 
resolve until years later, the outcome should be reported as ‘resolved with sequelae’ as soon as the 
event has stabilised or returned to baseline. Follow-up information for the SAE should be actively 
sought and submitted as the information becomes available. 
 Adverse Events of Special Interest 
The following AEs will be classified as AESIs in this study: 
 
Hypocalcaemia 
 
Hypersensitivity to IP 
 
Osteonecrosis of the jaw 
 
Atypical femoral fractures 
 
Skin infections 
8.3.1. Hypocalcaemia 
It is important to identify subjects at risk for hypocalcaemia. Clinical monitoring of calcium levels 
will be done at each pre-defined visit. If any subject presents with suspected symptoms of 
hypocalcaemia during the study, calcium levels should be measured. Subjects should be encouraged 
to report symptoms indicative of hypocalcaemia. 
8.3.2. Hypersensitivity 
Hypersensitivity reactions to denosumab including rash, urticaria, facial swelling, erythema, and 
anaphylactic reactions have been reported. If a hypersensitivity reaction to denosumab occurs, 
appropriate treatment should be given. If serious hypersensitivity reactions such as anaphylaxis occur, 
the IP should be permanently discontinued. 
8.3.3. Osteonecrosis of the Jaw 
Osteonecrosis of the jaw is generally associated with tooth extraction and/or local infection with 
delayed healing and has been reported with denosumab use. All subjects will be enrolled after 
assessing subjects’ oral health by the Investigator and should be encouraged to maintain good oral 
hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental 
mobility, prolonged pain involving jaw or gingival swelling or non-healing ulcers or discharge during 
treatment with denosumab. Discontinuation of IP should be considered. 
8.3.4. Atypical Femoral Fractures 
Atypical femoral fractures have been reported in patients receiving denosumab. Atypical femoral 
fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the 
femur. Specific radiographic findings characterise these events. Atypical femoral fractures have also 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 58 of 90 
 
been reported in patients with certain co-morbid conditions (e.g., vitamin D deficiency, rheumatoid 
arthritis, and hypophosphatasia) and with use of certain pharmaceutical agents (e.g., bisphosphonates, 
glucocorticoids, and proton pump inhibitors). These events have also occurred without antiresorptive 
therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore, 
the contralateral femur should be examined in denosumab-treated patients who have sustained a 
femoral shaft fracture. 
Discontinuation of the IP in subjects suspected to have an atypical femur fracture should be 
considered depending evaluation of the subject based on an individual benefit-risk assessment. 
During denosumab treatment, subjects should be advised to report new or unusual thigh, hip, or groin 
pain. Subjects presenting with such symptoms should be evaluated for an incomplete femoral 
fracture. 
8.3.5. Skin infections 
Patients receiving denosumab may develop skin infections (predominantly cellulitis) leading to 
hospitalisation. Skin infections leading to hospitalisation will be separately reported as well. Subjects 
should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis. 
 Unblinding of Assigned Treatment 
Unblinding should be considered only when knowledge of the treatment assignment is deemed essential 
for the subject’s safety by their Investigator or a regulatory body. Emergency unblinding should be 
decided based on the medical decision by Investigator considering subjects’ safety. In general, 
unblinding of subjects during the conduct of the clinical study should only be performed where there 
are compelling medical or safety reasons to do so. The responsibility to break the treatment code in 
emergency situations resides solely with the Investigator. The IWRS will be used to break the blind and 
details on how to do this are provided in the IWRS manual.  
The Sponsor must be notified immediately after a subject and/or the investigator is unblinded during 
the course of the study along with the reason for breaking the blind. Pertinent information regarding the 
circumstances of unblinding of a subject’s treatment code must be documented in the subject’s source 
documents. This includes who performed the unblinding, the subject(s) affected, the reason for the 
unblinding, the date of the unblinding and the relevant IP information. In case failure of unblinding 
through IWRS system, the Investigator will follow the manual unblinding process described in IWRS 
manual. 
 Independent Data and Safety Monitoring Board 
An independent DSMB will be assigned for this study. The DSMB will consist of external experts 
and will review the safety and tolerability data from the study at pre-specified intervals. The details 
of the safety data and time points for review will be described in the DSMB Charter and in the DSMB 
statistical analysis plan (SAP). 
In addition, an ongoing blinded review of AEs, including clinical laboratory data will be continuously 
undertaken by the Sponsor medical monitor and project safety monitor. 
9. Statistical Methods and Data Analysis 
Further information on the statistical methods for this study will be provided in the SAP, which will be 
finalised prior to the database lock for reporting the final clinical study report (CSR). 
Statistical analysis and reporting will be performed as follows: 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 59 of 90 
 
 
Interim safety analysis for independent DSMB meeting 
- 
A DSMB SAP, describing the methodology and presentation of results and access to results 
will be prepared as a separate document. The safety reports for the DSMB data review 
meetings will be prepared according to the DSMB SAP. 
- 
The statistical analysis will be performed by an independent statistical reporting team and 
the results will be communicated to the DSMB directly by an independent unblind 
statistician. 
 
Final CSR 
- 
The final analysis will take place after the last subject completes the procedures at Month 
18 or the corresponding visit. All study data will be analysed and reported for the final CSR. 
 Statistical Hypotheses 
This is a study to demonstrate equivalence, in terms of percent change from baseline in lumbar spine 
BMD at Month 12 between SB16 and Prolia®. The null hypothesis tested for the primary efficacy 
analysis is that either (1) SB16 is inferior to Prolia® or (2) SB16 is superior to Prolia® based on a pre-
specified equivalence margin. 
 Analysis Sets 
The following sets will be used for the analyses performed in the study: 
 
Randomised Set (RAN) consists of all subjects who have received a randomisation number. 
 
Full Analysis Set (FAS) consists of all RAN subjects. Following the intent-to-treat principle, 
subjects will be analysed according to the treatment group they are assigned at Randomisation. 
However, subjects who do not have any lumbar spine BMD assessment result after 
Randomisation by accident and do not receive any IP during the study period will be excluded 
from this analysis set. 
 
Per-Protocol Set (PPS) consists of all FAS subjects who have lumbar spine BMD assessment 
results at baseline and Month 12 without any major protocol deviations that have impact on 
the lumbar spine BMD assessment results. Major protocol deviations may include deviations 
from inclusion/exclusion criteria, withdrawal criteria, IP compliance, concomitant medication, 
and study procedure. Major protocol deviations that will lead to exclusion from this set will 
be pre-defined using the final version of merged protocol deviation list prior to unblinding the 
treatment group assignment for analyses. 
 
Safety Set (SAF1) consists of all subjects who receive at least one IP. Subjects will be analysed 
according to the treatment received. 
 
Safety Set for the Transition period (SAF2) consists of all subjects in the SAF1 who receive 
IP after re-randomisation at Month 12. Subjects will be analysed according to the treatment 
received. 
 
PK Analysis Set (PKS) consists of all subjects in the SAF1 who have at least one PK sample 
analysed. 
 
PD Analysis Set (PDS) consists of all subjects in the SAF1 who have at least one CTX or 
P1NP sample analysed. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 60 of 90 
 
 Subject Demographic and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarised by treatment group for the RAN. 
Continuous variables (e.g., age, weight, height) will be summarised with descriptive statistics (n, mean, 
standard deviation, median, minimum, maximum) and categorical variables (e.g., gender, race, and 
ethnicity) will be summarised with frequency and percentage. 
Comparison between treatment groups in demographics and baseline characteristics will be performed 
using the chi-square test or F-test as appropriate. The results of these tests will be provided including 
the p-value only for descriptive purposes and will not be used as a formal basis to determine the factors 
to be included in primary or secondary efficacy analysis models. If baseline imbalances are detected for 
any of the factors, additional analyses may be performed to adjust for these baseline differences. 
Relevant medical history, and continuing medical conditions will be summarised by treatment group 
for the RAN. 
 Analysis of the Primary Objective 
The primary efficacy analysis will aim to demonstrate equivalence in terms of percent change from 
baseline in lumbar spine BMD at Month 12 between SB16 and Prolia®. 
For the EMA, Korea Ministry of Food and Drug Safety (MFDS), and other regulatory submissions, the 
primary efficacy analysis will be performed for the PPS using an analysis of covariance with the 
baseline value of lumbar spine BMD as a covariate and treatment group as factor. The equivalence will 
be declared if the two-sided 95% CI of the mean difference in percent change from baseline in lumbar 
spine BMD at Month 12 between SB16 and Prolia® lies within the pre-defined equivalence margin of 
[−2.0%, 2.0%]. To conduct the sensitivity analysis for the FAS, missing data will be imputed using 
multiple imputation method for subjects who drop out for the study prior to the primary analysis time 
point under the assumption of missing at random. Available case analysis will also be performed for the 
FAS. 
For the US FDA submission, the primary efficacy analysis will be performed for the FAS using an 
analysis of covariance with the baseline value of lumbar spine BMD as a covariate and treatment group 
as factor. The equivalence will be declared if the two-sided 90% CI of the mean difference in percent 
change from baseline in lumbar spine BMD at Month 12 between SB16 and Prolia® lies within the pre-
defined equivalence margin of [−1.45%, 1.45%]. Missing data will be imputed using multiple 
imputation method for subjects who drop out for the study prior to the primary analysis time point. For 
sensitivity analysis, available case analysis will be performed for the FAS and the same analysis will be 
repeated for the PPS. 
No formal adjustment of Type I error rates will be performed. 
 Analysis of the Secondary Objectives 
9.5.1. Efficacy Analyses 
As the secondary efficacy endpoint, percent change from baseline in BMD (lumbar spine, total hip, and 
femoral neck) will be analysed similarly to the primary endpoint. 
9.5.2. Safety Analyses 
Safety analyses will be performed for Main period, Transition period, and overall study period unless 
specified otherwise. Analyses for Main and Transition period will be performed in the SAF1 and SAF2 
respectively and analyses for the overall study period will be performed in the SAF1. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 61 of 90 
 
All reported terms for AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA®). For all AE and SAE tables, subjects will be counted once for each preferred term and each 
system organ class. 
A TEAE will be defined as any AE with an onset date on or after the date of the initiation of study drug. 
AEs which are already present before the initiation of study drug and increase in severity after the 
initiation of study drug will be considered as TEAEs. Pre-existing AEs before the initiation of study 
during with no increase in severity after the initiation of study drug will not be considered as TEAEs. 
All TEAEs and SAEs will be summarised by the frequency and percentage of subjects experiencing 
events by system organ class, preferred term, and treatment group. SAEs leading to IP discontinuation 
and TEAEs by causality and severity will be summarised similarly. All AEs including those pre-existing 
before the initiation of study drug will be listed by subject. 
Changes in vital signs and clinical laboratory parameters will be summarised descriptively by treatment 
group and visit. Other safety variables will be summarised unless otherwise specified, and all safety 
variables will be listed. 
Duration of exposure to IP and number of subcutaneous injections will be summarised descriptively by 
treatment group for the SAF1. Prior and concomitant medications will be summarised by treatment 
group with frequency and percentage. 
9.5.3. Pharmacokinetic and Pharmacodynamic Analyses 
PK analyses will be performed for the PKS. Serum drug concentration will be summarised descriptively 
by treatment group and visit. 
PD analyses will be performed for the PDS. Serum CTX and P1NP concentrations will be summarised 
descriptively by treatment group and visit. 
In addition, the AUEC0-M6 of percent change from baseline in serum CTX will be analysed using an 
analysis of variance model. 
9.5.4. Immunogenicity Analyses 
Immunogenicity analyses will be performed for the SAF1 and SAF2. ADA and NAb results will be 
summarised with frequency and percentage by treatment group and visit. In addition, incidence of 
overall ADA will be summarised by treatment group. 
 Sample Size Calculations 
The equivalence margin for the mean difference of percent change from baseline in lumbar spine BMD 
at Month 12 is derived from 3 historical studies with Prolia®. In denosumab Phase II study, mean 
(standard error) percent change from baseline in lumbar spine BMD at Month 12 is 4.55% (0.47) and ‒
0.81% (0.48) for denosumab and placebo arms, respectively. [1] FREEDOM study reported the mean 
percent change from baseline as 5.5% and 0.0%, [2] and in Bone study, mean percent change from 
baseline is 4.4% and ‒0.5% for denosumab and placebo arms, respectively. [3] 
A meta-analysis estimates 5.35% of mean percent change from baseline in lumbar spine BMD at Month 
12 with 95% CI of [4.83%, 5.87%]. For the EMA submission, 40% of lower limit of 95% CI was 2.0%, 
which implies that approximately 60% treatment effect is obtained to preserve the treatment effect over 
placebo, and this margin is corresponds to the EMA’s recommendation. For the US FDA submission, 
1.45% which is 30% of lower limit of 95% CI was chosen to preserve approximately 70% of the 
treatment effect over placebo per the US FDA’s recommendation. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 62 of 90 
 
With the given equivalence margin of [‒2.0%, 2.0%] for the EMA submission, 140 subjects per 
treatment group was calculated with the assumptions of no mean difference, common standard deviation 
of 5.13 at the overall 5% significance level. Assuming a 15% loss from randomised subjects after 12 
months, a sample size of 165 subjects per treatment group (overall sample size of 330) will give 140 
completers per treatment group after 12 months, which is estimated to give 80% power to detect the 
equivalence within the margin of [‒2.0%, 2.0%]. 
With the given equivalence margin of [‒1.45%, 1.45%] for the US FDA submission, 216 subjects per 
treatment group was calculated with the assumptions of no mean difference, common standard deviation 
of 5.13 at the overall 10% significance level. Overall sample size of 432 is estimated to give 80% power 
to detect the equivalence within the margin of [‒1.45%, 1.45%]. 
Therefore, the sample size of 432 allows enough power to detect the equivalence in both situations. 
10. Data Collection and Management 
 Data Confidentiality 
Study information will be labelled with a code number, and will not include the subject’s name, hospital 
number or other information that could identify them. A list linking the code and the subject’s name 
will be kept in the site files as required by ICH E6 (R2) Good Clinical Practice (GCP). 
The coded information will be sent to the Sponsor (or designee) who will analyse it and report the study 
results both to regulatory and ethical authorities. The Sponsor may also place data on public websites 
or publish journal articles based upon these results. Care will be taken to prevent subjects being 
identified through these publications. In addition, data may be shared with other companies or 
researchers to aid further research. Such data sharing practices will be covered by confidentiality 
agreements. No-one outside the investigator site will have access to subject-identifiable information. 
 Monitoring 
The Sponsor has engaged the services of a CRO to perform all monitoring functions within this clinical 
study. The monitors will work in accordance with the CRO standard operating procedures (SOPs) and 
have the same rights and responsibilities as monitors from the Sponsor organisation. Monitors will 
establish and maintain regular contact between the Investigator and the Sponsor. 
Monitors will verify adherence to the protocol at the Investigator site. All protocol deviations will be 
reported to the Sponsor. Monitors will arrange for the supply of IP and ensure appropriate storage 
conditions are maintained. 
Monitoring visits will be conducted at regular intervals according to ICH E6 (R2) GCP. The monitor 
will provide written reports to the Sponsor on each occasion they contact the Investigator regardless of 
whether it is by phone or in person. 
Further details on the monitoring processes and the level of source data verification to be performed 
will be outlined in the monitoring plan. 
 Data Handling and Record Keeping 
The Investigator must maintain essential study documents (protocol and protocol amendments, 
completed eCRFs, signed ICFs, relevant correspondence, and all other supporting documentation) until 
at least 2 years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years after the formal 
discontinuation of clinical development of the IP, or whichever longer according to the relevant local 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 63 of 90 
 
laws and/or regulation. These documents should be retained for a longer period if required by the 
applicable regulatory requirements or the hospital, institution or private practice in which the study is 
being conducted. Subject identification codes (subject names and corresponding study numbers) will 
be retained for the same period of time. These documents may be transferred to another responsible 
party, deemed acceptable by the Sponsor, and who agrees to abide by the retention policies. Written 
notification of transfer must be submitted to the Sponsor. The Investigator must contact the Sponsor 
prior to disposing of any study records and obtain written permission to do so. 
 Future Use of Stored Specimens and Data 
The Sponsor or designated representative can store PK, PD, and/or immunogenicity samples for the 
maximum 10 years after the end of the clinical study. The Sponsor or designated representative should 
operate under the same regulations related to and take the same responsibility to save personal data. 
The sample may be used for additional assay to be performed if considered scientific relevant or 
requested by regulatory authorities in order to have the possibility to perform the assay. 
 Database Management and Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the data 
management and biostatistics departments of the Sponsor (or an appropriate company designated by 
the Sponsor to perform these activities). Subject data will be captured in an eCRF and reviewed by the 
monitor in order to check adherence to the protocol and to detect any data inconsistency or discrepancy. 
The Investigator must ensure that the clinical data required by the study protocol are carefully reported 
in the eCRF. He/she must also check that the data reported in the eCRF correspond to those in the 
medical records. 
Data must be entered into eCRFs in English by the designated investigator site personnel in a timely 
manner. Forms should be available during periodic visits by study monitors to enable review for 
completeness and acceptability. Any correction to the data entered into the eCRF must be carried out 
by the Investigator or a designated member of staff. These changes may be made either on the initiative 
of the site staff or in response to monitoring or data queries. Any changes to written data must be made 
using ICH E6 (R2) GCP corrections and any change to electronic data should be made in a system 
which can provide an audit trail. Monitors and clinical data managers will review the eCRF for accuracy 
and can generate queries to the investigational staff for resolution. Corrections will be recorded in an 
audit trail that records the old information, the new information, and identification of the person making 
the changes, date of correction made and reason for change. The Investigator must sign and date the 
eCRF pages as indicated. 
Medical/surgical history and underlying diseases and AEs will be coded using the MedDRA®. 
Concomitant medications will be coded using the WHO-Drug Dictionary. The versions of coding 
dictionaries used will be stated in the CSR. 
 Quality Control and Quality Assurance 
During the conduct of the study, the Sponsor or its agent will conduct periodic monitoring visits to 
ensure that the protocol and ICH E6 (R2) GCP are being followed. The monitors may review source 
documents to confirm that the data recorded are accurate. The Investigator and institution will allow the 
domestic and foreign regulatory authorities and the authorised representative of the Sponsor including 
monitors and auditors’ direct or remote access to source documents to perform this verification without 
violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations. 
The investigational site may be subject to review by the IRB/IEC, and/or to quality assurance audits 
performed by the Sponsor, and/or to inspection by appropriate regulatory authorities. It is important that 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 64 of 90 
 
the Investigators and their relevant personnel are available during the monitoring visits and possible 
audits and/or regulatory inspections and that sufficient time is devoted to the process. 
 Protocol Deviation 
Protocol deviations will be pre-defined prior to subject enrolment and documented separately named as 
‘Protocol Deviation Definition List’ which includes category (e.g., violation of inclusion/exclusion 
criteria, use of prohibited medication, and non-compliance with treatment), deviation description, 
severity (major or minor), time point for each protocol deviation. Major protocol deviations are defined 
as those deviations from the protocol likely to have an impact on the perceived efficacy and/or safety 
of study treatments. 
Protocol deviations will be reviewed and confirmed prior to database lock to decide which subjects 
and/or subject data will be excluded from certain analyses. Decisions regarding the exclusion of subjects 
and/or subject data from analyses will be documented and approved prior to database lock. 
11. Ethics Considerations and Administrative procedures 
 Institutional Review Boards and Independent Ethics Committees 
The Investigator and the Sponsor will follow all local laws and regulations relating to contact with and 
approvals from the IRB/IEC. 
The Investigator must provide the Sponsor with documentation of IRB/IEC approval of the protocol 
and informed consent before the study may begin at the Investigator site. The Investigator will supply 
documentation to the Sponsor relating to the annual renewal of the protocol from the IRB/IEC and any 
approvals of revisions to the ICF or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC any new information that may adversely affect 
the safety of subjects or the conduct of the study. Similarly, the Investigator will submit written 
summaries of the study status to the IRB/IEC on a regular basis and in accordance with the timelines 
required locally. Upon completion of the study, the Investigator will provide the ethics committee with 
a report on the outcome of the study if required by local regulations. 
 Ethical Conduct of the Study 
This study will be conducted and informed consent will be obtained from each subject according to the 
ethical principles stated in the Declaration of Helsinki (2013), the applicable guidelines for ICH E6 (R2) 
GCP and the applicable drug and data protection laws and regulations of the countries where the study 
will be conducted. 
 Subject Information and Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the subject in simple 
terms before the subject enters into the study. The ICF contains a statement that the consent is freely 
given, that the subject is aware of the risks and benefits of entering the study, and that the subject is free 
to withdraw from the study at any time. Written consent must be given by the subject and/or legal 
representative, after the receipt of detailed information on the study. 
The Investigator is responsible for ensuring that informed consent is obtained from each subject or legal 
representative and for obtaining the appropriate signatures and dates on the ICF prior to the performance 
of any protocol procedures and prior to the administration of IP. The Investigator will provide each 
subject with a copy of the signed and dated ICF and this will be documented in the subject’s source 
notes. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 65 of 90 
 
 Investigator Information 
11.4.1. Investigator Obligations 
This study will be conducted in accordance with the ICH E6 (R2) GCP (2016), the ethical principles 
that have their origin in the Declaration of Helsinki (2013) and local laws and regulations. 
The Investigator is responsible for ensuring that the study is conducted according to the signed 
Investigator statement, the study protocol and applicable regulations; for protecting the rights, safety, 
and welfare of subjects under the Investigator’s care; and for the control of drugs under investigation. 
The Investigator must obtain the informed consent of each subject to whom IP is administered. 
11.4.2. Training of Investigator Site Personnel 
Before the first subject is enrolled into the study, a Sponsor representative will review and discuss the 
requirements of the clinical study protocol and related documents with the investigational staff and will 
also train them in any study-specific procedures. 
The Investigator will ensure that appropriate training relevant to the study is given to all investigational 
site staff and that any new information relevant to the performance of this study is forwarded to the 
investigational staff involved. 
The Investigator will maintain a record of all individuals involved in the study (medical, nursing, and 
other investigational staff). 
11.4.3. Protocol Signatures 
The Investigator must sign the Investigator Signature Page of this protocol prior to starting recruitment 
for the study. By signing the protocol, the Investigator confirms in writing that he/she has read, 
understands and will strictly adhere to the study protocol and will conduct the study in accordance with 
ICH E6 (R2) GCP and applicable regulatory requirements 
11.4.4. Coordinating Investigator 
The Sponsor will designate the Coordinating Investigator who will have the responsibility for the 
coordination of the Investigators in a multicentre clinical study. 
11.4.5. Financing and Insurance 
Samsung Bioepis Co., Ltd. is the Sponsor of this study and will support the financial aspects for the 
study conduct at the investigational site. Details of financial agreements are provided in the Clinical 
Study Agreements with the Investigator sites and in contracts with other companies involved in study 
operations. 
The Sponsor has obtained suitable insurance for this study. A copy of the insurance details will be 
provided to each Investigator who will be responsible for providing the IRB/IEC with these details 
according to local requirements. 
12. Publication Policy 
The Sponsor supports the efforts of health authorities to increase the transparency of medical research 
conducted in human subjects. The Sponsor will register and maintain the information of clinical studies 
on a public registry program. The Sponsor is committed to the public disclosure of the results from 
clinical studies through posting on public clinical study data banks. The Sponsor will comply with the 
guidelines of regulatory authorities with regards to public registration and disclosure of clinical study 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 66 of 90 
 
data. 
The clinical study data collected during the study are confidential and proprietary to the Sponsor. 
Sponsor shall have the right to delete any confidential or proprietary information contained in any 
proposed abstract or presentation. 
Any publications from this study should be approved by the Sponsor prior to publication or presentation. 
The rights of the Investigator with regard to publication of this study are described in the Clinical Study 
Agreement. 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 67 of 90 
 
13. References 
1. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low 
bone mineral density. N Engl J Med. 2006; Feb 23;354(8):821-31. 
2. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in 
postmenopausal women with osteoporosis. N Engl J Med. 2009; Aug 20;361(8):756-65. 
3. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab on bone mineral density and bone 
turnover in postmenopausal women. J Clin Endocrinol Metab. 2008; Jun;93(6):2149-57. 
4. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J 
Med. 1993; Jun;94(6):646-50. 
5. Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019; 393(10169):364–376. 
6. Odén A, McCloskey EV, Johansson H, et al. Assessing the impact of osteoporosis on the burden of 
hip fractures. Calcif Tissue Int. 2013; Jan;92(1):42-9. 
7. Guideline on the evaluation of medicinal products in the treatment of primary osteoporosis. EMA. 
(Nov 16, 2006). CPMP/EWP/552/95 Rev. 2. Retrieved Mar 31, 2020 from 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-medicinal-
products-treatment-primary-osteoporosis en.pdf 
8. Prescribing Information of Prolia®. FDA. (Apr 23, 2020). Retrieved Apr 15, 2021 from 
https://www.accessdata.fda.gov/drugsatfda docs/label/2020/125320s205lbl.pdf 
9. Summary of Product Characteristics of Prolia®. EMA. (Dec 04, 2020) Retrieved Apr 15, 2021 from 
https://www.ema.europa.eu/en/documents/product-information/prolia-epar-product-
information en.pdf 
10. Prescribing Information of Xgeva®. FDA. (Jun 09, 2020). Retrieved Apr 15, 2021 from 
https://www.accessdata.fda.gov/drugsatfda docs/label/2020/125320s203lbl.pdf 
11. Summary of Product Characteristics of Xgeva®. EMA. (Aug 07, 2020) Retrieved Apr 15, 2021 
from 
https://www.ema.europa.eu/en/documents/product-information/xgeva-epar-product-
information en.pdf 
12. Guideline on similar biological medicinal products containing biotechnology-derived protein as 
active 
substance: 
non-clinical 
and 
clinical 
issues. 
EMA. 
(Dec 
18, 
2014). 
EMEA/CHMP/BMWP/42832/2005 Rev1. Retrieved Mar 31, 2020 from 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-
medicinal-products-containing-biotechnology-derived-proteins-active en-2.pdf 
13. Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference 
product. FDA. (Apr 2015). Retrieved Mar 31, 2020 from 
https://www.fda.gov/media/82647/download 
14. Guideline on similar biological medicinal products containing biotechnology-derived proteins as 
active 
substance: 
quality 
issues 
(revision 
1). 
EMA. 
(May 
22, 
2014). 
EMA/CHMP/BWP/247713/2012. Retrieved Mar 31, 2020 from 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-
medicinal-products-containing-biotechnology-derived-proteins-active en-0.pdf 


SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 68 of 90 
 
15. Guideline on similar biological medicinal products containing monoclonal antibodies: non-clinical 
and clinical studies. EMA. (May 30, 2012). EMA/CHMP/BMWP/403543/2010. Retrieved Mar 31, 
2020 
from 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-
biological-medicinal-products-containing-monoclonal-antibodies-non-clinical en.pdf 
 
 




SB16 (proposed denosumab biosimilar) 
SB16-3001 
Version 2.0, May 03, 2021 
 
Samsung Bioepis – Confidential and Proprietary Information 
Page 70 of 90 
 
 
 
SIGNATURE PAGE 
 
Declaration of the Principal Investigator 
Protocol Title: A Phase III, Randomised, Double-blind, Multicentre Clinical Study to Compare the 
Efficacy, Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity between SB16 (proposed 
denosumab biosimilar) and Prolia® in Postmenopausal Women with Osteoporosis 
This clinical study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational medicinal product, as well as 
with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration 
of Helsinki, 2013 and the guidelines on Good Clinical Practice applicable to this clinical study. 
Principal Investigator 
Name: 
 
Institution: 
 
Signature: 
 
Date: 
 
 
 
 
(MMM DD, YYYY) 









































SAP_001.pdf: 
SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 1 of 63 
 
 
 
 
 
Clinical Study Report (CSR) 
Statistical Analysis Plan 
 
A Phase III, Randomised, Double-blind, Multicentre Clinical Study to 
Compare the Efficacy, Safety, Pharmacokinetics, Pharmacodynamics, and 
Immunogenicity between SB16 (proposed denosumab biosimilar) and 
Prolia in Postmenopausal Women with Osteoporosis 
 
 
 
 
 
 
Protocol Number 
SB16-3001 
Study Phase 
Phase III 
Type of analysis 
Clinical Study Report 
Authors 
, Biostatistics Lead, Parexel 
 
 Biostatistics Lead, Samsung 
Version and Effective Date 
Version 1.0 
  Jan 31, 2023 
 
 
This document contains confidential information belonging to Samsung Bioepis Co., Ltd.  
Your acceptance or review of this document constitutes agreement that you will not copy 
or disclose the information contained herein to others or use it for unauthorised purposes 
without written authorization from the Sponsor. 
 




SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 3 of 63 
 
TABLE OF CONTENTS 
Modification History ........................................................................................................................... 2 
List of Tables ....................................................................................................................................... 5 
List of Abbreviations ........................................................................................................................... 6 
1. 
Introduction .............................................................................................................................. 8 
2. 
Study Objectives ....................................................................................................................... 8 
2.1. 
Primary Objective ................................................................................................................. 8 
2.2. 
Secondary Objectives ........................................................................................................... 8 
2.3. 
Sample Size Calculation ....................................................................................................... 8 
3. 
General Considerations .......................................................................................................... 10 
3.1. 
Analysis Sets ....................................................................................................................... 11 
3.2. 
Protocol Deviations............................................................................................................. 13 
3.3. 
Disposition and Withdrawals .............................................................................................. 13 
3.4. 
Study Day ........................................................................................................................... 14 
3.5. 
Baseline ............................................................................................................................... 15 
3.6. 
Retests, Unscheduled Visits and Early Termination Data and Analysis Visit Mapping .... 15 
3.7. 
Common Calculations ......................................................................................................... 17 
3.8. 
Software Version ................................................................................................................ 18 
4. 
Statistical Considerations ....................................................................................................... 18 
4.1. 
Multicentre Studies ............................................................................................................. 18 
4.2. 
Missing Data ....................................................................................................................... 18 
4.3. 
Multiple Comparisons/Multiplicity .................................................................................... 18 
4.4. 
Active-Control Studies Intended to Show Equivalence ...................................................... 18 
4.5. 
Examination of Subgroups .................................................................................................. 19 
5. 
Demographic and Other Baseline Characteristics .................................................................. 19 
6. 
Medical and Surgical History ................................................................................................. 21 
7. 
Efficacy, Pharmacokinetic and Pharmacodynamic Analyses ................................................. 22 
7.1. 
Primary Efficacy Analysis .................................................................................................. 23 
7.1.1. 
Analysis of Primary Efficacy Endpoint .......................................................................... 23 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 4 of 63 
 
7.1.2. 
Missing Data Imputation Methods of Primary Efficacy Endpoint .................................. 24 
7.1.3. 
Sensitive Analysis of Primary Efficacy Endpoint ........................................................... 25 
7.1.4. 
Supportive Analysis of Primary Efficacy Endpoint ........................................................ 26 
7.2. 
Secondary Efficacy Analysis .............................................................................................. 26 
7.3. 
Exploratory Efficacy Analysis ............................................................................................ 26 
7.4. 
Pharmacokinetic Analysis ................................................................................................... 27 
7.5. 
Pharmacodynamic Analysis ................................................................................................ 28 
7.5.1. 
CTX and P1NP Concentration ........................................................................................ 29 
7.5.2. 
Pharmacodynamic Parameters ........................................................................................ 29 
8. 
Safety Analysis ....................................................................................................................... 30 
8.1. 
Study Medication Exposure ................................................................................................ 30 
8.2. 
Prior/Concomitant Medications and Procedures ................................................................ 31 
8.3. 
Prohibited Medications and Procedures .............................................................................. 32 
8.4. 
Laboratory Evaluations ....................................................................................................... 32 
8.5. 
Vital Signs and Weight ....................................................................................................... 35 
8.6. 
Immunogenicity Analysis ................................................................................................... 35 
8.7. 
Other Observations Related to Safety ................................................................................. 37 
9. 
Adverse Events ....................................................................................................................... 37 
10. 
References .............................................................................................................................. 43 
APPENDIX 1. PARTIAL DATE CONVENTIONS ..................................................................... 44 
APPENDIX 2. LABORATORY TEST PARAMETERS ............................................................. 48 
APPENDIX 3. NOMRAL RANGE FOR VITAMIN D IN KOREAN SITES ........................... 50 
APPENDIX 4. WORST CASE OF LABORATORY PARAMETERS ...................................... 51 
APPENDIX 5. CTCAE V5.0 GRADING FOR LABORATORY VALUES .............................. 52 
APPENDIX 6. PROHIBITED MEDICATIONS AND PROCEDURES .................................... 55 
APPENDIX 7. VISIT NAME ......................................................................................................... 60 
APPENDIX 8. SAMPLE CODES FOR PRIMARY ANALYSIS ............................................... 61 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGES ............................................................ 63 
 
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 5 of 63 
 
LIST OF TABLES 
Figure 1 Graphical Study Design .......................................................................................... 10 
Table 1: Analysis Visit Window for Haematology, Biochemistry, Urinalysis, Vital Signs, 
Weight, Anti-drug Antibody (ADA), and Neutralising Antibody (NAb) ..................... 15 
Table 2: Analysis Visit Window for Vitamin D ................................................................. 16 
Table 3: Analysis Visit Window for BMD ......................................................................... 16 
Table 4: Analysis Visit Window for PD and PK ................................................................ 17 
Table 5: Parameters for Clinical Laboratory Tests ............................................................. 32 
Table 6: Clinically Significant Abnormal Criteria of Vital Signs ...................................... 35 
 
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 6 of 63 
 
LIST OF ABBREVIATIONS 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
AUEC 
Area Under the Effect Curve 
AUEC0-M6 
Area Under the Effect Curve from time zero to Month 6 
BLQ 
Below the Limit of Quantification 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease 2019 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
C-telopeptide of Type I Collagen 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
ENR 
Enrolled Set 
EOS 
End of Study 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GE 
General Electric 
HBsAG 
Hepatitis B Virus Surface Antigen 
HCV-Ab 
Hepatitis C Virus Antibody 
HLT 
High Level Term 
ICF 
Informed Consent Form 
IE 
Intercurrent Event 
IP 
Investigational Product 
IQC 
Instrument Quality Control 
IWRS 
Interactive Web Response Systems 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 7 of 63 
 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFDS 
Ministry of Food and Drug Safety 
MNAR 
Missing Not at Random 
NAb 
Neutralising Antibody 
P1NP 
Procollagen Type I N-terminal Propeptide 
PD  
Pharmacodynamic(s) 
PDS 
Pharmacodynamic Analysis Set 
PK 
Pharmacokinetic(s) 
PKS 
Pharmacokinetic Analysis Set 
PMO 
Postmenopausal Osteoporosis 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
PTH 
Parathyroid Hormone 
QTc 
corrected QT interval 
RAN 
Randomised Set 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SI units 
International System of Units 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States of America 
WHO 
World Health Organisation 
Xcal 
Cross-calibration 
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 8 of 63 
 
1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analyses of 
efficacy, safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity data for 
Protocol SB16-3001. It describes the data to be summarised and analysed, including specifics of the 
statistical analyses to be performed. This Statistical Analysis Plan (SAP) is based on the Protocol 
version 2.0, dated May 03, 2021. 
The CSR SAP will be used for the final analysis after database lock. All efficacy, safety, PK, PD, and 
immunogenicity data will be analysed and reported for the final CSR. 
2. STUDY OBJECTIVES 
2.1. Primary Objective 
The primary objective of this study is to demonstrate the equivalence of SB16 to Prolia, in terms of 
percent change from baseline in lumbar spine bone mineral density (BMD) at Month 12 in 
postmenopausal osteoporosis (PMO). 
2.2. Secondary Objectives 
The secondary objectives are: 
• 
To evaluate the efficacy of SB16 compared to Prolia by 
- 
Percentage change from baseline in lumbar spine BMD 
- 
Percentage change from baseline in total hip BMD 
- 
Percentage change from baseline in femoral neck BMD 
• 
To evaluate the safety and tolerability of SB16 compared to Prolia  
• 
To evaluate the PK profile of SB16 compared to Prolia  
• 
To evaluate the PD profile of SB16 compared to Prolia  
• 
To evaluate the immunogenicity of SB16 compared to Prolia  
• 
To evaluate the safety, tolerability, immunogenicity, PK, PD, and efficacy in subjects with 
PMO who transitioned to SB16 from Prolia compared to subjects who maintained Prolia 
from the main period 
2.3. Sample Size Calculation 
The equivalence margin for the mean difference of percent change from baseline in lumbar spine 
BMD at Month 12 is derived from 3 historical studies with Prolia. In denosumab Phase II study, mean 
(standard error) percent change from baseline in lumbar spine BMD at Month 12 is 4.55% (0.47) and 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 9 of 63 
 
0.81% (0.48) for denosumab and placebo arms, respectively.[1] FREEDOM study reported the mean 
percent change from baseline as 5.5% and 0.0%,[2] and in Bone study, mean percent change from 
baseline is 4.4% and ‒0.5% for denosumab and placebo arms, respectively.[3] 
A meta-analysis estimates 5.35% of mean percent change from baseline in lumbar spine BMD at 
Month 12 with 95% confidence interval (CI) of [4.83%, 5.87%]. For the European Medicines Agency 
(EMA) submission, 40% of lower limit of 95% CI was 2.0%, which implies that approximately 60% 
treatment effect is obtained to preserve the treatment effect over placebo, and this margin is 
corresponds to the EMA’s recommendation. For the United States of America (US) Food and Drug 
Administration (FDA) submission, 1.45% which is 30% of lower limit of 95% CI was chosen to 
preserve approximately 70% of the treatment effect over placebo per the US FDA’s recommendation. 
With the given equivalence margin of [‒2.0%, 2.0%] for the EMA submission, 140 subjects per 
treatment group was calculated with the assumptions of no mean difference, common standard 
deviation (SD) of 5.13 at the overall 5% significance level. Assuming a 15% loss from randomised 
subjects after 12 months, a sample size of 165 subjects per treatment group (overall sample size of 
330) will give 140 completers per treatment group after 12 months, which is estimated to give 80% 
power to detect the equivalence within the margin of [‒2.0%, 2.0%].  
With the given equivalence margin of [‒1.45%, 1.45%] for the US FDA submission, 216 subjects per 
treatment group was calculated with the assumptions of no mean difference, common SD of 5.13 at 
the overall 10% significance level. Overall sample size of 432 is estimated to give 80% power to 
detect the equivalence within the margin of [‒1.45%, 1.45%]. 
Therefore, the sample size of 432 allows enough power to detect the equivalence in both situations. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 10 of 63 
 
3. GENERAL CONSIDERATIONS 
Figure 1 Graphical Study Design 
 
ICF = informed consent form; ® = Randomisation; n = number of subjects; IP = investigational product; BMD = bone 
mineral density; PK = pharmacokinetic; PD = pharmacodynamic; EOS = end of study 
1 Informed consent should be obtained prior to any study related procedures. 
2 At Month 12, subjects receiving Prolia will be randomised in a 1:1 ratio to either continue to receive Prolia or be 
transitioned to SB16. Subjects receiving SB16 will continue to receive SB16 up to Month 18 but they will also follow the 
randomisation procedure to maintain blinding. 
All summaries by period defined in the SAP refers to the analysis period. The analysis period consists 
of the main, transition and overall study periods; each period is defined as below:  
Main period starts from the first administration of Investigational Product (IP) at Month 0 (including 
IP administration time), or starts from the randomisation for subject who do not receive IP at Month 0, 
ends prior to the administration of IP at Month 12 post re-randomisation (excluding IP administration 
time) for subjects treated post re-randomisation, ends at re-randomisation date for discontinued 
subject without receiving IP at Month 12, or ends at Early Termination (ET) visit (study 
discontinuation decision date, when ET visit is not conducted) for subjects discontinued prior to re-
randomisation.  
Transition period starts from the administration of IP at Month 12 post re-randomisation (including IP 
administration time), or starts from the post re-randomisation for subject who do not receive IP at 
Month 12, ends at End of Study (EOS)/ET visit (study discontinuation decision date, when ET visit is 
not conducted). 
Overall study period starts from the first administration of IP at Month 0 (including IP administration 
time), or starts from the randomisation for subject who do not received IP at Month 0, ends at 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 11 of 63 
 
EOS/ET visit (study discontinuation decision date, when ET visit is not conducted). 
For the summaries of the main period, the treatment group refers to the treatment assigned at 
Month 0 or received during the main period, labelled as follows: 
• 
SB16  
• 
Prolia 
 
For the summaries of the transition period, the treatment group refers to the treatment assigned at 
Month 12 or received during the transition period, labelled as follows: 
• 
SB16+SB16 
• 
Prolia Overall (Prolia+SB16 / Prolia+Prolia) 
• 
Prolia+SB16 
• 
Prolia+Prolia 
 
For the overall study period, summary will be provided for the following overall treatment groups. 
• 
SB16 (SB16* / SB16+SB16) 
• 
Prolia Overall (Prolia* / Prolia+SB16 / Prolia+Prolia) 
• 
Prolia+SB16 
• 
Prolia+Prolia 
 
For analysis using planned treatment group (e.g Full Analysis Set, Per-Protocol set), SB16* or Prolia* 
means subjects initially randomised to SB16 or Prolia and early terminated before re-randomisation at 
Month 12. 
For analysis using actual treatment group (e.g Safety Set 1), SB16* or Prolia* means subjects initially 
received to SB16 or Prolia and early terminated before receiving IP at Month 12, including subjects 
who were re-randomised and not treated at Month 12. 
Treatment groups for the listing will be presented as below: 
• 
SB16 
• 
SB16+SB16 
• 
Prolia 
• 
Prolia+SB16 
• 
Prolia+Prolia 
3.1. Analysis Sets 
The following sets will be used for the analyses performed in the study: 
• 
Enrolled Set (ENR) consists of all subjects who provide informed consent for this study. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 12 of 63 
 
• 
Randomised Set (RAN) consists of all subjects who have received a randomisation number. 
• 
Full Analysis Set (FAS) consists of all RAN subjects. Subjects will be analysed according to the 
treatment assigned at randomisation. However, subjects who do not have any lumbar spine BMD 
assessment result after randomisation by accident and do not receive any IP during the study 
period will be excluded from this analysis set. 
• 
Per-Protocol Set (PPS) consists of all FAS subjects who have lumbar spine BMD assessment 
results at baseline and Month 12 without any major protocol deviations that have impact on the 
lumbar spine BMD assessment results. Major protocol deviations may include deviations from 
inclusion/exclusion criteria, withdrawal criteria, IP compliance, concomitant medication, and 
study procedure. Major protocol deviations that will lead to exclusion from this set will be pre-
defined using the final version of merged protocol deviation list prior to unblinding the treatment 
group assignment for analyses. Subjects meeting of following criteria will be excluded from PPS 
as well even if it’s not captured as a protocol deviation: 
a. Lumbar spine BMD assessment (+/- 14 days) at Month 12 (including ET visit mapping to 
Month 12, when subject discontinued before Month 12) is out of visit window 
• 
Safety Set 1 (SAF1) consists of all subjects who receive at least one IP. Subjects will be analysed 
according to the treatment received. 
• 
Safety Set 2 (SAF2) consists of all subjects in the SAF1 who receive IP after re-randomisation at 
Month 12. Subjects will be analysed according to the treatment received. 
• 
Pharmacokinetic Analysis Set (PKS) consists of all subjects in the SAF1 who have at least one 
PK sample analysed.  
• 
Pharmacodynamic Analysis Set (PDS) consists of all subjects in the SAF1 who have at least one 
C-telopeptide of Type I Collagen (CTX) or Procollagen type I N-terminal Propeptide (P1NP) 
sample analysed without any major protocol deviations that have an impact on the 
pharmacodynamic results. Definition of PDS is revised from the definition specified in the 
protocol since some major protocol deviations impact the serum CTX and P1NP results. These 
subjects will not be included in PDS. 
The number of subjects in the analysis sets will be summarised by overall treatment group for the 
RAN. A by-subject listing of analysis population details will be provided for the RAN by treatment 
group and will include country, centre, subject identifier, inclusion/exclusion flag for each analysis set 
and reason for exclusion from PPS and PDS. 
A by-subject listing of allocation to treatment consisting of randomisation number, treatment 
allocation and randomised date for main and transition periods respectively will be provided for the 
RAN. A listing of allocation to treatment will be also provided by centre for the RAN. A listing of 
allocation to treatment in transition period will be provided by centre for the RAN. 
A listing of allocated IPs information consisting Interactive Web Response Systems (IWRS) 
dispensed medication ID, treatment and lot number, actual medication ID, treatment and lot number 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 13 of 63 
 
will be provided for the RAN. 
3.2. Protocol Deviations 
Protocol deviations will be pre-defined prior to subject enrolment and documented separately named 
as Protocol Deviation Definition List which includes classification (e.g., violation of 
inclusion/exclusion criteria, use of prohibited medication, non-compliance with study procedure), 
deviation description, severity (major or minor), and time point for each protocol deviation. Major 
protocol deviations are defined as those deviations from the study protocol likely to have an impact on 
the perceived efficacy and/or safety of study treatments. Protocol deviations that are a result of 
Coronavirus Disease 2019 (COVID-19) will be identified in the DV (protocol deviation) domain 
through protocol deviation categories of COVID-19. This will allow the reporting of the protocol 
deviations related to COVID-19 in the Study Data Tabulation Model (SDTM) datasets. 
Protocol deviations and analysis sets will be reviewed and confirmed prior to database lock to decide 
which subjects and/or subject data will be excluded from certain analyses. Decisions regarding the 
exclusion of subjects and/or subject data from analyses will be documented and approved prior to 
database lock. 
A summary of the number and percentage of subjects with protocol deviation by protocol deviation 
severity (major and minor), and protocol deviation classification will be presented by main treatment 
group for the RAN. The summary of protocol deviation will be also provided by centre and main 
treatment group. The summary of COVID-19 related protocol deviation will be presented by main 
treatment group. 
A by-subject listing of protocol deviations will be provided by treatment group including subject 
identifier, visit, protocol deviation classification, protocol deviation description, protocol deviation 
severity, exclusion from analyses set (Yes/No) for the RAN. Additionally, a by-subject listing of 
COVID-19 related protocol deviations will be provided by treatment group. 
3.3. Disposition and Withdrawals 
Subject Disposition 
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
enrolment to study completion. The subject disposition summaries by overall treatment group include 
the following: 
• 
A summary of the number of enrolled subjects, the number and percentage of screen failures and 
major reasons for screening failures, using the ENR. Subjects with multiple screening records will 
be counted once as a unique subject based on the latest screening result. For re-screened subjects 
who subsequently deemed ineligible, the latest screening failure reason will be counted. 
• 
A summary of the number of subjects randomised at Month 0, received treatment (at least one 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 14 of 63 
 
dose of IP), completed, discontinued from main period of study, with the primary reason for study 
discontinuation before Month 12 and relationship to COVID-19, using the RAN. 
Completion of the main period is defined as completion of required assessment prior to re-
randomisation at Month 12 visit. 
- 
If a subject is re-randomised at Month 12, the subject is considered as having completed 
the main period. 
- 
If a subject is discontinued without re-randomisation at Month 12, neither completing 
Month 12 assessment, the subject is considered as having discontinued during the main 
period. 
- 
If a subject is discontinued without re-randomisation at Month 12, but completed 
Month 12 BMD assessment, either at scheduled or ET visit, the subject is considered as 
having completed the main period. 
• 
A summary of the number of subjects re-randomised at Month 12, received treatment, completed, 
discontinued from transition period, with the primary reason for study discontinuation and 
relationship to COVID-19, using the RAN. The completion of transition period is defined as 
completion of Month 18 visit. 
The summary of subject disposition above will be also provided by country and overall treatment 
group. 
• 
A by-subject listing of subject disposition will be generated using the ENR, including the primary 
reasons of study discontinuation or screening failure, and the first/last date of IP administration, 
and relationship with COVID-19 for study discontinuation. 
Visit not performed/ window deviation (including relatedness to COVID-19) 
• 
Subjects with planned visit not done, primary reason for visit not done including relatedness to 
COVID-19 will be summarised using the RAN by visit and the overall treatment group. 
• 
Subjects with planned visit window deviation and primary reason for visit window deviation will 
be summarised using the RAN by visit and the overall treatment group. 
• 
A by-subject listing of planned visits not done, visit window deviation will be generated using the 
RAN, including primary reasons not done, primary reasons for visit window deviation, and 
relatedness to COVID-19 for not done. 
3.4. Study Day 
Study day will be calculated from the first IP dosing date. Study day of the first IP dosing date will be 
Day 1.  
• 
If the date of interest is on or after the first IP dosing date, then: 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 15 of 63 
 
Study Day = (date of interest – first IP dosing date) + 1 
• 
If the date of interest is prior to the first IP dosing date, then: 
Study Day = (date of interest – first IP dosing date) 
When the date of interest is partial or missing, study day will be calculated after proper imputation as 
described in APPENDIX 1 and the date of interest will appear as partial date along with the calculated 
study day in the listing. 
3.5. Baseline 
Baseline value will be defined as the last available measurement value recorded prior to first IP 
administration. Per protocol, on the first IP dosing date, the prior to dosing assessment is the last 
planned measurement prior to IP administration. Serum vitamin D (25-hydroxyvitamin D) has no 
planned measurement on the first IP dosing date (Month 0), therefore unscheduled serum vitamin D 
assessment on the first IP dosing date is considered as prior dosing assessment. For subjects who have 
been randomised but not treated with any IP, the randomisation date will be used as the reference date 
for baseline value calculation. 
3.6. Retests, Unscheduled Visits and Early Termination Data and Analysis Visit 
Mapping 
In general, the measurements collected at the scheduled visit will be presented in the by-visit 
summaries. 
Measurements collected at ET visit will be mapped to the scheduled visit according to the analysis 
visit window for different measurement. Measurement of Haematology, Biochemistry, Urinalysis, 
vital signs, weight, and immunogenicity follows Table 1. BMD measurement follows Table 3. PD and 
PK measurement follow Table 4. If ET measurement allocates to a visit without a scheduled 
measurement, ET measurement will be considered for analysis by visit. If ET measurement allocates 
to a visit with existing scheduled measurement, ET measurement will not be considered for analysis 
by visit. By-subject listings will display the ET visit without mapping. 
Table 1: Analysis Visit Window for Haematology, Biochemistry, Urinalysis, Vital Signs, 
Weight, Anti-drug Antibody (ADA), and Neutralising Antibody (NAb) 
Study Analysis Visit 
Target 
Study Day 
Time Interval (Study Day) 
Start 
End 
Month 0 
Day 1 
1 
1 
Month 0.5 
Day 16 
2 
23 
Month 1 
Day 31 
24 
61 
Month 3 
Day 92 
62 
137 
Month 6 
Day 183 
138 
IP administration at 
Month 6 (if available)* 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 16 of 63 
 
Study Analysis Visit 
Target 
Study Day 
Time Interval (Study Day) 
Start 
End 
Month 9 
Day 274 
IP administration at 
Month 6 (if available)* 
319 
Month 12 
Day 365 
320 
The earlier of day 456 or 
IP administration at 
Month 12 (if available)** 
Month 18 
Day 547 
IP administration at 
Month 12 (if available)** 
 
* On the date of IP administration at Month 6, the procedures performed prior to IP administration 
should be included in Month 6 (Refer protocol Section 7.1.2.5). The procedures performed post 
dosing should be included in Month 9. 
** On the date of IP administration at Month 12, the procedures performed prior to IP administration 
should be included in Month 12 (Refer protocol Section 7.1.2.7). The procedures performed post IP 
dosing should be included in Month 18. 
 
Table 2: Analysis Visit Window for Vitamin D 
Study Analysis Visit 
Target Study Day 
Time Interval (Study Day) 
Start 
End 
Screening 
Day -28 to Day -1 
− 28 
1 
Month 6 
Day 183 
2 
IP administration at 
Month 6 (if available)* 
Month 12 
Day 365 
IP administration at 
Month 6 (if available)* 
The earlier of day 456 or 
IP administration at 
Month 12 (if available)** 
* On the date of IP administration at Month 6, the procedures performed prior to IP administration 
should be included in Month 6 (Refer protocol Section 7.1.2.5). The procedures performed post 
dosing should be included in Month 12. 
** On the date of IP administration at Month 12, the procedures performed prior to IP administration 
should be included in Month 12 (Refer protocol Section 7.1.2.7). 
 
Table 3: Analysis Visit Window for BMD 
Study Analysis Visit Target Study Day 
Time Interval (Study Day) 
Start/End 
Month 6 
Day 183 
−/+ 30 Day 
Month 12 
Day 365 
−/+ 30 Day 
Month 18 
Day 547 
−/+ 30 Day 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 17 of 63 
 
Table 4: Analysis Visit Window for PD and PK 
Study Analysis Visit 
Target Study Day 
Time Interval (Study Day) 
Start/End 
Month 0 
Day 1  
NA 
Month 0.5 
Day 16 
−/+ 3 Day 
Month 1 
Day 31 
−/+ 3 Day 
Month 3 
Day 92 
−/+ 7 Day 
Month 6[1] 
Day 183 
−/+ 14 Day 
Month 9 
Day 274 
−/+ 14 Day 
Month 12[2] 
Day 365 
−/+ 14 Day 
Month 18 
Day 547 
−/+ 14 Day 
[1] The procedures performed after IP administration at Month 6 should be excluded from Month 6. 
[2] The procedures performed after IP administration at Month 12 should be excluded from Month 
12. 
 
The unscheduled/retested measurements will not be included in the by-visit summaries. Unless stated 
otherwise, unscheduled/retested measurements (except for baseline) will contribute to the post-
baseline worst-case value for shift tables and incidence of post-baseline significant abnormality tables. 
If the unscheduled/retested measurement recorded on the same day as first IP administration, the 
unscheduled/retested measurement will be assumed to be post-dose, unless there is clear evidence to 
suggest the measurement is conducted prior to IP administration by comparing measurement time. 
Unscheduled/retested measurements will be mapped to scheduled visit according to the visit window 
for different measurements. Unscheduled/retested measurements of Haematology, Biochemistry, 
Urinalysis follow Table 1. Vitamin D measurement follows Table 2. PD measurement follows Table 
4. 
Listings will include scheduled, unscheduled, retested, and ET visit. And visit label of Month X 
(R0X) is to indicate if the measurement is retested or unscheduled. 
3.7. Common Calculations 
For the purpose of converting days to years or months, 1 year will be equal to 365.25 days and 1 
month will be equal to 30.44 days. One week will be equal to 7 days. 
For continuous measurements, change from baseline and percent change from baseline at Visit X will 
be calculated respectively as follows: 
• 
Change from baseline at Visit X = Test Value at Visit X – Baseline Value 
• 
Percent change from baseline at Visit X  
= [(Test Value at Visit X – Baseline Value) / Baseline Value] × 100 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 18 of 63 
 
3.8. Software Version 
All report outputs will be conducted using SAS version 9.3 or higher. 
4. STATISTICAL CONSIDERATIONS 
4.1. Multicentre Studies 
This study will be conducted by multiple investigators at multiple centres internationally. Centre is 
included as a stratification factor in the randomisation scheme, for the primary efficacy analysis, no 
formal adjustments for the central effect will be conducted. Multicentre will be pooled by country, 
and treatment effect by country will be explored by a forest plot showing two-sided 90% CI and 95% 
CI of the mean difference in primary efficacy endpoint between main treatment group within each 
country.  
Summaries of subject disposition, demographics, and other baseline characteristics by country and 
overall treatment group will be provided. 
4.2. Missing Data 
Imputation of missing efficacy endpoint BMD will be handled as described in Section 7.1.2. Missing 
safety endpoint will not be imputed, unless otherwise specified in the relevant section. 
Imputation of partial dates for date of last menstruation, diagnosed date of PMO, medications, 
procedures, non-Investigation product (non-IP), and adverse events (AEs) is described in APPENDIX 
1. 
4.3. Multiple Comparisons/Multiplicity 
One primary endpoint has been defined for this study, with one critical treatment contrast (SB16 vs 
Prolia) and one time point of primary interest (Month 12). The secondary endpoints defined are 
intended to provide supportive evidence relating to the primary objective. No interim analyses are 
planned for the primary analysis. Hence no formal adjustments for multiplicity will be performed. 
4.4. Active-Control Studies Intended to Show Equivalence 
This is an active-control study intended to demonstrate equivalence between SB16 and Prolia in terms 
of percent change from baseline in lumbar spine BMD at Month 12. The null hypothesis tested for the 
primary efficacy analysis is that either (1) SB16 is inferior to Prolia or (2) SB16 is superior to Prolia 
based on a pre-specified equivalence margin. 
For EMA, Korea Ministry of Food and Drug Safety (MFDS), and other regulatory submissions, 
equivalence will be declared if the two-sided 95% CI of the mean difference in percent change from 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 19 of 63 
 
baseline in lumbar spine BMD at Month 12 between SB16 and Prolia lies within the pre-defined 
equivalence margin of [−2.0%, 2.0%]. 
For the US FDA submission, equivalence will be declared if the two-sided 90% CI of the mean 
difference in percent change from baseline in lumbar spine BMD at Month 12 between SB16 and 
Prolia lies within the pre-defined equivalence margin of [−1.45%, 1.45%]. 
4.5. Examination of Subgroups 
The uniformity of the treatment effect for the primary efficacy analysis will be examined for the 
following subgroups: 
• 
Age (< 65 years vs. ≥ 65 years) 
• 
BMI (< 25 kg/m2 vs. ≥ 25 kg/m2) 
• 
Prevalent vertebral fracture (Yes, No, Not assessable) 
• 
Country (Czech Republic, Denmark, South Korea, Lithuania, Poland) 
• 
Overall ADA result up to Month 12 (Positive, Negative, Inconclusive) 
Summaries of the primary efficacy variable by main treatment group and subgroup will be produced. 
Primary efficacy analysis will be repeated within each subgroup. A forest plot showing the least 
squares mean difference and 90% and 95% CI within each subgroup and overall will be provided. No 
formal statistical analysis will be performed within subgroup. 
5. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Subject demographics and other baseline characteristics will be summarised by overall treatment 
group for the RAN, PKS, and PDS. 
Continuous variables (e.g., age, weight, height, and body mass index [BMI]) will be summarised with 
descriptive statistics (n, mean, SD, median, minimum, and maximum). Categorical variables (e.g., 
sex, race, and ethnicity) will be summarised with frequency and percentages. The summaries provided 
include the following: 
• 
A summary of demographic characteristics variables by overall treatment group. 
• 
A summary of demographic characteristics variables by overall treatment group and country. 
• 
A summary of other baseline characteristics variables by overall treatment group. 
• 
A summary of other baseline characteristics variables by overall treatment group and country for 
the RAN. 
By-subject listings will be provided for the following: 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 20 of 63 
 
• 
By-subject listings of demographic and other baseline characteristics will be provided by 
treatment group for the RAN. 
• 
By-subject listing of X-ray assessment will be provided by treatment group for the RAN. 
Demographics Characteristics 
• 
Age (years) – calculated as Year of Informed Consent – Year of birth 
• 
Age group (< 65 years, ≥ 65 years) 
• 
Sex – Female 
• 
Race – American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, Other 
• 
Ethnicity – Hispanic or Latino, Indian (Indian subcontinent), Chinese, Japanese, Mixed ethnicity, 
Other 
• 
Country - Czech Republic, Denmark, South Korea, Lithuania, Poland 
• 
Height (cm) at screening and Weight (kg) at baseline 
• 
BMI (kg/m2) – derived as weight (kg) / [height (m)]2 
• 
BMI level (< 25 kg/m2 , ≥ 25 kg/m2) 
Other Baseline Characteristics 
• 
Years since diagnosis of PMO, calculated as (Randomisation date – Diagnosed date of PMO + 1) 
/ 365.25 
• 
Years since menopause, calculated as (Randomisation date – Date of last menstruation + 1) / 
365.25 
• 
Previous fracture history (Yes, No) 
• 
Hip fracture history of the parents (Yes, No) 
• 
Prevalent vertebral fracture (Yes, No, Not assessable), number of vertebral fracture (0, 1, 2, >2, 
Not assessable), and grade of most severe vertebral fracture (Normal, Mild, Moderate, Severe, 
Not assessable) 
- 
Prevalent vertebral fractures were diagnosed based on lateral thoracic and spine 
radiographs (T4 to L4) using a Genant scoring method. There are two primary 
radiograph reviewers (double read) and an adjudicator in the independent radiograph 
review. The result of the adjudication will be considered the final assessment if 
adjudication is available. If adjudication is not available, the result of the first 
reviewer will be considered the final assessment. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 21 of 63 
 
- 
The grade of most severe vertebral fracture will be determined as follows: 
1) ‘Normal’ if all vertebrae among T4 to L4 is evaluable and there is no fracture 
2) ‘Mild’, ‘Moderate’, ‘Severe’ if there is any fracture among T4 to L4, the worst-
case will be reported 
3) ‘Not assessable’ if there is unknown fracture status at no less than one vertebra 
and there is no fracture at remaining evaluable vertebrae  
- 
The fracture number will be calculated based on the actual number of vertebral 
fractures. 
• 
Active healing fracture (Yes, No) – only included in listing 
• 
Serum 25 (OH) vitamin D level (nmol/L) 
• 
Oral bisphosphonate history (Yes, No), total cumulated period of oral bisphosphonate 
administration prior to screening (months) 
• 
Duration of oral bisphosphonate administration (year ≤ 1, 1 < years ≤ 2, 2 < years ≤ 3) 
• 
BMD (g/cm2) of lumbar spine, total hip, and femoral neck – the lumbar spine BMD measurement 
in data set up to Month 12 which specified in Section 7 will be used. 
• 
T-score at lumbar spine, total hip, and femoral neck – Original BMD T-score used for eligibility 
confirmation 
• 
Serum CTX (ng/mL) and Serum P1NP (ng/mL) – the major protocol deviation or active healing 
fracture which specified in Section 7.5 may affect the data. 
• 
Current smoking status (Yes, No) 
• 
Current alcohol consumption status (Yes, No) and consumption amount (< 3 units/day, ≥ 3 
units/day) 
Statistical Tests for Demographic and Other Baseline Characteristics 
Comparison between main treatment group in demographics and other baseline characteristics will be 
performed for the RAN using the chi-square test for categorical variables or analysis of variance 
(ANOVA) for continuous variables. The results of these tests will be provided including the p-value 
only for descriptive purposes and will not be used as a formal basis to determine the factors to be 
included in primary or secondary efficacy analysis models. If baseline imbalances are detected for any 
of the factors, additional analyses may be performed to adjust for these baseline differences. 
6. MEDICAL AND SURGICAL HISTORY 
Medical and surgical histories will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) central coding dictionary version 23.0 or higher. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 22 of 63 
 
Medical and surgical histories will be summarised by MedDRA primary System Organ Class (SOC) 
and Preferred Term (PT) for overall treatment group using number and percentage of subjects for the 
RAN. Primary SOC will be presented alphabetically; PT will be sorted within each primary SOC in 
descending order of subject frequency based on the treatment SB16 group, then alphabetically if tied. 
If a subject had multiple conditions with the same PT and primary SOC, the subject will be counted 
only once under the same PT and primary SOC. 
By-subject listing of medical and surgical histories will be provided by treatment group for the RAN. 
7. EFFICACY, PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES 
BMD will be measured by either General Electric (GE) Lunar or Hologic machines. There are three 
type of measurements for the BMD result, original BMD measurement, Instrument Quality Control 
(IQC) corrected BMD measurement, and IQC and Cross-calibration (Xcal) corrected BMD 
measurement. IQC and Xcal corrected BMD measurement will be summarised and analysed by 
treatment group in CSR analysis. Original BMD measurement and IQC corrected BMD measurement 
will be included in listings only. 
Lumbar spine BMD is assessed at four locations, L1 to L4 vertebrae. If during the study, more than 
one vertebra becomes un-evaluable (within L1-4) due to artifacts, deformity or sequelae of prior 
orthopedic surgery or trauma, central imaging will process the remaining spine scans for evaluable 
vertebrae (within L1-4) as long as there are at least 2 evaluable vertebrae to analyse. This will be done 
for all post-screening timepoints per subject whenever at least one timepoint has un-evaluable 
vertebrae. For consistency in lumbar spine BMD measurement across visits, if a vertebra is excluded 
at one timepoint, the same vertebra will be excluded at all other timepoints. For example, an L1 
exclusion made at Month 12 will also be applied to Screening and Month 6 and will be applied to 
subsequent visits as well. In this example the total lumbar spine BMD for all visits would only include 
L2, L3, and L4. Therefore, lumber spine BMD will be reported as two sets of data, assessment up to 
Month 12, and assessment up to Month 18. 
Lumber spine BMD up to Month 12 is calculated based on Screening assessment, scheduled and 
unscheduled assessment up to Month 12, and ET assessment within Month 12 window (refers to 
Table 3). Primary efficacy analysis will use IQC and Xcal corrected lumber spine BMD measurement 
in data set up to Month 12. Missing value will be imputed as specified in Section 7.1. And the 
secondary endpoint analysis for lumbar spine BMD at Month 6 will use this data. 
Lumbar spine BMD up to Month 18 is calculated based on Screening assessment, all scheduled and 
unscheduled assessment, and ET assessment. Exclusion of vertebrae assessment after Month 12 may 
result in additional exclusion prior to or at Month 12. Lumber spine BMD at Screening, Month 6, and 
Month 12 among the data set up to Month 18 will be difference from the lumbar spine BMD value in 
data set up to Month 12. The secondary endpoint for lumbar spine BMD at Month 18 will be analysed 
using IQC and Xcal corrected lumbar spine BMD measurement in data set up to Month 18. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 23 of 63 
 
7.1. Primary Efficacy Analysis 
7.1.1. Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is percent change from baseline in lumbar spine BMD at Month 12, 
calculated as [(lumbar spine BMD at Month 12 – lumbar spine BMD at baseline) / lumbar spine BMD 
at baseline] × 100%. 
For the EMA, MFDS, and other regulatory submissions, the primary efficacy analysis will be 
performed for the PPS using an analysis of covariance (ANCOVA) with the baseline value of lumbar 
spine BMD as a covariate and treatment group as a factor. The equivalence will be declared if the 
two-sided 95% CI of the mean difference in percent change from baseline in lumbar spine BMD at 
Month 12 between SB16 and Prolia lies within the pre-defined equivalence margin of [−2.0%, 2.0%]. 
For the US FDA submission, the primary efficacy analysis will be performed for the FAS using an 
ANCOVA with the baseline value of lumbar spine BMD as a covariate and treatment group as a 
factor. The equivalence will be declared if the two-sided 90% CI of the mean difference in percent 
change from baseline in lumbar spine BMD at Month 12 between SB16 and Prolia lies within the 
predefined equivalence margin of [−1.45%, 1.45%]. Missing data will be imputed using multiple 
imputation method for subjects who drop out for the study prior to the primary analysis time point 
under the assumption of missing at random (MAR). 
Primary Estimand 
The primary estimand including supplementary estimand is as follows: 
 
EMA, MFDS, and other regulatory 
submissions 
US FDA submission 
Population 
Subjects who met the inclusion/exclusion 
criteria and adhere to protocol as defined in 
the Section 3.1 (PPS) 
Subjects who met the inclusion/exclusion 
criteria as defined in the Section 3.1 (FAS) 
Treatment condition 
SB16 vs. Prolia 
SB16 vs. Prolia 
Endpoint 
Percent change from baseline in lumbar 
spine BMD at Month 12 
Percent change from baseline in lumbar 
spine BMD at Month 12 
Population-level 
summary 
Mean difference in percent change from 
baseline in lumbar spine BMD at Month 12 
Mean difference in percent change from 
baseline in lumbar spine BMD at Month 12 
Intercurrent Events 
(IEs) and strategies 
Restrict the inclusion of subjects with IEs 
that impact the assessment of treatment 
effect; hence the main estimator will be 
based on the PPS as defined in Section 3.1. 
 
IE1: Early discontinuation from study prior 
the Month 6  
Hypothetical strategy: primary endpoint 
will not be collected; treatment effect will 
be estimated as if patients remain on 
treatment.     
 
IE2: Early discontinuation from study after 
the Month 6 and prior to Month 12  


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 24 of 63 
 
 
EMA, MFDS, and other regulatory 
submissions 
US FDA submission 
Treatment policy strategy: primary 
endpoint will be collected; treatment effect 
will be estimated regardless of IE2 
 
IE3: subjects who do not have any lumbar 
spine BMD assessment result after 
randomisation by accident and do not 
receive any IP 
Restrict the inclusion of subjects with IE3, 
hence the main estimator will be based on 
the FAS as defined in Section 3.1. 
  
Main Estimator 
A two-sided 95% CI of the mean 
difference in percent change from baseline 
in lumbar spine BMD at Month 12 will be 
obtained using an ANCOVA with the 
baseline value of lumbar spine BMD as a 
covariate and treatment group as a factor. 
 
 
A two-sided 90% CI of the mean 
difference in percent change from baseline 
in lumbar spine BMD at Month 12 will be 
obtained using an ANCOVA with the 
baseline value of lumbar spine BMD as a 
covariate and treatment group as a factor. 
Missing data will be imputed using 
multiple imputation method for subjects 
who drop out for the study prior to the 
primary analysis time point under the 
assumption of MAR. 
Sensitivity Estimator 
 
Tipping point 
Supportive Estimand 1 
Primary efficacy analysis (ANCOVA) will 
be repeated using FAS, missing data will 
be imputed using multiple imputation 
method for subjects who drop out for the 
study prior to the primary analysis time 
point under the assumption of MAR. 
 
Primary efficacy analysis (ANCOVA) will 
be repeated using PPS. 
 
Supportive Estimand 1 
Sensitivity Estimator 
Tipping point 
 
Supportive Estimand 2 
Available case analysis will also be 
performed using the FAS. 
Available case analysis will also be 
performed for the FAS. 
 
7.1.2. Missing Data Imputation Methods of Primary Efficacy Endpoint 
A summary of the number and percentage of subjects missing BMD assessment and reason of missing 
will be provided for the FAS. Reason of missing BMD assessment may be the same as the reason of 
visit not done and will be excluded from this summary, when the visit is skipped. 
When analysing primary efficacy endpoint using FAS, missing data will be imputed using multiple 
imputation method for subjects who drop out for the study prior to the primary analysis time point 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 25 of 63 
 
under the assumption of MAR. Intermittent missing prior to drop out/study completion will be 
imputed using the same approach. 
Multiple imputation methods replace each missing primary efficacy endpoint value with a set of 
(m=25) plausible values based on a prediction model. The prediction model will be a regression 
model with the following covariates: treatment group, baseline lumbar spine BMD, percent change 
from baseline in lumbar spine BMD at Month 6 and Month 12. 
Algorithm for the Multiple Imputation of Missing Values 
If non-monotone missing pattern (intermittent missing) is observed, the Markov Chain Monte Carlo 
(MCMC) monotone-data imputation method will first be used to generate a monotone missing data 
pattern. A set (m=25) of imputed dataset with monotone missing pattern will be generated from the 
above method. 
For data with monotone missing pattern, the monotone regression imputation method will be used to 
generate a set (m=25) of imputed complete dataset. If MCMC monotone-data imputation is performed 
prior to using monotone regression method, monotone regression imputation will create single 
imputed dataset based on each of 25 imputed datasets from MCMC monotone-data imputation. The 
pseudo SAS code and seed (899745) can be found in APPENDIX 8. 
Analysing Multiply Imputed Datasets 
ANCOVA model as defined in Section 7.1.1 will be performed in each of the imputed complete 
datasets (m=25). The analysis results (least square mean difference and associated standard errors) 
will be combined for making statistical inference. The pseudo SAS code can be found in APPENDIX 
8. 
7.1.3. Sensitive Analysis of Primary Efficacy Endpoint 
Under the Estimand framework, tipping point analysis will be conducted to evaluate the robustness of 
multiple imputation under the assumption of MAR. A two-dimensional tipping point analysis will be 
applied to ANCOVA model as defined in Section 7.1.1 using the FAS, to assess the robustness of the 
conclusions based on the assumption of MAR. A succession of delta adjustments via multiple 
imputation methods will be used to impute the missing primary endpoint point in two treatment 
groups independently, exploring various missing not at random (MNAR) assumption. The tipping 
point is denoted as the delta adjustment that would have to be imputed to overturn a statistically 
significant result. Clinical judgement will be applied to the plausibility of the tipping point (delta 
adjustment). The pseudo SAS code can be found in APPENDIX 8. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 26 of 63 
 
7.1.4. Supportive Analysis of Primary Efficacy Endpoint 
When primary estimand uses PPS, ANCOVA model as defined in Section 7.1.1 will be repeated for 
the FAS, missing data will be imputed using multiple imputation method for subjects who drop out 
for the study prior to the primary analysis time point under the assumption of MAR. To stress-test the 
supportive analysis result for robustness to MAR assumption, tipping point analysis will be 
conducted, using same method as described in section 7.1.3. Available case analysis will also be 
performed for the FAS. 
When primary estimand uses FAS, available case analysis will be performed for the FAS and the 
same analysis will be repeated for the PPS.  
7.2. Secondary Efficacy Analysis 
Percent Change from Baseline in Lumbar Spine BMD 
The percent change from baseline in lumbar spine at Month 6 and 18 will be analysed using the same 
model for primary analysis as described in Section 7.1 for the FAS based on available case and 
multiple imputation assuming MAR respectively; and the PPS. The treatment comparison of interest 
for time points prior to re-randomisation (Month 12 included) include the comparison between main 
treatment group SB16 and Prolia; treatment comparison of interest for time points after re-
randomisation include the comparison between transition treatment group SB16+SB16 and Prolia 
Overall; SB16+SB16 and Prolia+Prolia; Prolia+SB16 and Prolia+Prolia. 
A descriptive summary of lumbar spine BMD value and percent change from baseline by treatment 
group and visit will be provided for the FAS and PPS. The percent change from baseline in lumbar 
spine BMD will be plotted by treatment group and visit for the FAS and PPS with mean and standard 
error based on available case. 
By-subject listings of lumbar spine BMD will be provided by treatment group for the FAS. 
Percent Change from Baseline in Total Hip and Femoral Neck BMD 
A descriptive summary of total hip and femoral neck BMD value and percent change from baseline 
by treatment group and visit will be provided for the FAS and PPS. The percent change from baseline 
in total hip and femoral neck BMD will be plotted by treatment group and visit for the FAS and PPS 
with mean and standard error based on available case. 
A listing of total hip and femoral neck BMD will be provided by treatment group for the FAS. 
7.3. Exploratory Efficacy Analysis 
Exploratory efficacy analysis is not needed for CSR analysis. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 27 of 63 
 
7.4. Pharmacokinetic Analysis 
The PK analysis will be performed using the PKS.  
Blood sample collection compliance will be confirmed during protocol deviation review. In the case 
of a major protocol deviation, PK data collected during the affected treatment period will be excluded 
from summary statistics, but will be included in listing and individual serum concentration figure. If 
the serum concentration results at ET visit are not mapped to the analysis visit, they will be listed in 
listing only. The major protocol deviations that may affect the PK data defined as follows. 
• 
A blood sample collected after dosing at Month 0, 6, and 12 will be excluded from the PK 
analysis. 
• 
If IP administration is not performed at any one of visit, the sample from the next visit will be 
excluded from the PK analysis. 
• 
If treatment group is switched, the sample from the next visit will be excluded from the PK 
analysis. 
• 
If IP which underwent a temperature excursion is administered and it is deemed unacceptable 
use, the sample from the next visit will be excluded from the PK analysis. 
A blood sample excluded from the PK analysis will still be reported in the listing. 
Serum pharmacokinetic concentrations will be summarised descriptively by overall treatment group 
and scheduled visit. The following descriptive statistics will be presented for serum concentrations: n, 
arithmetic mean, SD, coefficient of variation (CV%), geometric mean, geometric SD, geometric CV% 
(calculated as: gCV% =SQRT(es²-1)*100; where s is the SD of the log-transformed values), median, 
minimum  and maximum values. Below the limit of quantification (BLQ) values will be treated as 
zero for the computation of descriptive statistics, and the generation of individual serum 
concentration-time profile, except for geometric mean, geometric SD, and geometric CV%, for which 
they will be excluded. BLQ will be presented as BLQ in the listings. 
The following figure of serum concentrations will be generated. SB16 and Prolia will be shown in 
same figure with different legend. Figures will be displayed in black and white.   
• 
Arithmetic Mean (±SD) serum drug concentration over time by overall treatment group − 
linear scale.  
• 
Individual serum drug concentration over time by overall treatment group − linear scale. 
By-subject listing of serum pharmacokinetic concentrations will be provided for the SAF1 who have 
at least one PK sample available for analysis. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 28 of 63 
 
7.5.  Pharmacodynamic Analysis 
The PD analysis will be performed for the PDS. All PD assessment data will be reported and analysed 
with the same precision as the source regardless of how many significant figures or decimals the data 
carry. Values of serum CTX and P1NP concentration outside the quantification range will be imputed 
as for the descriptive statistics: values with ‘<xxx’ will be set to ‘xxx’, where xxx is lower limit of 
quantification (LLOQ). However, for the listing, the original values of ‘<xxx’ will be presented as it is 
recorded. The LLOQ of serum CTX and P1NP concentration is 0.043 ng/mL and 9.92 ng/mL, 
respectively.  
Blood sample collection compliance will be confirmed during protocol deviation review. In the case 
of a major protocol deviation, PD assessment data collected during the affected treatment period will 
be excluded from summary statistics, but will be included in listing and individual serum CTX and 
P1NP concentrations figure. If the serum CTX and/or P1NP concentration results at ET visit are not 
mapped to the analysis visit, they will be listed in listing only. The major protocol deviations that may 
affect the PD assessment data defined as follows. 
• 
If a blood sample is not collected prior to dosing at Month 0, 6, and 12, the sample at the visit 
will be excluded from the PD analysis.  
• 
If a blood sample is not collected after fasting for at least 8 hours, the sample at the visit will 
be excluded from the PD analysis. 
• 
If a blood sample is not collected in the morning (prior to 12:00 PM), the sample at the visit 
will be excluded from the PD analysis. 
• 
If a blood sample for CTX at Month 0 is collected after taking calcium, the sample at the visit 
will be excluded from the PD analysis. 
• 
If IP administration is not performed at any one of visit, the sample from the next visit will be 
excluded from the PD analysis. 
• 
If treatment group is switched, the sample from the next visit will be excluded from the PD 
analysis. 
• 
If IP which underwent a temperature excursion is administered and it is deemed unacceptable 
use, the sample from the next visit will be excluded from the PD analysis. 
• 
If prohibited medication is used, the sample after taking the prohibited medication for the first 
time will be excluded from the PD analysis.  
In addition, if an active healing fracture containing ‘Fracture’ but not “Tooth fracture” in AE 
preferred term occurs in the middle of the study, the serum CTX or P1NP concentrations after having 
fracture will be excluded from the PD analysis. 
A blood sample excluded from the PD analysis will still be reported in the listing. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 29 of 63 
 
7.5.1. CTX and P1NP Concentration 
The following summaries will be provided for serum CTX and P1NP concentrations using the PDS: 
• 
A summary of percent change from baseline in serum CTX concentration by overall treatment 
group and visit.   
• 
A summary of percent change from baseline in serum P1NP concentration by overall treatment 
group and visit.  
• 
By-subject listing of PD assessment will be provided by treatment group for the SAF1 who have 
at least one serum CTX or P1NP sample available for analysis. 
The following figure of serum CTX and P1NP concentrations will be generated. The treatment group 
will be shown in same figure with different legend. Figures will be displayed in black and white.   
• 
Median (±interquartile range) percent change from baseline in serum CTX concentration over 
time by overall treatment group using the PDS − linear scale.  
• 
Median (±interquartile range) percent change from baseline in serum P1NP concentration over 
time by overall treatment group using the PDS − linear scale.  
• 
Individual serum CTX concentration over time by overall treatment group using the SAF1 − 
linear scale. 
• 
Individual serum P1NP concentration over time by overall treatment group using the SAF1 − 
linear scale. 
7.5.2. Pharmacodynamic Parameters 
The geometric mean of area under the effect curve (AUEC) from time zero to Month 6 (AUEC0-M6) of 
percent change from baseline in serum CTX concentration will be analysed by main treatment group 
using ANOVA on the log-transformed AUEC0-M6 of percent change from baseline in serum CTX 
concentration with the main treatment group as a fixed effect. The ratio of least-squares geometric 
mean (SB16 vs. Prolia) will also be presented with corresponding 90% CI. 
The AUEC0-M6 will be calculated using the trapezoidal rule, including serum CTX concentration at 
Month 0, 0.5, 1, 3, and 6. Actual study day of serum CTX sample collection should be used. Subjects 
who have serum CTX concentration available for analysis at Month 0, 0.5, 1, 3, and 6 will be included 
in the calculation of AUEC. AUEC will be calculated as: 
∑{0.5 × (𝑌𝑖
𝑏−1
𝑖=𝑎
+ 𝑌𝑖+1) × (𝑡𝑖+1 −𝑡𝑖)} 
where 𝑌𝑖 is the percent change from baseline in serum CTX concentration at visit 𝑖, 𝑡 is the time at 
the specified visit 𝑖 (the actual date and time of serum CTX sample collection for post-baseline visit; 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 30 of 63 
 
the actual date and time of first IP administration at Month 0 for baseline visit), 𝑎 is the baseline 
assessment, and 𝑏 is the last assessment up to Month 6. If AUEC yield a negative value, the absolute 
value of AUEC will be used in summary and further analysis. 
Serum CTX concentration is expected to decrease after IP administration. After reaching maximum 
reduction, the reduction effect of serum CTX will gradually diminish, may become zero, or even 
increase from baseline. If change from baseline in serum CTX concentration at Month 6 is positive 
value, the AUEC0-M6 will be calculated from baseline up to the time where percent change from 
baseline equals zero. Upon the first measurement of CTX value increase from baseline, 𝑌𝑖′ and 𝑡𝑖 ′ 
at the time when percent change equals zero can be calculated based on linear equation, 𝑡𝑖 ′= 
𝑌𝑖𝑡𝑖−1−𝑌𝑖−1𝑡𝑖
𝑌𝑖−𝑌𝑖−1
, 𝑌𝑖′= 0. AUEC0-M6 equals AUEC0-ti’. Considering this rebound effect, the net AUEC0-M6 
will be provided for listing. If the rebound is seen, the net AUEC0-M6 equals AUEC0-ti’ minus AUECti’-
M6. Otherwise, net AUEC0-M6 equals AUEC0-M6  
8. SAFETY ANALYSIS 
Safety analyses will be performed for the main, transition, and overall study periods unless specified 
otherwise. Analyses for the main and transition periods will be performed in the SAF1 and SAF2 
respectively and analyses for the overall study period will be performed in the SAF1. There will be no 
statistical comparisons between the treatment groups for safety data, unless otherwise specified with 
the relevant section. 
8.1. Study Medication Exposure 
IP refers to SB16 (proposed denosumab biosimilar) or Prolia. Non-IP refers to Calcium and/or 
Vitamin D. Exposure to study medication in main period (up to Month 12) and overall study period 
(up to Month 18) will be provided respectively for IP, using the SAF1.  
Prior non-IP is defined as non-IP with stop date prior to the first administration date of IP. 
Concomitant non-IP is defined as any non-IP ongoing at the first administration date of IP or with a 
start date on or after the first administration date of IP. Algorithm of concomitant non-IP is detailed in 
APPENDIX 1. 
The duration of exposure for IP will be calculated as follows. 
  Duration of exposure (days) in main period = minimum of [maximum of (study 
discontinuation decision date, ET visit date), IP 
administration date at Month 12, (last IP administration date 
before Month 12 + 182)] – first IP administration date + 1 
  Duration of exposure (days) in overall study period = minimum of [maximum of (study 
discontinuation decision date, ET visit date), EOS visit date, 
(last IP administration date + 182)] – first IP administration 
date + 1 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 31 of 63 
 
Maximum (study discontinuation decision date, ET visit date) will be included above calculation if 
subjects discontinued from study. The IP exposure summaries includes the following: 
• 
A summary of statistics for total number of subcutaneous injections (1 injection, 2 injections, 3 
injections), duration of exposure to IP in main period and overall study period by treatment group. 
By-subject listings of IP administration (including the evaluation of injection site reaction) and non-IP 
administration will be provided by treatment group for the SAF1, respectively. 
8.2. Prior/Concomitant Medications and Procedures 
Prior and concomitant medications will be coded using the World Health Organisation (WHO) Drug 
dictionary version dated Mar 2020 or above.  
See APPENDIX 1 for handling of partial date for medications and procedures, in the case where it is 
not possible to define a medication as prior or concomitant, the medication will be classified by the 
worst case: i.e., concomitant. 
Prior medication or procedure is defined as medication or procedure with stop date prior to the first 
administration date of IP. Concomitant medication or procedure will be presented for main, transition, 
and overall study periods separately. Concomitant medication or procedure during the overall study 
period is defined as any medication or procedure ongoing at the first administration date of IP or with 
a start date on or after the first administration date of IP. Algorithm of concomitant medications and 
procedures is detailed in APPENDIX 1. 
Any concomitant medication or procedure which started prior to, on or after the date of the first 
administration of IP, and stopped before the date of IP administration post re-randomisation (the 
EOS/ET visit if a subject discontinued prior to the IP administration post re-randomisation or study 
discontinuation decision date, when ET visit is not conducted) or are ongoing at the date of IP 
administration post re-randomisation (the EOS/ET visit if a subject discontinued prior to the IP 
administration post re-randomisation or study discontinuation decision date, when ET visit is not 
conducted) will be included in main period. 
Any concomitant medication or procedure which started prior to, on or after the date of IP 
administration post re-randomisation will be included in transition period. 
A summary of the number and percentage of subjects with prior, and concomitant medication will be 
provided by Anatomical Therapeutic Chemical (ATC) Drug Class and preferred term for treatment 
group. If a subject takes multiple medication with the same ATC Drug Class and preferred term, the 
subject will be counted only once under the same ATC Drug Class and preferred term. ATC Drug 
Class will be presented in alphabetical order. Preferred term will be sorted within each ATC Drug 
Class in descending order based on the treatment SB16 group, then alphabetically if tied.  
• 
Summary of prior medications will be provided by overall treatment group using SAF1. 










SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 36 of 63 
 
In addition, the number and percentage of subjects with ADA positive will be summarised by titre and 
overall treatment group in each visit using the SAF1. 
The incidence of overall ADA results (i.e., Positive, Negative, Inconclusive) up to Month 6, Month 12 
and Month 18 will be presented by overall treatment group using the SAF1. 
Overall ADA result up to Month 6, Month 12 and Month 18 will be summarised for subjects with 
baseline ADA and have at least one ADA result after first IP administration up to above visit. Overall 
ADA result is defined as below: 
• 
“Positive” for a subject with treatment-induced or treatment-boosted ADA, where treatment-
induced ADA indicates at least one positive result after first IP administration at Month 0 for 
subjects with negative ADA at baseline, and treatment-boosted ADA indicates at least one 
positive result with higher titre level compared to baseline after first IP administration at 
Month 0 for subjects with positive ADA at baseline. 
• 
“Negative” for a subject with negative ADA at baseline and without positive ADA post-
baseline. 
• 
“Inconclusive” for a subject with positive ADA at baseline and without positive result with 
higher titre level observed post-baseline. 
In addition, the incidence of overall ADA results (i.e., Positive, Negative, Inconclusive) for the 
transition period (from Month 12 to Month 18) will be presented by transition treatment group using 
the SAF2. 
Overall ADA results for the transition period will be summarised for subjects with at least ADA result 
up to Month 12 and have at least one ADA result after transition up to Month 18. Overall ADA result 
for the transition period is defined as below: 
• 
“Positive” for a subject with treatment-induced or treatment-boosted ADA, where treatment-
induced ADA indicates at least one positive result after IP administration at Month 12 for 
subjects with overall negative ADA up to Month 12, and treatment-boosted ADA indicates at 
least one positive result with higher titre level after IP administration at Month 12 compared 
to maximum positive ADA up to Month 12 for subjects with at least one positive ADA 
results up to Month 12. 
• 
“Negative” for a subject with overall negative ADA up to Month 12 and without positive 
ADA after IP administration at Month 12 until Month 18. 
• 
“Inconclusive” for a subject with at least one positive ADA up to Month 12 and without 
positive result with higher titre level observed after IP administration at Month 12 up to 
Month 18, compared to the maximum positive ADA up to Month 12. 
A by-subject listing for immunogenicity assessment will be provided. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 37 of 63 
 
8.7. Other Observations Related to Safety 
12-lead Electrocardiogram (ECG)  
ECG are collected at screening only. ECG summary includes: 
• 
A summary of QT interval, corrected QT interval (QTc), and the number and percentage of 
subjects experiencing clinically significant result by overall treatment group using the SAF1. 
A by-subject listing of ECG results will be provided. 
9. ADVERSE EVENTS 
AE analyses will be performed for the main, transition, and overall study periods unless specified 
otherwise. All summaries of main and overall study periods will be based on the SAF1. Summary of 
transition period will be based on the SAF2. All reported AEs will be coded using MedDRA central 
coding dictionary version 23.0 or higher. 
• 
Pre-treatment AE is defined as any AE with an onset date before the date of first administration of 
IP. 
• 
TEAE will be defined as any AE with an onset date on or after the date of the first administration 
of IP until 6 months after last IP dose, or EOS/ET (study discontinuation decision date, when ET 
visit is not conducted), whichever occur later. AEs which are already present before the initiation 
of IP and increase in severity after the initiation of IP will be considered as TEAEs. Pre-existing 
AEs before the initiation of IP with no increase in severity after the initiation of IP will not be 
considered as TEAEs. See APPENDIX 1 for handling of partial dates for AEs. 
• 
AE of Special Interest (AESI) includes hypocalcaemia, hypersensitivity to IP, osteonecrosis of the 
jaw, atypical femoral fractures, and skin infections. AESI will be evaluated by investigator and 
recorded in eCRF. 
• 
Serious Adverse Event (SAE) will be evaluated by investigator and recorded in eCRF. 
In general, AE summaries will provide the number and percentages of subjects reporting at least one 
AE and the total number of events reported by SOC, PT for each analysis period and treatment group. 
Subject will be counted once under each PT and each SOC. SOC will be presented in descending 
order of subject frequency based on the treatment SB16 (main and overall study periods) or 
SB16+SB16 (transition period), then alphabetically if tied. PT will be sorted within each SOC in 
descending order of subject frequency based on the treatment SB16 (main and overall study periods) 
or SB16+SB16 (transition period), then alphabetically if tied. 
Any TEAE with an onset date on or after the date of the first administration of IP and before IP dose 
post re-randomisation will be included in the main period analysis. AEs that start in the main period 
and continue into the transition period will be included in the main period only. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 38 of 63 
 
Any TEAE with an onset date on or after the date of IP administration at Month 12 will be included in 
the transition period. 
Summary of all Adverse Events 
A summary of all AEs will be provided, including number and percentage of subjects and number of 
events under each category. The following categories will be presented for each analysis period as 
specified at Section 3 (main, transition, and overall study periods). SAEs will be collected until 6 
months after last IP administration or EOS/ET, whichever occur later. Six months after the last IP 
administration date or EOS/ET will be considered in the definition of end date for each analysis 
period for AE. 
• 
AEs (only included in the overall study period summary) 
• 
Pre-treatment Adverse Events (Pre-AEs) (only included in the overall study period summary) 
• 
TEAEs 
• 
TEAEs by severity and causality 
• 
TEAEs of special interest by category  
• 
TEAEs leading to IP permanent discontinuation (only included in the overall study period 
summary) 
• 
TEAEs leading to IP permanent discontinuation related to IP/non-IP (only included in the overall 
study period summary) 
• 
Injection site reactions 
• 
Serious TEAEs 
• 
Serious TEAEs by severity and causality 
• 
Serious TEAEs leading to IP permanent discontinuation (only included in the overall study period 
summary) 
• 
Serious TEAEs leading to IP permanent discontinuation related to IP/non-IP (only included in the 
overall study period summary) 
• 
TEAEs leading to death 
A by-subject listing of all AEs will be provided by treatment group. 
Adverse Events for COVID-19  
Summaries of TEAEs for COVID-19 will be provided for each analysis period as specified at 
Section 3 (main, transition, and overall study periods), where the verbatim term contains key text 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 39 of 63 
 
“COVID”, including number and percentage of subjects and number of events under each category. 
However, if the AE is related to COVID-19 vaccination, it will be excluded from COVID-19 
summary statistics and listing. The following categories will be presented. 
• 
TEAEs for COVID-19: includes TEAEs, where the PT contains key text “COVID-19”.   
• 
TEAEs related to COVID-19: includes TEAEs other than COVID-19 which have a relationship 
with COVID-19 infection/disease. 
• 
TEAEs post COVID-19 infection: includes TEAEs post first occurrence of COVID-19 infection 
(except COVID-19) in subjects infected with COVID-19. TEAEs post COVID -19 infection is 
defined as any TEAE with an onset date on or after the start date of the first of TEAEs for 
COVID-19.     
• 
Serious TEAEs for COVID-19 
• 
Serious TEAEs related to COVID-19 
• 
Serious TEAEs among COVID-19 infected subjects 
A by-subject listing of AEs for COVID-19 will be provided by treatment group.  
Pre-treatment AEs (Pre-AEs) 
• 
A summary of pre-treatment AEs using SAF1 by overall treatment group, SOC and PT, using 
number and percentage of subjects and number of events. 
Treatment-Emergent Adverse Events (TEAEs) 
The following TEAEs will be summarised by treatment group for each analysis period as specified at 
Section 3 (main, transition, and overall study periods). 
• 
Summaries of TEAEs by treatment group, SOC and PT, using number and percentage of subjects 
and number of events. 
• 
Summaries of TEAEs > 2% in either treatment group by SOC and PT, using number and 
percentage of subjects and number of events. 
• 
Summaries of TEAEs > 5% in either treatment group by SOC and PT, using number and 
percentage of subjects and number of events. 
Other AEs 
The following other AEs will be summarised by treatment group for each analysis period as specified 
at Section 3 (main, transition, and overall study periods). 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 40 of 63 
 
• 
Summaries of other AEs (TEAEs excluding SAEs) > 5% in either treatment group by SOC and 
PT, using number and percentage of subjects and number of events. 
TEAEs by Severity 
• 
Summaries of TEAEs by treatment group for each analysis period as specified at Section 3 (main, 
transition, and overall study periods), SOC, PT, and severity using number and percentage of 
subjects and number of events. 
Severity will be reported as mild, moderate, or severe. TEAEs with a missing severity will not be 
taken into account when calculating worst-case severity. If a subject reported TEAEs in the same 
SOC (or PT) more than once with different severity in each analysis period, the subject will be 
counted once in the worst-case severity. 
TEAEs by Relationship (Causality) 
The following TEAEs by causality will be summarised by treatment group for each analysis period as 
specified at Section 3 (main, transition, and overall study periods). 
• 
Summaries of TEAEs by treatment group, SOC, PT, and IP causality using number and 
percentage of subjects and number of events. 
• 
Summaries of TEAEs by treatment group, SOC, PT, and non-IP causality using number and 
percentage of subjects and number of events. 
Relationship with IP/non-IP will be reported as “Related”, and “Not related”. Missing relationship 
will not be taken into account when calculating worst-case relationship. If a subject reported TEAEs 
in the same SOC (or PT) more than once within difference causality in each analysis period, the 
subject will be counted once in the worst-case relationship. 
Injection Site Reactions 
Clinically significant injection site reaction will be reported in AE form. Injection site reaction will be 
identified by coded High Level Term (HLT), where HLT is “Injection site reactions”. 
• 
Summaries of injection site reactions by treatment group for each analysis period as specified at 
Section 3 (main, transition, and overall study periods), SOC, and PT using number and percentage 
of subjects and number of events. 
A by-subject listing of injection site reactions will be provided by treatment group. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 41 of 63 
 
TEAEs Leading to IP Permanent Discontinuation 
• 
Summaries of TEAEs leading to IP permanent discontinuation for overall study period by overall 
treatment group, SOC, and PT using number and percentage of subjects and number of events. 
A by-subject listing of TEAEs leading to permanent discontinuation of IP will be provided by 
treatment group. 
TEAEs Leading to Death 
• 
Summaries of TEAEs leading to death by treatment group for each analysis period as specified at 
Section 3 (main, transition, and overall study periods), SOC, and PT using number and percentage 
of subjects and number of events. 
A by-subject listing of TEAEs leading to death will be provided by treatment group. 
Serious Adverse Events (SAEs) 
The following serious TEAEs will be summarised by treatment group for each analysis period as 
specified at Section 3 (main, transition, and overall study periods). 
• 
Summaries of serious TEAEs by treatment group, SOC, and PT using number and percentage of 
subjects and number of events. 
• 
Summaries of serious TEAEs leading to IP permanent discontinuation for overall study period by 
overall treatment group, SOC, and PT using number and percentage of subjects and number of 
events. 
• 
Summaries of serious TEAEs by treatment group, SOC, PT, and severity using number and 
percentage of subjects and number of events. 
• 
Summaries of serious TEAEs by treatment group, SOC, PT, and IP causality using number and 
percentage of subjects and number of events. 
• 
Summaries of serious TEAEs by treatment group, SOC, PT, and non-IP causality using number 
and percentage of subjects and number of events. 
A by-subject listing of SAEs will be provided by treatment group. 
AEs of Special Interest  
• 
Summaries of treatment-emergent AESIs by treatment group for each analysis period as specified 
at Section 3 (main, transition, and overall study periods), SOC, and PT using number and 
percentage of subjects and number of events. 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 42 of 63 
 
A by-subject listing of AESIs will be provided by treatment group. 
Deaths 
A by-subject listing of deaths will be provided by treatment group, including primary cause of death.  
TEAEs by overall ADA result 
As specified in Section 8.6, all TEAEs based on categories of overall ADA result (Positive, Negative, 
and Inconclusive) will be summarised by treatment group, SOC, and PT using number and percentage 
of subjects and number of events. 
• 
Summaries of TEAEs by overall ADA result up to Month 12, main treatment group, SOC, and PT 
for SAF1 and main period 
• 
Summaries of TEAEs by overall ADA result after transition up to Month 18, transition treatment 
group, SOC, and PT for SAF2 and transition period 
• 
Summaries of TEAEs by overall ADA result up to Month 18, overall treatment group, SOC, and 
PT for SAF1 and overall period 
 
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 43 of 63 
 
10. REFERENCES  
1. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low 
bone mineral density. N Engl J Med. 2006; Feb 23;354(8):821-31.  
2. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in 
postmenopausal women with osteoporosis. N Engl J Med. 2009; Aug 20;361(8):756-65.  
3. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab on bone mineral density and 
bone turnover in postmenopausal women. J Clin Endocrinol Metab. 2008; Jun;93(6):2149-57. 
 
 






SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 46 of 63 
 
Algorithm for Treatment-Emergent 
After imputation for partial dates is implemented, whether AE is TEAE will be decided. 
 
When start date is present, 
• 
If known/imputed start date ≥ the date of first dose of IP and ≤ 6 months after last IP dose or 
EOS/ET (study discontinuation decision date, when ET visit is not conducted), whichever occur 
later, then AE is considered as TEAE  
 
When start date is completely missing but end date is present, 
• 
If known/imputed end date ≥ the date of first dose of IP and ≤ 6 months after last IP dose or 
EOS/ET (study discontinuation decision date, when ET visit is not conducted), whichever occur 
later, then AE is considered as TEAE 
 
When both start date and end date are completely missing, 
• 
AE is considered as TEAE  
 
Algorithm for Concomitant Medications, Procedures, and non-IP 
After imputation for partial dates is implemented, whether medication, procedure, or non-IP is 
concomitant will be decided. 
 
When both start date and end date are present, 
• 
If known/imputed end date ≥ the date of first dose of IP and known/imputed start date ≤ the date 
of EOS/ET visit (study discontinuation decision date, when ET visit is not conducted), then 
medication/procedure/non-IP is considered as concomitant 
 
When start date is present and end date is completely missing, 
• 
If known/imputed start date ≤ the date of EOS/ET visit (study discontinuation decision date, when 
ET visit is not conducted), then medication/procedure/non-IP is considered as concomitant 
 
When start date is completely missing but end date is present, 
• 
If known/imputed end date ≥ the date of first dose of IP, then medication/procedure/non-IP is 
considered as concomitant 
 






























SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 61 of 63 
 
APPENDIX 8. SAMPLE CODES FOR PRIMARY ANALYSIS 
 
/* Non-Monotone missing data to be imputed to monotone missing */ 
proc mi data=indat seed=899745 nimpute=25 out=out_mono; 
by trt_group; 
var trt_group BMD_BL BMD_pchg_M6 BMD_pchg_M12; 
mcmc  chain=multiple impute=monotone; 
run;  
/* Monotone missing data to be imputed by regression predictive 
model */ 
proc mi data=out_momo seed=899745 nimpute=1 out=out_complete; 
by _Imputation_ ; 
class trt_group; 
monotone reg; 
var trt_group BMD_BL BMD_pchg_M6 BMD_pchg_M12; 
run; 
 
/* Analysis of covariance (ANCOVA) */ 
ods output lsmeans=lsm diffs=LSmean_diff; 
proc mixed data = out_complete; 
by _ Imputation_; 
class trt_group; 
model BMD_pchg_M12 = trt_group BMD_BL/ solution; 
lsmeans trt_group /stderr diff cl alpha=0.05 (alpha=0.1 for US 
FDA); 
run; 
 
/* Estimation and inference for multiply imputed datasets*/ 
ods output ParameterEstimates=milsm; 
proc mianalyze data= lsm alpha=0.05 (alpha=0.1 for US FDA) ; 
by trt_group; 
modeleffects estimate; 
stderr stderr; 
run; 
 
ods output ParameterEstimates=midiff; 
proc mianalyze data=LSmean_diff alpha=0.05 (alpha=0.1 for US FDA); 
modeleffects estimate; 
stderr stderr; 
run;  
 
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 62 of 63 
 
/* Tipping point analysis*/ 
Monotone missing data will be imputed for a tipping point analysis with incremental or decre
mental shifts (k) of delta value for the SB16 and Prolia treatment groups independently. This 
is illustrated by the example PROC MI code shown below: 
 
/* need to define the maximum plausible BMD_pchg shift value. For 
example, 0.5 departure from group mean with ten equal space, coded 
as i= -0.5 to 0.5 by 0.1 */ 
 
%do k = - max_BMD_shift %to max_BMD_shift %by &delta;  
%do j = - max_BMD_shift %to max_BMD_shift %by &delta; 
 
 
proc mi data= out_momo seed=899745 nimpute=1 out=out_complete; 
class trt_group; 
monotone reg; 
var trt_group BMD_BL BMD_pchg_M6 BMD_pchg_M12; 
mnar   adjust(BMD_pchg_M12/ shift=&k 
adjustobs=(trt='SB16')) 
adjust(BMD_pchg_M12/ shift=&j 
adjustobs=(trt='Prolia')); 
 
run; 
 
/* repeat the primary analysis ANCOVA and combined inference for 
multiply imputed datasets as above */ 
 
%end; 
%end; 
 
 
Note: Please add BMD_pchg_M18 to code for imputation if the analysis 
includes Month 18 visit.  
 
 


SB16 (proposed denosumab biosimilar) 
SB16-3001 CSR SAP 
Version 1.0, Jan 31, 2023 
 
Samsung Bioepis – Confidential 
Page 63 of 63 
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGES 
 
SIGNATURE PAGE 
Declaration of the authors 
Protocol Title Applicable to this CSR Statistical Analysis Plan:  
A Phase III, Randomised, Double-blind, Multicentre Clinical Study to Compare the Efficacy, Safety, 
Pharmacokinetics, Pharmacodynamics, and Immunogenicity between SB16 (proposed denosumab 
biosimilar) and Prolia in Postmenopausal Women with Osteoporosis 
 
Protocol Number: SB16-3001 
Protocol Version and Effective Date:  
Amendment 1 (Version 2.0) 
May 03, 2021 
 
Authors 
Name: 
, Biostatisticis Lead  
Institution: 
Parexel 
Signature: 
 
Date: 
 
 
 
 
(Mmm dd, yyyy) 
Name: 
, Biostatistician 
Institution: 
Samsung Bioepies Co., Ltd. 
Signature: 
 
Date: 
 
 
 
 
(Mmm dd, yyyy)