Clinical trial NCT04934072
Conditions: Postmenopausal Osteoporosis
Keywords: Postmenopausal Osteoporosis FKS518 Denosumab US-licensed Prolia
Sponsor: Fresenius Kabi SwissBioSim GmbH
Start date: 2021-06-16; Completion date: 2023-08-07
Enrollment: 553 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to demonstrate equivalent efficacy of the proposed biosimilar denosumab FKS518 to US-licensed Prolia in women with postmenopausal osteoporosis (PMO).

Detailed description:

Arms: arm 1: FKS518 was administered on Day 1, and then every 26 weeks (6 months), i.e., Week 26 and Week 52, at a dose of 60 mg for a total of 3 administrations. arm 2: US-Prolia was administered on Day 1, and then every 26 weeks (6 months), i.e., Week 26 and Week 52, at a dose of 60 mg for a total of 3 administrations.
Interventions: intervention 1: FKS518 intervention 2: US-licensed Prolia (Amgen)
Intervention descriptions: intervention 1: subcutaneously by single-use prefilled syringe (PFS) intervention 2: subcutaneously by single-use PFS

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Number: FKS518-002 (LUMIADE-3) 
 
Official Title: A Double-blind, Randomized, Multicenter, Multiple-dose, 2-arm, Parallel-group 
Study to Evaluate Efficacy, Pharmacodynamics, Safety, and Immunogenicity of FKS518 -
Proposed Biosimilar to Denosumab with Prolia® in Postmenopausal Women with Osteoporosis 
(LUMIADE-3 Study) 
 
NCT Number: NCT04934072 
 
Document Date: 17 January 2023 
 
 










Sponsor Name: Fresenius Kabi SwissBioSim GmbH 
Protocol Number: FKS518-002 (LUMIADE-3) 
Protocol Version and Date: Final 6.0, 17 Jan 2023 
 
 
 
 
 
 
Confidential 
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PROTOCOL SIGNATURE PAGE – INVESTIGATOR 
A Double-blind, Randomized, Multicenter, Multiple-dose, 2-arm, Parallel-group 
Study to Evaluate Efficacy, Pharmacodynamics, Safety, and Immunogenicity of 
FKS518 - Proposed Biosimilar to Denosumab with Prolia® in Postmenopausal 
Women with Osteoporosis (LUMIADE-3 Study) 
The information contained in this protocol and all other information relevant to FKS518 
are the confidential and proprietary information of Fresenius Kabi SwissBioSim GmbH, 
and except as may be required by federal, state, or local laws or regulation, may not be 
disclosed to others without prior written permission of Fresenius Kabi SwissBioSim 
GmbH. 
I have read the protocol (Version 6.0 dated 17 Jan 2023, incorporating Protocol 
Amendment 5), including all appendices and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. I will conduct this 
study as outlined herein, in accordance with the regulations stated in the Federal Code of 
Regulations for Good Clinical Practice and International Council for Harmonisation 
guidelines and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Fresenius Kabi SwissBioSim 
GmbH or specified designees. I will discuss the material with them to ensure that they are 
fully informed about FKS518 and the study. 
My site has implemented risk minimization and the mitigation plan for COVID-19 in line 
with local regulations and best practices, including precautions such as use of personal 
protective equipment for subjects, site staff, and other visitors, site staff health-check, and 
the disinfection of site premises. 
Investigator:  Print Name; Title 
 
 
 
Institution 
 
 
 
 
 
 
Signature 
 
Date 
 
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Sponsor Name: Fresenius Kabi SwissBioSim GmbH 
Protocol Number: FKS518-002 (LUMIADE-3) 
Protocol Version and Date: Final 6.0, 17 Jan 2023 
 
 
 
 
 
 
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SERIOUS ADVERSE EVENT CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the Investigator will send a Safety Report 
Form immediately and no later than 24 hours after becoming aware of the SAE to: 
 
 
In Europe, Asia-Pacific, and Africa (EAPA): 
 
 
 
 
  
 
In the Americas: 
 
 
 
 
  
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Sponsor Name: Fresenius Kabi SwissBioSim GmbH 
Protocol Number: FKS518-002 (LUMIADE-3) 
Protocol Version and Date: Final 6.0, 17 Jan 2023 
 
 
 
 
 
 
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SUMMARY OF CHANGES 
Version 6.0, 17 Jan 2023 
Protocol Amendment 5 (Substantial) 
Rationale:  
Firstly, a Coordinating Investigator has been appointed for this study: 
  
Secondly, one of the changes included in the previous protocol amendment, clarifying 
that when 2 blood samples are required for the bone biomarker assessment the second 
sample does not need to be taken in a fasting state, had not been correctly implemented 
for the Week 52 samples, as only the pre-dose sample (fasting) is required at that visit. 
This has been corrected in the current protocol amendment.  
Similarly, one of the changes included in the previous protocol amendment, allowing 
the DXA to be performed within ±7 days of the Week 52 and Week 78 study visits, 
was not stated in all relevant sections of the protocol. This has now been corrected. 
Finally, the names of the Sponsor Signatories have been updated. 
The following changes are incorporated into Version 6.0 of the protocol: 
 
Description of change: 
A Coordinating Investigator, 
 has been included in the protocol. 
Sections of the protocol affected: 
New Coordinating Investigator Signature Page; Synopsis; Section 14; Section 18.1, 
Appendix 1. 
 
Description of change: 
Correction of wording regarding Week 52 bone biomarkers sampling. 
Sections of the protocol affected: 
Schedule of assessments Table 1, footnote n; Section 6.4. 
 
Description of change: 
Clarification that the DXA can be performed within ±7 days of the Week 52 and Week 
78 study visits. 
Sections of the protocol affected: 
Synopsis; Section 4.1; Section 6.2.1. 
 
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Sponsor Name: Fresenius Kabi SwissBioSim GmbH 
Protocol Number: FKS518-002 (LUMIADE-3) 
Protocol Version and Date: Final 6.0, 17 Jan 2023 
 
 
 
 
 
 
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The efficacy endpoints will be evaluated during the Core Treatment Period up to Week 52 (26 weeks 
after the second study drug administration), along with other endpoints, within ±7 days of the third 
investigational product (IP) injection. At Week 52, after efficacy, PD, and safety assessments have been 
performed, subjects will enter the Transition Period. Subjects who were originally randomized to receive 
US-Prolia will be re-randomized in a 1:1 ratio to receive a third administration of US-Prolia or to switch 
to FKS518 at Week 52. Subjects who discontinue the study before Week 52 will not be re-randomized. 
Subjects who were originally randomized to FKS518 will continue to receive this treatment at Week 52. 
Re-randomization will not impact the double-blind nature of the study as blinding will be kept. During 
the Transition Period, safety, immunogenicity, and efficacy data will be analyzed up to Week 78. 
In order to minimize missing data in the evaluation of the treatment effect under the treatment policy 
strategy, subjects who discontinue treatment early will be encouraged to remain in the study and attend 
all study visits of the period in which they were discontinued (Core Treatment or Transition Periods), 
even if it is decided that the next dose will not be administered.  
The clinical sites shall implement risk minimization and the mitigation plan for coronavirus disease 2019 
(COVID-19), including precautions such as use of personal protective equipment for subjects, site staff, 
and other visitors, site staff health-check, and the disinfection of site premises. 
Efficacy (including bone mineral density [BMD] and PD bone biomarkers, ie, C-terminal cross-linking 
telopeptide of type 1 collagen [CTX] and procollagen type 1 N-terminal propeptide [P1NP]), safety, 
immunogenicity, and PK assessments are detailed in the Schedule of Assessments (Table 1 and Table 2).  
Study duration: The study will include a Screening Period of maximum 4 weeks (28 days) prior to first 
drug administration, a double-blind Core Treatment Period up to Week 52, and a double-blind single 
Transition Period from Week 52 up to Week 78, with administration of the study drug on Day 1, 
Week 26 (Month 6), and Week 52 (Month 12). An End of Study Visit will be performed 26 weeks 
(6 months) after the last administration of study drug (at Week 78). Total study duration will be up to 
82 weeks (including up to 4 weeks of screening). 
The start of the study will be the date on which the first subject provides informed consent, and the end 
of the study will be the last subject’s last assessment.  
Planned number of subjects: It is planned to enroll 526 randomized subjects (263 subjects per arm) to 
obtain 446 completed subjects in the Per Protocol (PP) Analysis Set in the Core Period (up to Week 52), 
assuming a 15% drop-out rate (including clinically important protocol deviations). 
Target population: Female subjects aged ≥55 to ≤85 years with PMO.  
Inclusion criteria: 
1. Female ≥55 to ≤85 years of age, inclusive, at screening. 
2. Have a body mass index (BMI) ≥18 to ≤32 kg/m2. 
3. Subject should have confirmed postmenopausal status, defined as age-related or 
early/premature amenorrhea ≥12 consecutive months and increased follicle-stimulating 
hormone (FSH) >40 mIU/mL at screening; or surgical menopause (bilateral oophorectomy with 
or without hysterectomy) ≥12 months prior to screening. 
4. Absolute BMD consistent with T-score ≤-2.5 and ≥-4.0 at the lumbar spine as measured by 
DXA as per central assessment. 
5. At least 2 vertebrae in the L1-L4 region and at least 1 hip joint are evaluable by DXA. 
6. Clinically acceptable physical examinations and laboratory tests (hematology, clinical 
chemistry, coagulation panel, and urinalysis) and no history or evidence of any clinically 
significant concomitant medical disorder that, in the opinion of the Investigator, would pose a 
risk to subject safety or interfere with study evaluations or procedures. 
7. Subjects must voluntarily give written informed consent before any study-related activities are 
performed. Subjects must read and fully understand the ICF and the requirements of the trial 
and must be willing to comply with all trial visits and assessments. A separate Information 
Sheet (containing important information about COVID-19, clinical research study participation, 
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Protocol Number: FKS518-002 (LUMIADE-3) 
Protocol Version and Date: Final 6.0, 17 Jan 2023 
 
 
 
 
 
 
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and subject consent) will be provided to and signed by each subject to provide information on 
the general risks of study participation related to COVID-19 and to document that it is 
understood by the subject. 
Exclusion criteria: 
Disease-related  
1. History and/or presence of 1 severe or >2 moderate vertebral fractures or hip fracture confirmed 
by x-ray. 
2. Presence of active healing fracture at screening. 
3. History and/or presence of bone-related disorders, such as but not limited to Paget’s disease, 
osteomalacia, hyperparathyroidism (or parathyroid disorders), or renal osteodystrophy. 
4. Osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as invasive dental procedures (eg, 
tooth extraction, dental implants, or oral surgery in the past 6 months), poor oral hygiene, 
periodontal, and/or pre-existing dental disease as assessed by the Investigator. 
5. Evidence of hypocalcemia (albumin-adjusted serum calcium <2.13 mmol/L or <8.5 mg/dL) or 
hypercalcemia (albumin-adjusted serum calcium >2.6 mmol/L or >10.5 mg/dL) as assessed by 
the central laboratory at screening. 
6. Vitamin D deficiency (25-hydroxy vitamin D levels <12 ng/mL) as assessed by central 
laboratory at screening (retest is allowed once). 
7. Known intolerance to calcium or vitamin D supplements. 
Other medical conditions 
8. History of known or suspected clinically relevant drug hypersensitivity to any components of 
the study drug formulations, comparable drugs, or to latex.  
9. History of an episode of life-threatening or severe hypersensitivity in response to a medicinal 
product and/or environmental exposure. 
10. Renal impairment: creatinine clearance <30 mL/min at screening or receiving dialysis. 
11. Medical evidence of current or history of primary or secondary immunodeficiency as per 
Investigator’s judgment. 
12. Infection-related exclusions:  
a. 
Severe herpes zoster (disseminated, multidermatomal, herpes encephalitis, or ophthalmic 
herpes) or recurrent herpes zoster (defined as 2 episodes within 2 years), or any 
opportunistic invasive infection (eg, histoplasmosis, coccidioidomycosis, blastomycosis, 
pneumocystis, listeriosis, legionellosis, or parasitic infestations) within 6 months before 
screening. 
b. Frequent (more than 3 of the same type of infection per year requiring treatment) chronic 
or recurrent infections (eg, urinary tract or upper respiratory tract infections). 
c. 
A positive test for HIV subtype 1 or 2, or hepatitis C virus (HCV), or evidence of acute or 
chronic hepatitis B infection, evaluated by testing for hepatitis B (hepatitis B surface 
antigen [HBsAg] and/or core antibody) at screening. Polymerase chain reaction (PCR) for 
HCV RNA and hepatitis B virus (HBV) DNA is allowed to confirm active disease if HCV 
or HBV antibodies are present without a positive result for HBsAg. 
d. A serious infection defined as requiring hospitalization or treatment with intravenous 
antibiotics within 8 weeks before randomization. 
e. 
Required treatment with oral antibiotics and/or antifungal drugs within 14 days prior to 
screening. 
f. 
Confirmed or, based on the signs and symptoms observed at the time of assessment, 
suspected active COVID-19 infection at the time of screening and/or randomization.  
13. Major surgical procedure within 8 weeks prior to the screening or the subject is scheduled to 
have a surgical procedure during the study. 
14. Current or history of any malignancy, or myeloproliferative or lymphoproliferative disease 
within 5 years before screening. Exception: subjects with resected 
 basal cell or 
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squamous cell carcinoma, or carcinoma of cervix in situ that has been treated with no evidence 
of recurrence can be included. 
15. History of clinically significant drug or alcohol abuse within the last year prior to 
randomization. 
16. The subject should not participate in the study if they have any ongoing or recent (ie, at the time 
of screening) medical condition that may interfere with the study conduct, interpretation of 
study data, and/or otherwise put the subject at an unacceptable risk or could lead to 
noncompliance with requirements of the study; eg, subjects with rheumatoid arthritis or other 
autoimmune conditions are not eligible. The Investigator should specifically evaluate the 
subject’s eligibility taking into consideration COVID-19 risk factors and situation. 
Prior or concomitant therapy 
17. Prior denosumab (Prolia, Xgeva, or proposed denosumab biosimilar) exposure. 
18. Prior use of fluoride within the 5 years before inclusion in the study. 
19. Any current or prior use of strontium ranelate. 
20. Any current or prior use of intravenous bisphosphonates. Prior use of oral bisphosphonates is 
excluded if: 
a. More than 3 years cumulative use prior to screening, unless last dose received is >5 years 
prior to screening, OR 
b. Any dose within 12 months before screening, except if subject received less than 1 month 
of cumulative use between 6 and 12 months prior to screening. 
21. Current or prior use of teriparatide and other parathormone (PTH) analogs within 12 months 
before screening. 
22. Current or prior use of systemic oral or transdermal estrogen or selective estrogen receptor 
modulators or tibolone within 6 months before screening. 
23. Current or prior use of calcitonin or cinacalcet within 3 months before screening. 
24. Current or prior use of any cathepsin K inhibitor (eg, odanacatib) within 18 months before 
screening. 
25. Current or prior use of romosozumab or antisclerostin antibody. 
26. Current or prior use of other osteoporotic agents used for the prevention or treatment of 
osteoporosis will be excluded according to the Investigator’s judgment after consultation with 
the Medical Monitor. 
27. Current use within 3 months before screening of any medication with known influence on the 
skeletal system (eg, systemic corticosteroids, heparin, lithium, etc). Subjects with a stable dose 
of systemic prednisone <5 mg or equivalent systemic corticosteroid for more than 4 weeks 
before screening are eligible. However, use of systemic glucocorticosteroids ≥5 mg prednisone 
or equivalent per day for more than 14 days within 3 months before randomization is not 
permitted. 
28. Concomitant treatment with another biologic drug. 
29. Prior use of other biologic investigational drugs for the treatment of PMO. 
30. Prior use of any investigational drugs within 5 drug half-lives prior to screening or planned 
intake of an investigational drug during the course of this study. 
31. Have received a COVID-19 vaccine within 4 weeks before randomization or COVID-19 
vaccination is ongoing at the time of screening. COVID-19 vaccination is considered ongoing if 
a multidose regimen has been started but has not been completed. 
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Protocol Number: FKS518-002 (LUMIADE-3) 
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SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments: Screening to Week 52 
 
Screening 
Core Treatment Period 
(1:1 FKS518 vs US-Prolia) 
End of 
Core 
Treatment 
Period/ 
Start of 
Transition 
Period 
Visit  
V1 
V2  
V3 V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 
V15 
V16 
V17 
V18 
Week 
-4 to -1 Baseline W2 W4 W8 W12 W16 W20 W24 W26 W28 W30 W32 W36 W40 W44 W48 
W52 
Day (window) 
-28 to -1 
1  
15 
(±2) 
29 
(±2) 
57 
(±2) 
85 
(±2) 
113 
(±2) 
141 
(±2) 
169 
(±2) 
183 
(±2) 
197 
(±2) 
211  
(±2) 
225  
(±2) 
253 
(±2) 
281 
(±2) 
309 
(±2) 
337 
(±2) 
365 
(±2) 
Informed consent a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history including 
osteoporosis risk factors b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous and concomitant 
medications and procedures  
X c  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and height 
(with BMI calculation) e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG g 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Chest x-ray h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thoracic and lumbar x-ray i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
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Table 1 
Schedule of Assessments: Screening to Week 52 
 
Screening 
Core Treatment Period 
(1:1 FKS518 vs US-Prolia) 
End of 
Core 
Treatment 
Period/ 
Start of 
Transition 
Period 
Visit  
V1 
V2  
V3 V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 
V15 
V16 
V17 
V18 
Week 
-4 to -1 Baseline W2 W4 W8 W12 W16 W20 W24 W26 W28 W30 W32 W36 W40 W44 W48 
W52 
Day (window) 
-28 to -1 
1  
15 
(±2) 
29 
(±2) 
57 
(±2) 
85 
(±2) 
113 
(±2) 
141 
(±2) 
169 
(±2) 
183 
(±2) 
197 
(±2) 
211  
(±2) 
225  
(±2) 
253 
(±2) 
281 
(±2) 
309 
(±2) 
337 
(±2) 
365 
(±2) 
LS-BMD by DXA j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X u 
Femoral neck and total hip 
BMD by DXA k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X u 
FSH (subjects ≤60 years) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory m 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
 
X 
 
 
 
X 
PD (bone biomarkers) 
sampling n 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X  
X 
 
 
X 
X 
X 
X 
X 
PK sampling o 
 
X  
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity sampling p 
X 
X 
X 
X 
X 
X 
 
 
 
X  
 
 
X 
 
X 
 
 
X 
Eligibility check  
X q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization r 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
IP administration s 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Injection site reactions t 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
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Table 1 
Schedule of Assessments: Screening to Week 52 
 
Screening 
Core Treatment Period 
(1:1 FKS518 vs US-Prolia) 
End of 
Core 
Treatment 
Period/ 
Start of 
Transition 
Period 
Visit  
V1 
V2  
V3 V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 
V15 
V16 
V17 
V18 
Week 
-4 to -1 Baseline W2 W4 W8 W12 W16 W20 W24 W26 W28 W30 W32 W36 W40 W44 W48 
W52 
Day (window) 
-28 to -1 
1  
15 
(±2) 
29 
(±2) 
57 
(±2) 
85 
(±2) 
113 
(±2) 
141 
(±2) 
169 
(±2) 
183 
(±2) 
197 
(±2) 
211  
(±2) 
225  
(±2) 
253 
(±2) 
281 
(±2) 
309 
(±2) 
337 
(±2) 
365 
(±2) 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ADA=antidrug antibodies; AE=adverse event; BMD=bone mineral density; BMI=body mass index; COVID-19=coronavirus disease 2019; CTX=C-terminal 
cross-linking telopeptide of type 1 collagen; DXA=dual energy x-ray absorptiometry; ECG=electrocardiogram; FSH=follicle--stimulating hormone; 
HBcAb=hepatitis B core antibody; HBV=hepatitis B virus; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
IP=investigational product; LS-BMD=lumbar spine bone mineral density; NAb=neutralizing antibodies; P1NP=procollagen type 1 N-terminal- propeptide; 
PCR=polymerase chain reaction; PD=pharmacodynamic; PK=pharmacokinetic; V=Visit; W=Week 
a 
Informed consent must be obtained from each subject prior to performing any screening assessments. Note: A separate Information Sheet (containing 
important information about COVID-19, clinical research study participation, and subject consent) will be provided to and signed by each subject to 
provide information on the general risks of study participation related to COVID-19 and to document that it is understood by the subject. 
b 
Risk factors for osteoporosis include history of fractures, family history of hip fracture, low BMI, age ≥70 years, smoking status (former/current smoker), 
and alcohol consumption. 
c 
Subjects will be instructed to take 1000 mg calcium and at least 400 IU vitamin D supplementation daily. At screening, use of all prior and concomitant 
medication from 4 weeks before the Screening Visit and all previous osteoporosis treatments should be recorded.  
d 
A complete physical examination will be performed at Screening, Baseline, Week 26, and Week 52; a brief physical examination will be performed at all 
other study visits.  
e 
Height (by stadiometer) only at Screening, Week 26, and Week 52. Height should always be measured in the same stadiometer and following the same 
procedure (eg, without shoes). BMI will be calculated at screening only. 
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f 
Vital signs (including body temperature, respiratory rate, pulse rate, and blood pressure) will be measured after 5 minutes rest in the supine position. 
During the study, measurement of vital signs may be repeated at the discretion of the Investigator for safety reasons. Body temperature measurement 
should be performed first at each study visit and should precede every other assessment of each visit. In the case of an elevated temperature, it is the 
Investigator’s decision to determine any further actions according to local practice and their medical judgment.  
g 
Subjects are required to rest in a supine position for at least 5 minutes prior to recording of 12-lead ECG. ECGs will be assessed locally. 
h 
If a chest x-ray or radiograph was taken within 2 months prior to screening and shows no clinically significant abnormality, and there are no signs and 
symptoms suggestive of pulmonary disease that would exclude the subject from the study, then a chest x-ray or radiograph does not need to be repeated at 
screening. 
i 
Previous x-rays taken within 6 months prior to screening will be acceptable. Images will be evaluated centrally and should be submitted to the central 
imaging vendor. Additional spine x-rays will be performed if there is a suspicion of a fracture (eg, new onset of persistent or pronounced back pain or 
material worsening of back pain); these will be assessed locally. 
j 
The same DXA system (ie, Lunar or Hologic) must be used for all study procedures for a particular subject for the duration of the study. All DXA scan 
data will be submitted electronically to the central imaging vendor for analysis. DXA scans of the lumbar spine will be performed in duplicate, ie, subjects 
will be removed from the table in between scans. Lumbar spine scans must include L1 through L4. 
k 
The same DXA system (ie, Lunar or Hologic) must be used for all study procedures for a particular subject for the duration of the study. All DXA scan 
data will be submitted electronically to the central imaging vendor for analysis. For proximal femur DXA scans, the left side should be used for all scans 
at all study visits. If the right side must be used (eg, due to implants) or is inadvertently used at baseline, then it must be used consistently throughout the 
study. If a subject fractures the hip that has been scanned during the study up to the time of fracture, no further scans will be obtained for the affected 
location. 
l 
Includes tests for HIV-1 and HIV-2, HBsAg, HBcAb, and HCV antibody. Note: Reflex testing by PCR for HCV RNA and HBV DNA is allowed if HCV 
or HBV antibodies are present without a positive result for HBV surface antigen. 
m 
Clinical laboratory tests will include hematology, clinical chemistry, coagulation panel (screening only), and urinalysis (dipstick). 
n 
Bone biomarkers: serum CTX and P1NP. Blood sampling must be collected in the morning (between 8:00 and 10:00 am) after an overnight fast. On the 
first 2 dosing days (Day 1 and Week 26), 2 samples will be obtained for bone biomarkers: pre-dose (between 8:00 and 10:00 am and fasting) and 
5±1 hours post-dose (not fasting). On the third dosing day (Week 52), only the pre-dose sample (between 8:00 and 10:00 am and fasting) will be obtained. 
o 
PK samples must be collected prior to the immunogenicity sampling. On dosing days (Day 1, Week 26, and Week 52), 2 PK samples will be obtained: 
pre-dose and 5 ±1 hours post-dose. 
p 
Blood sampling for immunogenicity (ADA and NAb). Blood samples must be drawn prior to the IP when applicable, and the PK samples must be 
collected prior to the immunogenicity sampling. Separate samples will be collected for ADA and NAb assessments. The screening sample will be used for 
assay validation purposes, it will not be reported in the results. 
q 
Eligibility check to include COVID-19 eligibility, to be performed by the Investigator and the Medical Monitor.  
r 
On Day 1, subjects will be randomized in a 1:1 allocation ratio into 2 arms: US-Prolia or FKS518. At Week 52, the subjects in the US-Prolia arm will be 
1:1 randomized into 2 separate arms to either continue with US-Prolia or to transition to FKS518. 
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s 
Proposed biosimilar FKS518 and reference product will be injected as a single subcutaneous dose of 60 mg every 26 weeks; 3 drug administrations within 
78 weeks. 
t 
Late onset injection site reactions to be documented as recommended in the electronic case report form completion guide. 
u 
DXA can be performed within ±7 days of Day 365. 
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Table 2 
Schedule of Assessments: Week 52 to Week 78 – End of Study 
 
Transition Period 
End of Study/  
Early 
Termination a 
Visit  
V18 
V19 
V20 
V21 
V22 
V23 
V24 
Week 
W52 
W56 
W60 
W64 
W68 
W72 
W78 
Day (window) 
365 
(±2) 
393 
(±2) 
421 
(±2) 
449 
(±2) 
477 
(±2) 
505 
(±2) 
547 
(±7) 
Concomitant medication and procedures 
X 
X 
X 
X 
X 
X 
X 
Physical examination b 
X 
X 
X 
X 
X 
X 
X 
Body weight and height (with BMI calculation) c 
X 
X 
X 
X 
X 
X 
X 
Vital signs d 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG e 
X 
 
 
 
 
 
X 
Thoracic and lumbar x-ray f  
(X) 
 
 
 
 
 
(X) 
LS-BMD by DXA g 
X n 
 
 
 
 
 
X n 
Femoral neck and total hip BMD by DXA h 
X n 
 
 
 
 
 
X n 
Clinical laboratory i 
X 
X 
 
 
X 
 
X 
PD (biomarkers sampling) j 
X 
 
 
 
 
 
 
PK sampling k 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity sampling l 
X 
 
 
X 
 
 
X 
Injection site reaction m 
X 
X 
 
 
 
 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
ADA=antidrug antibodies; AE=adverse event; BMD=bone mineral density; BMI=body mass index; CTX=C-terminal cross-linking telopeptide of type 1 
collagen; DXA=dual energy x-ray absorptiometry; ECG=electrocardiogram; IP=investigational product; LS-BMD=lumbar spine bone mineral density; 
NAb=neutralizing antibodies; P1NP=procollagen type 1 N-terminal propeptide; PD=pharmacodynamic; PK=pharmacokinetic; V=Visit; W=Week 
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a 
The Week 78 Visit procedures will be performed for the End of Study Visit and the Early Termination Visit. In case of premature discontinuation from the 
study, the Investigator should make every effort to ensure the subject completes the Early Termination visit as soon as possible, but not earlier than 
4 weeks after last injection (for immunogenicity assessment). 
If a subject discontinues IP prior to Week 52, the subject will remain in the study up to the completion of the Week 52 assessments. If a subject 
discontinues IP during the Transition Period, the subject will remain in the study up to the completion of the End of the Study Visit. 
b 
A complete physical examination will be performed at Week 52 and at the End of Study/Early Termination Visit; a brief physical examination will be 
performed at the remaining study visits. 
c 
Height (by stadiometer) only at Week 52 and Week 78/End of Study. Height should always be measured in the same stadiometer and following the same 
procedure (eg, without shoes). BMI will be calculated at screening only. 
d 
Vital signs (including body temperature, respiratory rate, pulse rate, and blood pressure) will be measured after 5 minutes rest in the supine position. 
During the study, measurement of vital signs may be repeated at the discretion of the Investigator for safety reasons. Body temperature measurement 
should be performed first at each study visit and should precede every other assessment of each visit. In the case of an elevated temperature, it is the 
Investigator’s decision to determine any further actions according to local practice and their medical judgment.  
e 
Subjects are required to rest in a supine position for at least 5 minutes prior to recording of 12-lead ECG. ECGs will be assessed locally. 
f 
Spine x-rays will be performed if there is a suspicion of a fracture (eg, new onset of persistent or pronounced back pain or material worsening of back 
pain); these will be assessed locally. 
g 
The same DXA system (ie, Lunar or Hologic) must be used for all study procedures for a particular subject for the duration of the study. All DXA scan 
data will be submitted electronically to the central imaging vendor for analysis. DXA scans of the lumbar spine will be performed in duplicate, ie, subjects 
will be removed from the table in between scans. Lumbar spine scans must include L1 through L4. 
h 
The same DXA system (ie, Lunar or Hologic) must be used for all study procedures for a particular subject for the duration of the study. All DXA scan 
data will be submitted electronically to the central imaging vendor for analysis. For proximal femur DXA scans, the left side should be used for all scans 
at all study visits. If the right side must be used (eg, due to implants) or is inadvertently used at baseline, then it must be used consistently throughout the 
study. If a subject fractures the hip that has been scanned during the study up to the time of fracture, no further scans will be obtained for the affected 
location. 
i 
Clinical laboratory tests will include hematology, clinical chemistry, and urinalysis (dipstick). 
j 
Bone biomarkers: serum CTX and P1NP. Blood sampling must be collected in the morning (between 8:00 and 10:00 am) after an overnight fast.  
k 
PK samples must be collected prior to the immunogenicity sampling.  
l 
Blood sampling for immunogenicity (ADA and NAb). Blood samples must be drawn prior to the IP when applicable, and the PK samples must be 
collected prior to the immunogenicity sampling. Separate samples will be collected for ADA and NAb assessments. 
m 
Late onset injection site reactions to be documented as recommended in the electronic case report form completion guide. 
n 
DXA can be performed within ±7 days of the Day 365 and Day 547. 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...................................................................................1 
PROTOCOL SIGNATURE PAGE – SPONSOR ...........................................................2 
PROTOCOL SIGNATURE PAGE – CONTRACT RESEARCH 
ORGANIZATION ......................................................................................................3 
PROTOCOL SIGNATURE PAGE – COORDINATING INVESTIGATOR .............4 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR ...............................................5 
SERIOUS ADVERSE EVENT CONTACT INFORMATION .....................................6 
SUMMARY OF CHANGES .............................................................................................7 
PROTOCOL SUMMARY ..............................................................................................17 
STUDY SCHEMATIC ....................................................................................................24 
SCHEDULE OF ASSESSMENTS .................................................................................25 
TABLE OF CONTENTS ................................................................................................32 
LIST OF TABLES ...........................................................................................................35 
LIST OF FIGURES .........................................................................................................35 
LIST OF ABBREVIATIONS .........................................................................................36 
1 
INTRODUCTION AND RATIONALE .................................................................39 
1.1 
Background ..........................................................................................................39 
1.1.1 
Background ....................................................................................................39 
1.1.2 
Nonclinical Studies .........................................................................................39 
1.1.3 
Clinical Studies ...............................................................................................40 
1.2 
Study Rationale ....................................................................................................40 
1.3 
Benefit/Risk Assessment ......................................................................................40 
2 
STUDY OBJECTIVES ............................................................................................42 
2.1 
Primary Objective ................................................................................................42 
2.2 
Secondary Objectives...........................................................................................42 
 
 
3 
STUDY ENDPOINTS ..............................................................................................43 
3.1 
Primary Endpoint ................................................................................................43 
3.2 
Secondary Endpoints ...........................................................................................43 
 
 
4 
STUDY PLAN ...........................................................................................................45 
4.1 
Overall Study Design and Plan ...........................................................................45 
4.2 
Discussion of Study Design ..................................................................................46 
4.3 
End of Study .........................................................................................................47 
5 
STUDY POPULATION ...........................................................................................48 
5.1 
Inclusion Criteria .................................................................................................48 
5.2 
Exclusion Criteria ................................................................................................49 
5.3 
Screen Failures .....................................................................................................52 
5.4 
Premature Discontinuation .................................................................................52 
5.4.1 
Premature Discontinuation of Investigational Product..............................52 
5.4.2 
Premature Discontinuation from the Study ................................................54 
5.4.3 
Lost to Follow-up ...........................................................................................55 
5.4.4 
Medical Care of Subjects After End of Study .............................................55 
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6 
DESCRIPTION OF STUDY ASSESSMENTS ......................................................56 
6.1 
Demographics and Other Screening Assessments ............................................56 
6.1.1 
Informed Consent ..........................................................................................56 
6.1.2 
Medical History, Disease-related History, and Prior and 
Concomitant Medications and Procedures ..................................................56 
6.1.3 
Demographics .................................................................................................57 
6.2 
Efficacy Assessments ...........................................................................................57 
6.2.1 
Dual Energy X-ray Absorptiometry .............................................................57 
6.3 
Safety and Tolerability Assessments ..................................................................58 
6.3.1 
General Considerations .................................................................................58 
6.3.2 
Monitoring of Subjects with Adverse Events ..............................................58 
6.3.3 
Local Tolerability ...........................................................................................59 
6.3.4 
Physical Examination ....................................................................................59 
6.3.5 
Body Weight and Height ...............................................................................60 
6.3.6 
Vital Signs .......................................................................................................60 
6.3.7 
Electrocardiograms........................................................................................60 
6.3.8 
Chest X-ray .....................................................................................................61 
6.3.9 
Thoracolumbar Spine X-ray .........................................................................61 
6.3.10 
Clinical Laboratory Assessments .................................................................61 
6.4 
Pharmacodynamics: Bone Biomarkers..............................................................63 
 
 
6.6 
Immunogenicity....................................................................................................65 
7 
TREATMENTS ........................................................................................................67 
7.1 
Investigational Products ......................................................................................67 
7.1.1 
Description of Investigational Products .......................................................67 
7.1.2 
Preparation, Handling, and Storage ............................................................67 
7.1.3 
Packaging, Labeling, and Shipment .............................................................68 
7.2 
Blinding .................................................................................................................68 
7.3 
Method of Assigning Treatment .........................................................................68 
7.4 
Dose and Administration .....................................................................................69 
7.4.1 
Delayed Investigational Product Dose .........................................................70 
7.4.2 
Dose Modification ..........................................................................................70 
7.4.3 
Intervention After the End of the Study ......................................................70 
7.5 
Precautions and/or Lifestyle Considerations.....................................................70 
7.6 
Prior and Concomitant Medications and Procedures ......................................71 
7.6.1 
Permitted Medications...................................................................................71 
7.6.2 
Prohibited Medications .................................................................................72 
7.7 
Overdose ...............................................................................................................73 
7.8 
Compliance ...........................................................................................................74 
7.9 
Accountability ......................................................................................................74 
8 
ADVERSE EVENTS ................................................................................................75 
8.1 
Adverse Events Definitions .................................................................................75 
8.1.1 
Adverse Event.................................................................................................75 
8.1.2 
Severity Grading ............................................................................................75 
8.1.3 
Causality Assessment .....................................................................................75 
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8.1.4 
Abnormal Laboratory Findings and Other Abnormal 
Investigational Findings ................................................................................76 
8.1.5 
Serious Adverse Events .................................................................................76 
8.1.6 
Events that Do Not Meet the Definition of an SAE.....................................77 
8.1.7 
Events Not to Be Considered as AEs/SAEs .................................................77 
8.1.8 
Adverse Events of Special Interest ...............................................................77 
8.2 
Methods of Recording and Assessing Adverse Events .....................................78 
8.3 
Definition of the Adverse Event Reporting Period ...........................................78 
8.4 
Procedure for Reporting Serious Adverse Events, Adverse Events of 
Special Interest, and Dose Limiting Toxicities ..................................................79 
8.4.1 
Serious Adverse Events .................................................................................79 
8.4.2 
Adverse Events of Special Interest ...............................................................79 
8.4.3 
Unexpected Adverse Reactions .....................................................................79 
8.4.4 
Pregnancy and In Utero Drug Exposure .....................................................80 
8.5 
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards, and Investigators .........................81 
9 
STATISTICS .............................................................................................................83 
9.1 
General Procedures .............................................................................................83 
9.2 
Analysis Populations ............................................................................................83 
9.3 
Sample Size ...........................................................................................................84 
9.4 
Statistical Methods ...............................................................................................85 
9.4.1 
Primary Efficacy Analyses ............................................................................85 
9.4.1.1 
Percent Change from Baseline in LS-BMD by DXA at Week 52 ........85 
9.4.1.2 
AUEC of Serum CTX up to Week 26 (for MAA in the EU and 
EEA only) ..................................................................................................87 
9.4.2 
Secondary Efficacy Analyses ........................................................................88 
9.4.3 
Secondary Pharmacodynamic Analyses ......................................................88 
9.4.4 
Other Efficacy Analyses ................................................................................88 
9.4.5 
Safety Analyses ...............................................................................................88 
9.4.6 
Immunogenicity Analyses .............................................................................89 
9.4.7 
Demographic and Baseline Characteristics .................................................89 
 
 
9.4.9 
Subgroup Analyses.........................................................................................90 
9.4.10 
Handling of Missing Values ..........................................................................90 
9.5 
Interim Analysis ...................................................................................................90 
10 ETHICS AND RESPONSIBILITIES .....................................................................91 
10.1 
Good Clinical Practice .........................................................................................91 
10.2 
Institutional Review Board/Independent Ethics Committee ...........................91 
10.3 
Informed Consent ................................................................................................92 
10.4 
Financing and Insurance .....................................................................................93 
10.4.1 
Study Agreement ............................................................................................93 
10.4.2 
Insurance, Indemnity, and Compensation...................................................93 
10.4.3 
Financial Disclosure .......................................................................................93 
11 RECORDS MANAGEMENT..................................................................................94 
11.1 
Source Documentation.........................................................................................94 
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LIST OF ABBREVIATIONS 
ADA 
antidrug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUEC 
area under the effect curve  
BMD 
bone mineral density 
BMI  
body mass index 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019 
CRO 
Contract Research Organization 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
C-terminal cross-linking telopeptide of type 1 collagen 
DXA 
dual energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
EEA 
European Economic Area  
EMA 
European Medicines Agency 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FKSBS 
Fresenius Kabi SwissBioSim GmbH (the Sponsor) 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
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HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology 
ISR 
injection site reaction 
ITT 
Intention-to-Treat 
log 
logarithm 
LS 
least squares 
LS-BMD 
lumbar spine bone mineral density 
MAA 
Marketing Authorization Application 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
neutralizing antibodies 
NCI 
National Cancer Institute 
ONJ 
osteonecrosis of the jaw 
P1NP 
procollagen type 1 N-terminal propeptide 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PFS 
prefilled syringe 
 
 
PMO 
postmenopausal osteoporosis 
PP 
Per Protocol 
PTH 
parathormone 
RMP 
reference medicinal product 
RP 
reference product 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SMQ 
standardized Medical Dictionary for Regulatory Activities queries 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
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ULN 
upper limit of normal 
US 
United States (of America) 
WHO 
World Health Organization 
 
 
 
 
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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
1.1.1 
Background 
Denosumab is a fully human monoclonal antibody of immunoglobulin G2 subtype, 
inhibiting receptor activator of nuclear factor kappa-Β ligand, which is an essential factor 
for the formation, activation, and survival of osteoclasts. Its production is increased when 
estrogen is decreased, as it is after menopause and in conditions of hormone ablation, 
leading to an increased bone resorption.  
Denosumab is marketed in the European Union (EU) and United States (US) as Prolia® 
and Xgeva®. Prolia is indicated for the treatment of osteoporosis in postmenopausal 
women and in men at increased risk of fractures. It is also approved as treatment of bone 
loss associated with hormone ablation in men with prostate cancer at increased risk of 
fractures, and in adult patients with long-term systemic glucocorticoid therapy at 
increased risk of fracture. Indications for Xgeva include treatment of giant cell tumor of 
bone and prevention of skeletal-related events in patients with cancer. 
Prolia (60 mg) and Xgeva (120 mg) contain the same active substance (denosumab) and 
qualitatively the same excipients, but differ in strength and presentation. The mechanism 
of action of denosumab is the same across all indications currently approved for the 
reference products (RPs)/reference medicinal products (RMPs) Prolia and Xgeva (Prolia 
European Public Assessment Report [EPAR] Product Information, Xgeva EPAR Product 
Information, Food and Drug Administration [FDA] Prolia Prescribing Information, 
FDA Xgeva Prescribing Information).  
FKS518, containing the active substance denosumab, is being developed by Fresenius 
Kabi SwissBioSim GmbH (FKSBS, the Sponsor) as a proposed biosimilar to Prolia and 
Xgeva.  
1.1.2 
Nonclinical Studies 
A panel of state-of-the-art and fit-for-purpose methods measuring physicochemical and 
biological properties has been used to evaluate the analytical comparability, indicating 
similar results between FKS518 and the EU-approved RMP and the US-licensed RP 
Prolia and Xgeva. Based on the results of extensive structural and biological 
characterization to date, it is considered that the safety profile of the proposed biosimilar 
will be similar to that of the RP. Therefore, no animal studies are currently planned in the 
development program for FKS518, which is consistent with the European Medicines 
Agency (EMA) regulatory requirements for biosimilar development 
(EMA/CHMP/BMWP/403543/2010).  
Refer to the Investigator’s Brochure for further details on the nonclinical development. 
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1.1.3 
Clinical Studies 
The pharmacokinetic (PK) features of denosumab were evaluated in clinical studies of 
Prolia and Xgeva. The FKS518 clinical development plan is based on the available PK, 
efficacy, and safety data accumulated for the RP/RMP. In accordance with EMA 
Guideline (2012) and FDA Guidance (2016), the clinical comparability program of 
FKS518 consists of the following 2 clinical studies: 
• A Phase I PK, pharmacodynamic (PD), safety, and immunogenicity study comparing 
the proposed denosumab biosimilar FKS518 with US-Prolia in healthy subjects 
(Study FKS518-001). 
• The current Phase III efficacy, PD, safety, and immunogenicity study comparing the 
proposed denosumab biosimilar FKS518 with US-Prolia in women with 
postmenopausal osteoporosis (PMO). 
Subjects in the Phase III study will not be dosed until the first 10 subjects in the 
comparative Phase I PK/PD study have been exposed to a single dose of either FKS518 
or US-Prolia and followed for 48 hours and, after being evaluated by the Sponsor, no 
unexpected safety profile indicative of a materially altered benefit risk that would 
prohibit further recruitment of subjects is detected.  
1.2 
Study Rationale 
The purpose of this clinical study is to evaluate the efficacy, PD, safety, and 
immunogenicity of FKS518, a proposed biosimilar to denosumab compared to the 
US-licensed Prolia (US-Prolia), in women with PMO. Limits to prior osteoporosis 
treatment that could add risk for cumulative effect or affect the interpretation of results 
have been established as exclusion criteria. 
Data from this study, combined with the Phase I PK/PD equivalence study FKS518-001 
in healthy volunteers, will provide evidence to support similarity between FKS518 and 
denosumab in terms of PK, PD, efficacy, safety, tolerability, and immunogenicity. 
1.3 
Benefit/Risk Assessment 
FKS518 shows structural and functional similarity with the RP, US-Prolia, pointing 
toward a commonality of benefits and risks between FKS518 and the RP.  
The safety profile of denosumab is considered well-established through extensive 
experience in clinical studies and post-marketing surveillance, providing a robust 
reference point for safety assessment of the proposed biosimilar product. In general, 
biologic agents are highly specific in their pharmacologic actions. The predominant 
manifestations of their toxicity are the consequences of on-target effects, so called 
exaggerated pharmacology. Accordingly, most of the adverse effects causally related to 
denosumab appear to derive from its PD effects (ie, suppression of bone turnover). These 
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exaggerated pharmacology-related adverse events (AEs) include common events such as 
hypocalcemia, hypophosphatemia, and musculoskeletal pain, as well as relatively rare or 
uncommon events such as osteonecrosis/avascular necrosis (including osteonecrosis of 
the jaw [ONJ]) and atypical fractures. 
As high analytical similarity between FKS518 and the RP has been demonstrated, the 
AEs related to exaggerated PD effects can be expected at similar frequencies and, thus, 
the probability of detecting unexpected adverse effects is very low. The clinical benefits 
of FKS518 are based on the same PD effects. 
Minor variations in the safety profile between FKS518 and the RP cannot be excluded. If 
these are to become clinically noticeable, they are most likely to manifest in the form of 
hypersensitivity as a consequence of the discriminatory ability of the immune system. 
Occurrence of Grade ≥3 or serious hypersensitivity has been classified as an adverse 
event of special interest (AESI) and will be closely monitored during all clinical 
investigations with FKS518. 
More detailed information about the known and expected benefits, risks, and reasonably 
expected AEs of FKS518 can be found in the Investigator’s Brochure.  
Considering the measures taken to minimize risk to subjects participating in this study, 
the potential risks identified in association with FKS518 are justified by the anticipated 
benefits that may be afforded to subjects with PMO. 
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3 STUDY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint is the percent change from baseline in lumbar spine bone mineral 
density (LS-BMD) by dual energy x-ray absorptiometry (DXA) at Week 52. 
For MAA in the EU and EEA only: The co-primary endpoint is the area under the effect 
curve (AUEC) of serum C-terminal cross-linking telopeptide of type 1 collagen (CTX) up 
to Week 26. 
Information about the corresponding estimands is provided in Section 9.4.1. 
3.2 
Secondary Endpoints 
Efficacy: 
•
Percent change from baseline in bone mineral density (BMD) at femoral neck and
total hip by DXA at Week 52.
Pharmacodynamic: 
•
Percent change from baseline in serum procollagen type 1 N-terminal propeptide
(P1NP) at Week 52.
•
Percent change from baseline in serum CTX at Week 52.
Safety and tolerability: 
•
Occurrence of treatment-emergent adverse events (TEAEs), including serious adverse
events (SAEs) during the Core Treatment Period, Transition Period, and overall.
•
Occurrence of treatment-emergent AESIs: drug-related hypersensitivity/allergic
reactions (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥3 or
reported as SAEs) and AEs leading to investigational product (IP) discontinuation or
study withdrawal during the Core Treatment Period, Transition Period, and overall.
•
Occurrence of injection site reactions (ISRs) (local tolerability) during the Core
Treatment Period, Transition Period, and overall.
Immunogenicity: 
•
Antidrug antibody (ADA) incidence during the Core Treatment Period, Transition
Period, and overall.
•
ADA titer during the Core Treatment Period and Transition Period.
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4 STUDY PLAN 
4.1 
Overall Study Design and Plan 
This is a double-blind, randomized, multicenter, 2-arm, multiple-dose, parallel-group 
study with a transition period, to compare efficacy, safety, tolerability, and 
immunogenicity of the proposed biosimilar to denosumab FKS518 with US-Prolia in 
ambulatory women with PMO. Bone biomarkers (PD) and PK will also be assessed. The 
study design is outlined in Figure 1. 
This study will enroll female subjects aged 55 to 85 years with confirmed 
postmenopausal status and LS-BMD T-score ≤-2.5 and ≥-4.0, as measured by DXA. 
Subjects will be instructed to take 1000 mg calcium and at least 400 IU vitamin D 
supplementation daily. 
The Investigator will obtain signed informed consent form (ICF) from the subject before 
any study procedures are performed. Subjects whose eligibility is confirmed at baseline 
will be randomized in a 1:1 ratio by an Interactive Response Technology (IRT) system to 
receive either FKS518 or US-Prolia at a dose of 60 mg delivered by subcutaneous 
injection starting at Day 1, and then every 26 weeks (6 months) for a total of 
3 administrations within 78 weeks. Randomization will be stratified by age (<65 years; 
≥65 years), and prior bisphosphonates therapy (Yes; No). Subjects in this study will not 
be dosed until the first 10 subjects in the comparative Phase I PK/PD study 
(FKS518-001) have been exposed to a single dose of either FKS518 or US-Prolia and 
followed for 48 hours and, after being evaluated by the Sponsor, no unexpected safety 
profile indicative of a materially altered benefit-risk that would prohibit further 
recruitment of subjects is detected. 
The efficacy endpoints will be evaluated during the Core Treatment Period up to 
Week 52 (26 weeks after the second study drug administration), along with other 
endpoints, within ±7 days of the third IP injection. At Week 52, after efficacy and safety 
assessments have been performed, subjects will enter the Transition Period. Subjects who 
were originally randomized to receive US-Prolia will be re-randomized in a 1:1 ratio to 
receive a third administration of US-Prolia or to switch to FKS518 at Week 52. Subjects 
who discontinue the study before Week 52 will not be re-randomized. Subjects who were 
originally randomized to FKS518 will continue to receive this treatment at Week 52. 
During the Transition Period, safety, immunogenicity, and efficacy data will be analyzed 
up to Week 78. 
The study will have a duration of up to 82 weeks, including a Screening Period of 
maximum 4 weeks (28 days) prior to first drug administration, a double-blind Core 
Treatment Period up to Week 52, and a double-blind single Transition Period from 
Week 52 up to Week 78, with administration of the study drug on Day 1, Week 26 
(Month 6), and Week 52 (Month 12). An End of Study Visit will be performed 26 weeks 
(6 months) after the last administration of study drug (at Week 78). 
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In order to minimize missing data in the evaluation of the treatment effect under the 
treatment policy strategy, subjects who discontinue treatment early will be encouraged to 
remain in the study and attend all study visits of the period in which they were 
discontinued (Core Treatment or Transition Periods), even if it is decided that the next 
dose will not be administered.  
The clinical sites shall implement risk minimization and the mitigation plan for 
coronavirus disease 2019 (COVID-19), including precautions such as use of personal 
protective equipment for subjects, site staff, and other visitors, site staff health-check, and 
the disinfection of site premises. 
Efficacy (including BMD and PD bone biomarkers [ie, CTX and P1NP]), safety, 
immunogenicity, and PK assessments are detailed in the Schedule of Assessments 
(Table 1 and Table 2). 
4.2 
Discussion of Study Design 
The proposed clinical study is a double-blind, randomized, multicenter, 2-arm, multiple 
subcutaneous dose, parallel-group study with a single transition period, in women with 
PMO. The proposed study design allows a comparison of the efficacy, safety, and 
immunogenicity between FSK518 and US-licensed Prolia to be made. Additionally, 
further to FDA request, the comparative clinical study will assess the safety of a single 
transition from US-Prolia to FKS518 (compared to continuation of US-Prolia). The single 
transition will allow to evaluate general safety, hypersensitivity, and immunogenicity 
after switching from the RP to the biosimilar.  
The indication selected for the study is PMO women. This indication is considered to be 
the most sensitive and most likely to show any clinical differences between FKS518 and 
Prolia. Contraindications and special warnings for Prolia are taken into account as 
exclusion criteria in this study. Since age and previous treatment with bisphosphonates 
are known factors affecting efficacy, subjects will be stratified by age (<65 years; 
≥65 years) and previous treatment with bisphosphonates (Yes; No). The stratification is 
based on correlation of primary efficacy endpoint with age and extent of bone loss. 
Previous treatment with bisphosphonates is related to the efficacy and baseline CTX 
values. 
The selected primary endpoint LS-BMD is the most widely used PD measure correlated 
with fracture risk. BMD has a very low dynamic range and very high inter-subject 
variability making it a less sensitive marker. The limits of the acceptance range for the 
primary endpoint, percent change from baseline in LS-BMD at Week 52, are based on the 
meta-analysis of the following 3 FDA-reviewed studies which determined the treatment 
effect of denosumab compared to placebo as 5.35% (95% confidence interval [CI]: 
4.83% to 5.87%): Bone, 2008; Cummings, 2009; and McClung, 2006. 
The resorption marker serum CTX is a less universally validated endpoint for fracture 
risk than BMD, but it is a sensitive PD parameter to detect potential differences between 
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biosimilar denosumab and the RP (Vasikaran, 2011). Suppression of serum CTX levels 
occurs early in contrast to slow BMD increases after administration of denosumab. 
Serum CTX is selected as a secondary endpoint (change from baseline to Week 52), and 
as a co-primary endpoint (AUEC[0-W26]) for MAA in the EU and EEA only. To assess 
that the change in bone formation is similar between the biosimilar and the RP, the bone 
formation marker P1NP is also selected as secondary endpoint. 
A duration of 12 months (ie, 2 cycles of treatment) is considered appropriate for 
evaluation of efficacy, as it represents a time point when the BMD increase is measurable 
but has not reached a plateau. 
In agreement with EMA and FDA, the selected dose is the approved dose of Prolia: 
60 mg denosumab every 6 months by subcutaneous administration. 
4.3 
End of Study 
For each subject, participation in the study ends with the completion of the End of Study 
Visit. The study overall ends when the last subject has completed the last study visit.  
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5 STUDY POPULATION 
It is planned to enroll 526 randomized subjects (263 subjects per arm) in approximately 
75 sites globally.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
The following inclusion criteria must be met for a subject to be eligible for inclusion in 
the study: 
1. Female ≥55 to ≤85 years of age, inclusive, at screening. 
2. Have a body mass index (BMI) ≥18 to ≤32 kg/m2. 
3. Subject should have confirmed postmenopausal status, defined as age-related or 
early/premature amenorrhea ≥12 consecutive months and increased 
follicle-stimulating hormone (FSH) >40 mIU/mL at screening; or surgical menopause 
(bilateral oophorectomy with or without hysterectomy) ≥12 months prior to screening 
(see Section 6.1.2 for details on required FSH testing). 
4. Absolute BMD consistent with T-score ≤-2.5 and ≥-4.0 at the lumbar spine as 
measured by DXA as per central assessment. 
5. At least 2 vertebrae in the L1-L4 region and at least 1 hip joint are evaluable by DXA. 
6. Clinically acceptable physical examinations and laboratory tests (hematology, clinical 
chemistry, coagulation panel, and urinalysis) and no history or evidence of any 
clinically significant concomitant medical disorder that, in the opinion of the 
Investigator, would pose a risk to subject safety or interfere with study evaluations or 
procedures. 
7. Subjects must voluntarily give written informed consent before any study-related 
activities are performed. Subjects must read and fully understand the ICF and the 
requirements of the trial and must be willing to comply with all trial visits and 
assessments. A separate Information Sheet (containing important information about 
COVID-19, clinical research study participation and subject consent) will be provided 
to and signed by each subject to provide information on the general risks of study 
participation related to COVID-19 and to document that it is understood by the 
subject. 
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5.2 
Exclusion Criteria 
A subject who meets any of the following exclusion criteria will not be eligible for 
inclusion in the study: 
Disease-related  
1. History and/or presence of 1 severe or >2 moderate vertebral fractures or hip fracture 
confirmed by x-ray (see Section 6.3.9 for definition of severe and moderate fracture). 
2. Presence of active healing fracture at screening. 
3. History and/or presence of bone-related disorders, such as but not limited to Paget’s 
disease, osteomalacia, hyperparathyroidism (or parathyroid disorders), or renal 
osteodystrophy. 
4. Osteonecrosis of the jaw or risk factors for ONJ such as invasive dental procedures 
(eg, tooth extraction, dental implants, or oral surgery in the past 6 months), poor oral 
hygiene, periodontal, and/or pre-existing dental disease as assessed by the 
Investigator. 
5. Evidence of hypocalcemia (albumin-adjusted serum calcium <2.13 mmol/L or 
<8.5 mg/dL) or hypercalcemia (albumin-adjusted serum calcium >2.6 mmol/L or 
>10.5 mg/dL) as assessed by the central laboratory at screening. 
6. Vitamin D deficiency (25-hydroxy vitamin D levels <12 ng/mL) as assessed by 
central laboratory at screening (retest is allowed once). 
7. Known intolerance to calcium or vitamin D supplements. 
Other Medical Conditions 
8. History of known or suspected clinically relevant drug hypersensitivity to any 
components of the study drug formulations, comparable drugs, or to latex.  
9. History of an episode of life-threatening or severe hypersensitivity in response to a 
medicinal product and/or environmental exposure. 
10. Renal impairment: creatinine clearance <30 mL/min at screening or receiving 
dialysis. 
11. Medical evidence of current or history of primary or secondary immunodeficiency as 
per Investigator’s judgment. 
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12. Infection-related exclusions:  
a. Severe herpes zoster (disseminated, multidermatomal, herpes encephalitis, or 
ophthalmic herpes) or recurrent herpes zoster (defined as 2 episodes within 
2 years), or any opportunistic invasive infection (eg, histoplasmosis, 
coccidioidomycosis, blastomycosis, pneumocystis, listeriosis, legionellosis, or 
parasitic infestations) within 6 months before screening. 
b. Frequent (more than 3 of the same type of infection per year requiring treatment) 
chronic or recurrent infections (eg, urinary tract or upper respiratory tract 
infections). 
c. A positive test for HIV subtype 1 or 2, or hepatitis C virus (HCV), or evidence of 
acute or chronic hepatitis B infection, evaluated by testing for hepatitis B 
(hepatitis B surface antigen [HBsAg] and/or core antibody) at screening. 
Polymerase chain reaction (PCR) for HCV RNA and hepatitis B virus (HBV) 
DNA is allowed to confirm active disease if HCV or HBV antibodies are present 
without a positive result for HBsAg. 
d. A serious infection defined as requiring hospitalization or treatment with 
intravenous antibiotics within 8 weeks before randomization. 
e. Required treatment with oral antibiotics and/or antifungal drugs within 14 days 
prior to screening. 
f. Confirmed or, based on the signs and symptoms observed at the time of 
assessment, suspected active COVID-19 infection at the time of screening and/or 
randomization.  
13. Major surgical procedure within 8 weeks prior to the screening or the subject is 
scheduled to have a surgical procedure during the study. 
14. Current or history of any malignancy, or myeloproliferative, or lymphoproliferative 
disease within 5 years before screening. Exception: subjects with resected cutaneous 
basal cell or squamous cell carcinoma, or carcinoma of cervix in situ that has been 
treated with no evidence of recurrence can be included. 
15. History of clinically significant drug or alcohol abuse within the last year prior to 
randomization. 
16. The subject should not participate in the study if they have any ongoing or recent (ie, 
at the time of screening) medical condition that may interfere with the study conduct, 
interpretation of study data, and/or otherwise put the subject at an unacceptable risk 
or could lead to noncompliance with requirements of the study; eg, subjects with 
rheumatoid arthritis or other autoimmune conditions are not eligible. The Investigator 
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should specifically evaluate the subject’s eligibility taking into consideration COVID-
19 risk factors and situation. 
Prior or Concomitant Therapy 
17. Prior denosumab (Prolia, Xgeva, or proposed denosumab biosimilar) exposure. 
18. Prior use of fluoride within the 5 years before inclusion in the study. 
19. Any current or prior use of strontium ranelate. 
20. Any current or prior use of intravenous bisphosphonates. Prior use of oral 
bisphosphonates is excluded if: 
a. More than 3 years cumulative use prior to screening, unless last dose received is 
>5 years prior to screening, OR 
b. Any dose within 12 months before screening, except if subject received less than 
1 month of cumulative use between 6 and 12 months prior to screening. 
21. Current or prior use of teriparatide and other parathormone (PTH) analogs within 
12 months before screening. 
22. Current or prior use of systemic oral or transdermal estrogen or selective estrogen 
receptor modulators or tibolone within 6 months before screening. 
23. Current or prior use of calcitonin or cinacalcet within 3 months before screening. 
24. Current or prior use of any cathepsin K inhibitor (eg, odanacatib) within 18 months 
before screening. 
25. Current or prior use of romosozumab or antisclerostin antibody. 
26. Current or prior use of other osteoporotic agents used for the prevention or treatment 
of osteoporosis will be excluded according to the Investigator’s judgment after 
consultation with the Medical Monitor. 
27. Current use within 3 months before screening of any medication with known 
influence on the skeletal system (eg, systemic corticosteroids, heparin, lithium, etc). 
Subjects with a stable dose of systemic prednisone <5 mg or equivalent systemic 
corticosteroid for more than 4 weeks before screening are eligible. However, use of 
systemic glucocorticosteroids ≥5 mg prednisone or equivalent per day for more than 
14 days within 3 months before randomization is not permitted. 
28. Concomitant treatment with another biologic drug. 
29. Prior use of other biologic investigational drugs for the treatment of PMO. 
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30. Prior use of any investigational drugs within 5 drug half-lives prior to screening or 
planned intake of an investigational drug during the course of this study. 
31. Have received a COVID-19 vaccine within 4 weeks before randomization or 
COVID-19 vaccination is ongoing at the time of screening. COVID-19 vaccination is 
considered ongoing if a multidose regimen has been started but has not been 
completed. 
5.3 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but 
who fail to meet the eligibility criteria and should not be randomized or receive the IP. A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure subjects, to meet the Consolidated Standards of Reporting Trials publishing 
requirements, and to respond to queries from regulatory authorities. Minimal information 
includes demography, reasons for failure, and any SAE. For screen failures, non-serious 
AEs during the screening will be collected only in the source documents (subject’s 
records). 
For laboratory parameters that initially do not meet eligibility requirements, a single 
retest within the 28-day screening period is permitted if the results are due to a 
documented laboratory error. Retesting is also allowed once for low 25-hydroxy 
vitamin D levels after consultation with, and agreement by, the Medical Monitor. 
Consultation with the Medical Monitor is required to identify whether repeat testing of 
any particular parameter would be clinically relevant (see Section 6.3.10). If 
inclusion/exclusion criteria are not met based on the results of the repeated tests, the 
subject should be considered a screen failure and not be enrolled in the study.  
Re-screening of a screen failure subject is not allowed. 
5.4 
Premature Discontinuation 
5.4.1 
Premature Discontinuation of Investigational Product 
All subjects that receive at least 1 dose of IP and who are permanently discontinued from 
the IP should be encouraged to remain in the study and attend all study visits of the 
period in which they were discontinued (Core Treatment or Transition Periods), with the 
aim to collect as much safety and efficacy data as possible. If a subject discontinues IP 
prior to Week 52, the subject will remain in the study up to the completion of the 
Week 52 assessments. If the IP has been administered at Week 52 (last planned study 
dose), the subject should be encouraged to remain in the study up to the completion of the 
End of Study Visit.  
If premature withdrawal from IP occurs, the Investigator must make every effort to 
determine the primary reason for IP discontinuation. The date and primary reason for 
stopping study drug should be recorded in the electronic case report form (eCRF). In 
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addition, the Investigator must contact the IRT system to register the subject’s early 
permanent treatment discontinuation. 
The IP MUST be discontinued under the following circumstances: 
• Adverse events. 
o AEs that in the judgment of the Investigator, taking into account the subject’s 
overall status, advise against the subject continuing treatment. 
o Due to the language in the label of the comparator in this study 
(denosumab/US-Prolia), the IP should be discontinued if a subject develops: 
severe dermatologic reactions; severe bone, joint, or muscle pain; or anaphylactic 
or other clinically significant allergic reaction. 
o Any laboratory abnormalities that in the judgment of the Investigator, taking into 
consideration the subject’s overall status, advise against the subject continuing 
treatment. 
o Potential Hy’s Law events (elevations in liver biochemistry of alanine 
aminotransferase [ALT] or aspartate aminotransferase [AST] ≥3x upper limit of 
normal [ULN] together with total bilirubin ≥2x ULN confirmed in a second test). 
o Anaphylactic or other serious allergic reactions. 
o If study drug cannot be resumed due to a toxicity and/or in case of toxicity that 
unacceptably endangers the safety of the subject (see Section 7.4.1). 
• Lost to follow-up. 
• Protocol noncompliance (protocol deviations). Any important protocol deviation that 
results in a significant risk to the subject’s safety if the treatment is continued. 
o Use of prohibited medications following discussion with the Medical Monitor. 
• Lack of efficacy. 
• Withdrawal of consent from treatment. 
• Investigator’s decision. 
o The Investigator should withhold further dosing if the benefit risk of further 
exposure is no longer considered favorable for the subject. 
The IP may also be discontinued if there is a delay >2 weeks from the scheduled IP 
injection date (see Section 7.4.1). 
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Subjects who discontinue IP for any of the reasons listed above will continue to be 
followed for efficacy and safety assessments. They are NOT considered withdrawn from 
the study.  
In case of discontinuation for potential Hy’s Law events, subjects will be followed up 
until liver test elevations return to normal or to the baseline state.  
The IP can be re-introduced if the cause of IP interruption is solved and the re-start of 
treatment is medically justified and not otherwise prohibited (eg, treatment with 
prohibited medication), nevertheless it requires the approval of Medical Monitor. 
5.4.2 
Premature Discontinuation from the Study 
Participation in the study is strictly voluntary. A subject has the right to withdraw from 
the study at any time for any reason, without any reprisal. 
The Investigator has the right to terminate participation of a subject for any of the 
following reasons: 
• Adverse event. 
• Lost to follow-up. 
• Death. 
• Withdrawal of consent from the study. 
• Other.  
If a subject is withdrawn from the study, the Sponsor or designee will be informed 
immediately. If there is a medical reason for withdrawal, the subject will remain under 
the supervision of the Investigator until satisfactory health has returned. 
If the subject withdraws consent for disclosure of further information, the Sponsor may 
retain and continue to use any collected data before such a withdrawal of consent. If a 
subject withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
Although a subject is not obliged to give her reason(s) for withdrawing prematurely from 
a study, the Investigator should make a reasonable effort to ascertain the reason(s), while 
fully respecting the subject’s rights. 
At the time of premature withdrawal from the study, the Investigator should make every 
effort to ensure the subject completes the Early Termination visit as soon as possible, but 
not earlier than 4 weeks after last IP administration, for immunogenicity assessments (see 
Table 2). 
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Subjects who prematurely withdraw from the study cannot subsequently rejoin the study. 
Subjects who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled subjects. 
For details on the discontinuation of study sites or the study as a whole, see Section 15. 
5.4.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow-up, the Investigator (or designee) must 
make every effort to regain contact with the subject (there will be at least 2 attempts 
to contact the subject via telephone and 2 written communications). These contact 
attempts should be documented in the subject’s records. 
• Should the subject continue to be unreachable, she will be considered to have 
withdrawn from the study. 
5.4.4 
Medical Care of Subjects After End of Study 
After subjects leave the study, medical care will be at the discretion of the Investigator 
following institutional standard of care and the Sponsor will not provide any additional IP 
to subjects. 
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6 DESCRIPTION OF STUDY ASSESSMENTS 
A detailed schedule of study procedures/assessments is provided in Table 1 and Table 2. 
Unless indicated otherwise, all laboratory samples will be processed and shipped to the 
central laboratory, as described in the central laboratory manual. The central laboratory 
will analyze the samples or send them to reference laboratory(ies) for analysis, as 
indicated in the manual. Refer to the central laboratory manual for the maximum total 
volume of blood to be collected per subject throughout the study. 
6.1 
Demographics and Other Screening Assessments 
The screening procedures will be performed and completed within 28 to 1 days prior to 
randomization.  
Safety assessments that are also part of the screening assessments are described in 
Section 6.3.  
6.1.1 
Informed Consent 
Each subject must provide written informed consent before any study-required 
procedures are conducted, unless those procedures are performed as part of the subject’s 
standard care (see Section 10.3).  
A separate Information Sheet (containing important information about COVID-19, 
clinical research study participation, and subject consent) will be provided to and signed 
by each subject to provide information on the general risks of study participation related 
to COVID-19 and to document that it is understood by the subject. 
6.1.2 
Medical History, Disease-related History, and Prior and Concomitant 
Medications and Procedures 
Relevant information related to the subject’s PMO will be collected and entered in the 
eCRF. 
Postmenopausal status is defined as age-related amenorrhea ≥12 consecutive months and 
increased FSH >40 mIU/mL. Women aged >60 years, or with surgical menopause 
(bilateral oophorectomy with or without hysterectomy) ≥12 months prior to screening; or 
early/premature postmenopausal (confirmed previous postmenopausal status) will not 
need to undergo FSH testing (see Section 6.3.10).  
Assessment of BMD by DXA is described in Section 6.2.1. 
Risk factors for osteoporosis, including age of menopause and menarche, nulliparity, low 
dietary calcium intake, sedentary lifestyle, history of fractures, family history of hip 
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fracture (first degree relatives), low BMI, age ≥70 years, smoking status (former/current 
smoker), and alcohol consumption will be recorded in the eCRF at the Screening Visit. 
Other relevant medical history and current medical conditions (excluding PMO), history 
of tuberculosis or any treatment for active/latent tuberculosis, and previous surgeries 
before screening will be recorded in the eCRF for randomized subjects only. Note: If a 
therapy was administered for a previous medical history it will be collected in the Prior 
and Concomitant Medication or Procedures page of the eCRF.  
At the Baseline Visit, medical history will be reviewed and updated to ensure that the 
subject remains qualified for the study. Significant findings that are observed with an 
onset date after the subject has signed the ICF and that meet the definition of an AE must 
also be recorded in the Adverse Event eCRF page (see Section 8.3). 
Use of all prior and concomitant medication from 4 weeks before the Screening Visit 
until the Week 78/End of Study visit and all previous osteoporosis treatments should be 
recorded. Refer to Section 7.6 for further information about prior and concomitant 
medications and procedures. 
6.1.3 
Demographics 
The age at screening, and race and ethnicity (if permitted by local regulation) of the 
subject are to be recorded in the eCRF. 
6.2 
Efficacy Assessments 
6.2.1 
Dual Energy X-ray Absorptiometry 
Assessment of BMD by DXA will be performed at screening, Week 52, and 
Week 78/End of Study, as indicated in the Schedule of Assessments (Table 1 and 
Table 2). Efficacy assessments can be performed within ±7 days of study Day 365 and 
study Day 547. 
The same DXA system (ie, Lunar or Hologic) must be used for all study procedures for a 
particular subject for the duration of the study. The central facility will monitor DXA 
machines quality control throughout the study. 
Bone density will be measured at the lumbar spine and the proximal femur. Lumbar spine 
scans must include L1 through L4.  
DXA scans of the lumbar spine will be performed in duplicate, ie, subjects will be 
removed from the table in between scans. 
For proximal femur DXA scans, the left side should be used for all scans at all study 
visits. If the right side must be used (eg, due to implants) or is inadvertently used at 
baseline, then it must be used consistently throughout the study. If a subject fractures the 
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hip that has been scanned during the study up to the time of fracture, no further scans will 
be obtained for the affected location.  
All DXA scan data will be submitted electronically to the central imaging vendor for 
analysis. A separate procedure manual provided by the central imaging vendor will give 
specific instructions for acquisition of scans as well as performance of Instrument Quality 
Control. Sites unable to submit data electronically can submit on CD or other media as 
specified in the DXA Procedural Manual, but electronic submission is preferred.  
After analysis by the central imaging vendor, the study site may be asked to re-acquire a 
duplicate scan due to malpositioning or other technical reasons. The investigative sites 
should comply with the requests from the central imaging vendor and encourage the 
subject to return to the site for re-scan. Repeat scans should be performed as soon as 
possible after the request is received. 
Assessment of bone biomarkers is described in Section 6.4. 
6.3 
Safety and Tolerability Assessments 
6.3.1 
General Considerations 
The safety profile of the IP will be assessed through the recording, reporting, and analysis 
of AEs, physical examination findings, vital signs, a 12-lead ECG tracing, laboratory 
tests (clinical chemistry, hematology, and urinalysis), and local tolerability. Baseline 
medical conditions and concomitant medication will be recorded and accounted for 
during the evaluation of safety. 
Comprehensive assessment of any apparent toxicity experienced by any subject will be 
performed from the time of giving the informed consent until completion of the study or 
withdrawal from the study. The Investigator or delegate will report all AEs, whether 
observed by the Investigator or site staff, or reported by the participating subject. The 
reporting period for AEs is described in Section 8.3.  
Dedicated assessments of common and/or clinically important known or potential adverse 
reactions for the originator product will be performed and reported, as appropriate.  
Signs and symptoms suggestive of hypersensitivity as judged by the Investigator will be 
captured and reported. The corresponding standardized Medical Dictionary for 
Regulatory Activities (MedDRA) queries (SMQ) will be used to aggregate these reports. 
Local tolerability at the administration site will be assessed and reported. 
6.3.2 
Monitoring of Subjects with Adverse Events 
AEs are periodically assessed and documented during the study. The final outcomes of all 
AEs must be evaluated and recorded at the final study visit unless already done. All SAEs 
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that are not resolved at the time of the final study visit must be monitored and followed 
up by the Investigator until stabilized (or judged to be permanent) or until the outcome is 
known or otherwise explained, unless the subject is documented as “lost to follow-up.” 
Reasonable attempts to obtain this information must be made and documented. All 
information on AEs unresolved at study completion must be noted in the source 
documents. In addition, the Investigator should ensure that suitable ancillary care in 
accordance with local practices is provided to subjects with unresolved AEs, unless the 
subject is documented as “lost to follow-up.”  
Any SAE considered directly related to the IP with an onset after a subject has completed 
the final study visit must be recorded in the source documents and reported promptly to 
the study Sponsor. 
AEs will be followed, recorded, and reported in line with the procedures described in 
Section 8. 
6.3.3 
Local Tolerability 
Local tolerability in terms of ISRs will be assessed by inspection of the skin and 
appendages in proximity to the site of administration. This local tolerability assessment 
will be performed by the Investigator or designee to determine the presence of eg, 
erythema, rash, tenderness, swelling, itching, bruising, pain, extravasation, phlebitis, or 
other types of reaction. The Investigator is also requested to ask subjects during 
assessment about any such reactions that may have occurred since last assessment. All 
such findings including the time of onset and resolution as well as the need for ancillary 
care will be recorded in source data and transferred into the corresponding eCRF page. 
Non-serious ISRs are only to be reported in the dedicated eCRF page. ISR that qualify as 
SAEs (eg, ulceration that leads to or prolongs hospitalization) or meets definition of an 
AESI must be recorded as an SAE/AESI on the corresponding page of the eCRF. The 
severity of all ISRs is to be graded according to the current version of the National 
Cancer Institute (NCI)-CTCAE. Late onset ISRs will be documented as recommended in 
the eCRF completion guide. 
6.3.4 
Physical Examination 
Comprehensive and brief physical examinations will be performed at the times specified 
in the Schedule of Assessments (Table 1 and Table 2).  
The comprehensive physical examination will include assessments of the standard 
physical examination items, including general appearance, skin, head/neck, pulmonary, 
cardiovascular, gastrointestinal, external genitourinary, lymphatic, musculoskeletal 
system, extremities, eyes (inspection and vision control), nose, throat, and neurologic 
status. The brief physical examination will target on symptoms or findings previously 
reported and will include, at a minimum, general appearance, pulmonary, cardiovascular, 
and throat examination. 
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The results of physical examination should be recorded in source document and eCRF as 
normal or abnormal. Any abnormality should be specified as clinically significant or not 
clinically significant in the eCRF. All clinically significant abnormalities noted during a 
physical examination before signing of the first informed consent until the first IP 
administration are to be recorded in the medical history section of the eCRF; all clinically 
significant abnormalities occurring or worsening thereafter should be recorded as AEs in 
the AE section of the eCRF. 
6.3.5 
Body Weight and Height 
Body weight will be recorded at screening and at subsequent visits as specified in the 
Schedule of Assessments and documented in the eCRF.  
Height will be measured at screening, Week 26, Weeks 52, and Week 78/End of Study. 
Height should always be measured in the same stadiometer and following the same 
procedure (eg, without shoes).  
Body mass index will be calculated at screening only.  
6.3.6 
Vital Signs 
Vital signs (including body temperature, respiratory rate, pulse rate, and blood pressure) 
will be measured after 5 minutes rest in the supine position at the time points noted in the 
Schedule of Assessments (Table 1 and Table 2). During the study, measurement of vital 
signs may be repeated at the discretion of the Investigator for safety reasons.  
Body temperature measurement will be performed first and will precede every other 
assessment of each visit. In the case of an elevated temperature, it is the Investigator’s 
decision to determine any further actions according to local practice and their medical 
judgment. 
Blood pressure measurements (systolic and diastolic) and pulse rate should be obtained 
with the subject’s arm unconstrained by clothing or other material. The measurements 
will be obtained from the arm not used for blood sampling, where possible, using an 
appropriate cuff size and with the arm supported at the level of the heart. 
When vital signs are scheduled to be assessed at the same time as blood is being 
collected, the vital signs should be measured prior to the blood collection is performed.  
If the Investigator determines that there are any clinically significant abnormalities noted 
in the vital signs measurements, these should be recorded as AEs. 
6.3.7 
Electrocardiograms 
Standard 12-lead ECGs will be performed at the times specified in the Schedule of 
Assessments (Table 1 and Table 2). ECGs will be assessed locally by the Investigator. 
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Subjects should rest in the supine position for 5 minutes before the tracings start. Only 
the overall evaluation (normal/abnormal) will be recorded in the eCRF. If abnormal, the 
specific abnormality will be recorded. Abnormal evaluations will be judged as clinically 
significant or not clinically significant by the Investigator. Clinically significant ECG 
abnormalities should be recorded in the AE section of the eCRF. 
6.3.8 
Chest X-ray 
Posterior-anterior and lateral chest x-ray (or chest radiographs) should be obtained at 
screening and reviewed by the Investigator. If chest x-rays or radiographs were taken 
within 2 months prior to screening and show no clinically significant abnormality, and 
there are no signs and symptoms suggestive of pulmonary disease that would exclude the 
subject from the study, then a chest x-ray or radiograph does not need to be repeated at 
screening. The previous x-ray imaging should be available for the Investigator to review; 
otherwise, a report by a Radiologist is required. 
The chest x-ray finding should be recorded as normal or abnormal. Any abnormality 
should be specified. All clinically significant abnormalities noted in chest x-ray before 
signing of the informed consent until the first IP administration have to be recorded in the 
medical history section of the eCRF; all clinically significant abnormalities occurring or 
worsening thereafter should be recorded as AEs in the AE section of the eCRF. 
6.3.9 
Thoracolumbar Spine X-ray 
Fractures at screening will be assessed by thoracic and lumbar spine x-ray. Severe 
fracture is defined as vertebral height loss >50%, and moderate fracture is defined as 
height loss from 25% to 50%. 
Thoracic and lumbar spine x-ray should be obtained at screening and reviewed by the 
Investigator and sent for central reading. Previous x-rays taken within 6 months prior to 
screening will be acceptable.  
Additional spine x-rays will be performed if there is a suspicion of a fracture (eg, new 
onset of persistent or pronounced back pain or material worsening of back pain); these 
will be assessed locally. 
6.3.10 
Clinical Laboratory Assessments 
Blood samples will be collected for the laboratory tests outlined below in accordance 
with the timing noted in the Schedule of Assessments (Table 1 and Table 2), and sent to 
the central laboratory for analysis. All samples should be clearly identified. In the case 
that usage of the central laboratory is limited due to unforeseen changes in the COVID-19 
situation, certain safety assessments may be performed at a local laboratory with the 
pre-approval of the Sponsor.  
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The assay strategy is based on a multi-tiered approach. In the first tier, all samples will be 
assessed using a screening assay. In the second tier, samples testing putatively positive in 
the screening assay will then be analyzed in a confirmatory assay. Samples that are 
positive in the confirmatory assay will then be further characterized to determine the 
ADA titers. Finally, in the third tier, all confirmed positive samples will be tested in a 
NAb assay to determine if ADAs against the drug are neutralizing the biological activity. 
ADA assays will be performed by a bioanalytical laboratory under the responsibility of 
the Sponsor using methods validated according to regulatory guidelines. Immunogenicity 
assessments will be described in the bioanalytical plans, which will be finalized before 
the beginning of sample analysis. Bioanalytical reports will also be generated, one for 
each ADA and NAb analysis, by the bioanalytical laboratory and will be included in the 
CSR appendix. 
After completion of the study, immunogenicity samples will be stored for a maximum of 
10 years as from the last subject’s last visit in this study at the designated storage facility 
meeting the below requirements: 
• Utilize GCP-compliant sample management system. 
• Perform GCP-compliant receipt and storage of biosamples. 
• Perform GCP-compliant outbound shipment of biosamples. 
• Perform GCP-compliant destruction of biosamples (if requested). 
The immunogenicity samples will be processed, shipped, and stored as described in the 
laboratory manual. 
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subject screening log) of subjects who entered screening. See Section 5.3 for screening 
failures.  
Once the subject has been successfully screened and the Investigator has determined that 
the subject is eligible, the subject will be assigned a randomization number. 
Randomization will be performed via a centralized IRT system. Eligible subjects will be 
randomly assigned to either FKS518 or US-Prolia in a 1:1 ratio, stratified by age 
(<65 years; ≥65 years), and prior bisphosphonates therapy (Yes; No).  
Blinded IP supplies labeled with kit numbers and other information as per Master Label 
and in line with regulatory requirements will be provided to each study site. Dosing of 
study drug will be initiated at the site after randomization.  
The Investigator will contact the IRT system for each subsequent IP administration, ie, 
Week 26 and Week 52. At the Week 52 Visit, subjects who were initially randomized to 
the US-Prolia group will be re-randomized in a 1:1 ratio to receive either FKS518 or 
US-Prolia at the Week 52 Visit. Subjects who were initially randomized to the FKS518 
group will remain on the same treatment with FKS518 for the Week 52 administration. 
Subjects who discontinue study drug before or at Week 52 will not be re-randomized and 
will discontinue the study. Re-randomization will not impact the double-blind nature of 
the study as blinding will be kept. 
The same stratification factors will be used for the randomization and re-randomization. 
The same values of stratification will be maintained for re-randomization.  
Randomization will be conducted in permuted blocks.  
If a subject withdraws from study participation, her unique identification number cannot 
be re-used for another subject. 
7.4 
Dose and Administration 
The following IPs will be administered in the study: FKS518 and US-Prolia. The IPs will 
be administered at a dose of 60 mg by subcutaneous injection at the site on the Day 1 and 
Weeks 26 and 52 visits.  
The IP will be supplied in single-use PFSs and no further preparation is required. The 
PFSs must be kept in the original outer packaging until administration. The preparation 
should be carefully inspected before administration. The IP is a clear, colorless to pale 
yellow solution that may contain trace amounts of translucent to white proteinaceous 
particles. Do not use if the solution is discolored or cloudy or if it contains particles. 
Prior to administration, the IP must be removed from the refrigerator and must be kept at 
room temperature (up to 25°C) while remaining in the original container. This generally 
takes 15 to 30 minutes. The IP should not be warmed in any other way and must not be 
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put back in the refrigerator. The PFS should not be shaken. The IP should be 
administered up to 8 hours of removal from the refrigerator. 
The injection site should be the abdomen. The IP should be injected slowly. 
The IP will be administered by a healthcare professional experienced in giving 
subcutaneous injections. The exact date and injection time will be recorded in the eCRF. 
Subjects will be monitored for 2 hours following the IP administration and at the time of 
post-dose sampling for PK and PD on Day 1 (ie, 5±1 hours post-dose), including ISRs.  
Investigators are also requested to look at the injection site thereafter and make note of 
any findings such as redness (erythema), itching (localized pruritus), injection site pain, 
swelling, bleeding, bruising, or hematoma. For any injection site findings, the time of 
onset (ie, when first noticed) and the duration of the ISR should be recorded by the 
Investigator on the corresponding eCRF page.  
7.4.1 
Delayed Investigational Product Dose 
If for any reason (including a concurrent medical condition that is not an exclusionary 
criterion or a reason for IP discontinuation) the IP injection cannot be administered on the 
scheduled day, a ±2-week window is allowed. If the IP injection is not administered 
within this ±2-week window, the subject may be discontinued from the IP after 
consultation with the Medical Monitor. The exact date and injection time will be recorded 
in the eCRF. 
7.4.2 
Dose Modification 
Dose modifications are not allowed in this study. 
7.4.3 
Intervention After the End of the Study 
After subjects leave the study, medical care will be at the discretion of the Investigator 
following institutional standard of care and the Sponsor will not provide any additional 
care to subjects. 
7.5 
Precautions and/or Lifestyle Considerations 
All subjects should receive calcium 1000 mg daily and at least 400 IU vitamin D daily 
during the study. Subjects should be instructed on the importance of calcium and 
vitamin D supplementation.  
Several lifestyle recommendations may improve musculoskeletal integrity and balance, 
preserve bone strength, and prevent future fractures. These include a calcium-rich diet 
(eg, dairy products) and avoiding use of tobacco and excessive use of alcohol.  
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Patients with osteoporosis may benefit from physical therapy or other activities and other 
nonpharmacologic measures to improve strength and reduce the risk of falls and 
fractures. 
7.6 
Prior and Concomitant Medications and Procedures  
At each visit, all concomitant medications or procedures taken by the subject during the 
study from 4 weeks before the Screening Visit (including all previous treatment for 
osteoporosis) up to the completion of the final End of Study Visit are to be recorded in 
the appropriate section of the eCRF, noting the name (generic and tradename), 
dose/frequency/route, start/stop dates, duration, and indication of each drug. Non-drug 
interventions and any changes to a concomitant medication or other intervention should 
also be recorded in the eCRF. 
The Medical Monitor should be contacted if there are any questions regarding prior or 
concomitant medication or procedures. 
7.6.1 
Permitted Medications 
All subjects should receive calcium 1000 mg daily and at least 400 IU vitamin D daily 
during the study. 
Any other medications, therapies, or procedures (other than those excluded by the 
Clinical Study Protocol) that are considered necessary to protect subject welfare and will 
not interfere with the study drug may be given at the Investigator’s discretion. All 
permitted medication and dose modifications of permitted medication must be recorded 
in the eCRF. Permitted medication will not be provided by the Sponsor as it is considered 
standard of care background medication. 
While reductions in concomitant medication are allowed for safety reasons, it is 
important that medication dosages taken during the study remain stable to the extent 
possible. 
COVID-19 vaccination is allowed during study participation. However, to ensure 
distinction between the adverse reactions caused by vaccination and the IP, it should not 
occur within 1 week before and after study drug administrations. In addition, to exclude 
any potential interaction between the study drug and COVID-19 vaccination, it is 
recommended to perform COVID-19 vaccination as much as possible in between 2 doses 
of the IP (ie, around Weeks 13 or 39, or after last dose around Week 65). 
Any COVID-19 vaccination must be recorded in the eCRF, including all available data 
(tradename, manufacturer/Marketing Authorization Holder, date and time of vaccination, 
and batch number whenever available). 
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7.6.2 
Prohibited Medications 
The use of prohibited medications during the study will require the subject to be 
permanently discontinued from the study drug. The use of prohibited medications is also 
not permitted until the End of Study/Week 78 Visit. 
Medication may be administered for the treatment of AEs or emergency treatment at any 
time during the study and must be recorded in the eCRF. 
Table 4 presents a summary of prohibited medications with washout periods (before 
randomization). 
Table 4  
Summary of Prohibited Concomitant Medications with Washout 
Periods (Before Screening) 
Prohibited Medications 
Washout Period (Before Screening) 
Strontium ranelate 
Never 
Fluoride 
5 years 
Intravenous bisphosphonates 
Never 
Oral bisphosphonates  
>3 years cumulatively (unless last dose 
received >5 years) 
OR 
12 months (note: it is allowed to have 
received less than 1 month of 
cumulative use between 6 and 
12 months prior to screening) 
Teriparatide and other PTH analogs within 
12 months before screening 
12 months 
Systemic oral or transdermal estrogen or 
selective estrogen receptor modulators or 
tibolone  
6 months 
Calcitonin or cinacalcet  
3 months 
Any cathepsin K inhibitor (eg, odanacatib)  
18 months 
Romosozumab or antisclerostin antibody 
Never 
Other osteoporotic agents used for the 
prevention or treatment of osteoporosis  
Investigator judgment after consultation 
with the Medical Monitor 
Any medication with known influence on 
the skeletal system (eg, systemic 
corticosteroids, heparin, lithium, etc) 
3 months  
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Prohibited Medications 
Washout Period (Before Screening) 
A stable dose of systemic prednisone 
<5 mg or equivalent systemic 
corticosteroid for >4 weeks before 
screening is permitted 
Use of systemic glucocorticosteroids: 
≥5 mg prednisone or equivalent per day 
for more than 14 days within 3 months 
prior to randomization is not allowed 
Another biologic drug 
None 
Other biologic investigational drugs for the 
treatment of PMO 
Never 
Any investigational drugs  
30 days or 5 half-lives (whichever is 
longer) 
COVID-19 vaccination 
4 weeks before randomization 
COVID-19 vaccination-related 
restrictions/recommendations are 
detailed in Section 7.6.1. 
The Medical Monitor should be contacted if there are any questions regarding prior or 
concomitant medication or procedures. 
7.7 
Overdose 
There is no experience with overdosage with Prolia. 
An overdose is defined as any dose greater than the defined highest daily dose included 
in a Clinical Study Protocol. 
In the event of an overdose, subjects should receive appropriate supportive medical care 
and be followed until resolution/stabilization of any clinical issues. 
Even if it does not meet other criteria for an SAE, any instance of overdose (suspected or 
confirmed and irrespective of whether or not it involved FKS518 or US-Prolia) must be 
recorded in the study medication section of the eCRF and reported to the Sponsor or a 
specified designee in an expedited manner within 24 hours of awareness. Details of any 
signs or symptoms and their management should be fully recorded including details of 
any antidote(s) administered. 
In the event of a suspected overdose of IP, the Investigator should carefully observe the 
subject and contact the Medical Monitor immediately, and guidance for next steps will be 
provided. 
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Overdose does not automatically make an AE serious, but if the consequences of the 
overdose are serious, for example death or hospitalization, the event is serious and must 
be recorded and reported as an SAE (see Section 8.4). 
For overdoses associated with an SAE, the standard SAE reporting timelines apply (ie, 
24 hours, see Section 8.4.1). 
Overdoses will be reported in the Serious Adverse Event Form whether they are 
non-serious or serious AEs. The SAE criterion medically significant event is to be 
selected for overdoses that have been reported as SAEs. 
7.8 
Compliance 
Subjects will be administered IP by the Investigator or site personnel, under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in 
the source documents and in the eCRF. Treatment compliance will be assured by site 
reconciliation of all IP supplies. 
7.9 
Accountability 
The IP must not be used for any purpose other than that defined in this protocol. All 
supplies of IP will be accounted for in accordance with GCP. 
The pharmacist or (designee) should maintain accurate records of all IP supplies received 
during the study. These records should include the dates and amounts of IP that were 
received at the site, dispensed, and destroyed or returned to the Sponsor (or designee). If 
errors or damage in the IP shipments occur, the Investigator should contact the Sponsor 
(or its designee) immediately. Copies of the IP accountability records will be provided by 
each Investigator for inclusion in the trial master file. The study Monitor will periodically 
check the supplies of IP held by the Investigator or pharmacist to verify accountability of 
the IP used. 
The Investigator (or designee) will administer the IP only to the identified subjects in this 
study, according to the procedures described in this study protocol. Details of IP 
administered to subjects will be recorded in the eCRF. Investigators should maintain 
records that document adequately that the subjects were provided the doses specified by 
the protocol and reconcile all IP received from the Sponsor (or designee). 
After the end of the study, all unused IP and all medication containers should be 
destroyed at the study center or returned to the Sponsor (or designee) for destruction. In 
either instance, complete documentation will be returned to the Sponsor. The IP resupply 
will be managed by the IRT system. 
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8 ADVERSE EVENTS 
8.1 
Adverse Events Definitions 
8.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a participating subject regardless of a 
causal relationship with an administered IP. An AE can therefore be any unfavorable and 
unintended sign (see Section 8.1.4), symptom, or disease temporally associated with the 
use of the IP irrespective of a relationship to the exposure. 
For surgical or diagnostic procedures, the condition/illness leading up to it is considered 
the AE rather than the procedure itself. 
Any untoward medical occurrence in a participating subject occurring after exposure to 
IP is defined as a TEAE.  
8.1.2 
Severity Grading 
The intensity or severity of AEs is to be graded by Investigators using the version of the 
NCI-CTCAE current at the time the Clinical Study Protocol was signed (unless otherwise 
specified). The NCI-CTCAE provides grading for specific events as well as a general 
grading scale. If no specific guidance is provided by the NCI-CTCAE, the Investigator is 
to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or 
her best medical judgment.  
The 5 general grades are: 
• Grade 1 or Mild 
• Grade 2 or Moderate 
• Grade 3 or Severe 
• Grade 4 or Life-threatening 
• Grade 5 or Death 
8.1.3 
Causality Assessment 
Investigators must also systematically assess the causal relationship of AEs to IPs using 
the definitions below. Aspects to be considered when assessing a causal relationship of an 
AE to the IP include the temporal relationship between the AE and the exposure, the 
mechanism of action of the IP, the subject’s medical history, the course of any underlying 
disease, any concomitant medications, or performed study procedures. 
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• Unrelated: Not reasonably related. The AE is not plausibly 
(pharmacologically/clinically) attributable to the IP under study. In this case a 
reasonable alternative explanation must be available. 
• Related: Reasonably related. The AE is plausibly (pharmacologically/clinically) 
attributable to the IP under study in this Clinical Study Protocol.  
8.1.4 
Abnormal Laboratory Findings and Other Abnormal Investigational 
Findings 
Abnormal laboratory findings or investigational findings (eg, an ECG trace) should not 
be reported as AEs unless they are clinically significant. Only abnormal laboratory 
findings or investigational findings that are associated with clinical signs or symptoms, 
that lead to treatment discontinuation, and/or are considered otherwise medically 
important by the Investigator, qualify as clinically significant. The corresponding sign, 
symptom, or medical condition (eg, anemia) must be reported as an AE rather than the 
abnormal value (eg, low hemoglobin). 
8.1.5 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. (Note: The term “life-threatening” refers to an event in which the 
subject is at risk of death at the time of the event, not an event that hypothetically 
might have caused death if it was more severe.)  
• Requires hospitalization or prolongs an existing hospitalization. (This does not 
include outpatient consultation in an emergency room of a hospital.) 
• Results in persistent or significant disability or incapacity. 
• Is associated with a congenital anomaly or a birth-defect. 
• Is otherwise considered to be medically important. (Note: Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be 
considered as SAEs when, based upon appropriate medical judgment, they may 
jeopardize the subject or may require medical or surgical intervention to prevent one 
of the outcomes listed above. For example, an episode of allergic bronchospasm 
requiring intensive treatment in an emergency room that does not result in 
hospitalization.) 
○ Confirmed COVID-19 cases should be considered as ‘otherwise medically 
important’ and accordingly reported as SAEs. 
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If several untoward medical occurrences have contributed to an SAE, Investigators are 
asked to identify the leading event that provides the main reason for the classification as 
an SAE. This event term will be used to assign the corresponding SAE narrative upon 
study completion. 
According to Sponsor convention, any clinical AE with severity of Grade 4 or 5 must 
also be reported as an SAE. However, a laboratory abnormality of Grade 4, such as 
anemia or neutropenia, is considered serious only if the condition meets one of the 
serious criteria described above. 
If death occurs, the primary cause of death or the event leading to the subject’s death, 
should be recorded and reported as an SAE. “Fatal” will be recorded as the outcome of 
this event and death will not be recorded as separate event. Only, if no cause of death can 
be reported (for example, sudden death, unexplained death), the death per se might then 
be reported as an SAE. 
For the purposes of reporting, any suspected transmission of an infectious agent via an IP 
is also considered an SAE.  
8.1.6 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify study treatment or study procedures 
(eg, sample collection) are not considered SAEs. Similarly, hospitalization foreseen 
before enrolment in the study due to an underlying medical condition that did not 
materially worsen during the study (eg, hip replacement for a pre-existing coxarthrosis) is 
not considered an SAE. However, all instances of an unplanned hospitalization or 
unplanned prolongation of an elective hospitalization (for example, undesirable effects of 
any administered treatment) must be documented and reported as SAEs. 
8.1.7 
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the Screening Visit that do not worsen in severity or 
frequency during the study are categorized as Baseline Medical Conditions (ie, Medical 
History), and are not to be considered AEs. 
8.1.8 
Adverse Events of Special Interest 
The following are considered pre-defined AESIs for this study: 
• Drug-related hypersensitivity/allergic reactions (CTCAE Grade ≥3 or reported as 
SAEs), and 
• AEs leading to IP discontinuation or study withdrawal. 
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8.2 
Methods of Recording and Assessing Adverse Events 
At each study visit, the subject will be queried on changes in her medical condition. 
During the reporting period, any unfavorable changes in the subject’s condition will be 
recorded as AEs, whether reported by the subject or observed by the Investigator or site 
staff. 
Complete, accurate, and consistent information on all AEs experienced for the duration of 
the reporting period is to be reported on an ongoing basis in the appropriate section of the 
eCRF. In addition, all SAEs must be documented and reported using the appropriate SAE 
Report Form. 
It is important that each AE report includes a description of the event, the onset and 
resolution dates (and times when the event is occurring in close temporal proximity to the 
administration – for example in the case of an acute hypersensitivity reaction), its 
severity, its causal relationship with the study treatment, any other potential causal 
factors, any treatment given or other action taken, including dose modification, 
interruption or discontinuation of the IP, and its outcome. In addition, SAEs should be 
identified and the qualifying seriousness criteria documented. 
In case of AEs for which severity changes during the study, it should be recorded as a 
single AE with severity changes, and the highest severity (grade) will be chosen to 
document the single AE at the end, instead of having the event recorded as different AEs.  
Specific guidance can be found in the eCRF Completion and Monitoring Conventions 
provided by the Sponsor. 
8.3 
Definition of the Adverse Event Reporting Period 
The safety reporting period begins when the subject is initially screened for the study 
(date of signature of the ICF) and continues until completion of the study (Week 78/End 
of Study Visit) or withdrawal from the study. To complete the AE/SAE report, follow-up 
AE reporting may extend to the last visit of the subject. Data collected for all subsequent 
AE follow-up will be recorded only in the source data.  
All AEs following ICF signature should be captured in the subject’s source data. For 
randomized subjects, all AEs (serious and non-serious) should also be recorded on the 
eCRF for the reporting period. AEs that begin or increase in severity or frequency on or 
after the date of first administration of IP up to the Early Termination/End of Study Visit 
are considered TEAEs. All SAEs occurring after the date of the signature of the ICF must 
be reported as outlined below. See Section 5.3 for AE reporting on screen failures. 
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8.4 
Procedure for Reporting Serious Adverse Events, Adverse Events of Special 
Interest, and Dose Limiting Toxicities 
8.4.1 
Serious Adverse Events 
In the event of a new onset/worsening SAE occurring during the reporting period, the 
Investigator must immediately (within 24 hours after becoming aware of the event) 
inform the Sponsor or its designee using the designated SAE Report Form (see SAE 
contact information on page 6 of this protocol). The form must be completed in 
accordance with the provided instructions. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by 
telephone; in these cases, an SAE Report Form must be provided without delay 
thereafter. 
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if 
available (for example, laboratory results, hospital report, autopsy report). In all cases, 
the information provided on the SAE Report Form must be consistent with the data with 
the corresponding information recorded in the eCRF. 
The Investigator must respond to requests for follow-up information (eg, further details 
on the event, information on the outcome, supporting evidence or records) or to questions 
the Sponsor or designee may have concerning the AE within the same timelines as for 
initial reports. This is necessary to ensure prompt assessment of the event and (as 
applicable) to allow the Sponsor to meet strict regulatory timelines associated with 
expedited safety reporting obligations. 
Requests for follow-up will usually be made via the responsible Monitor. A 
representative from the Clinical Safety & Pharmacovigilance department may in 
exceptional circumstances contact the Investigator directly to obtain further information 
or to discuss the event. 
8.4.2 
Adverse Events of Special Interest 
Serious AESIs, ie, that qualify as an SAE, must be reported using the forms and 
procedures outlined for SAE in an expedited manner according to the timelines outlined 
above for SAEs (see Section 8.4.1). Non-serious AESIs must be reported using the 
dedicated AESI form following same expedited timelines outlined for SAEs 
(Section 8.4.1). No AESI form needs to be completed for AESIs that are also SAEs. 
8.4.3 
Unexpected Adverse Reactions 
An AE that is considered related to the IP qualifies as an adverse reaction. Adverse 
reactions that are not listed in the Reference Safety Information section of the 
Investigator’s Brochure for FKS518 are considered “unexpected.” If this concerns an 
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event that also qualifies as serious (ie, is an SAE), the event meets the criteria of a 
SUSAR. For such events, specific reporting requirements to Ethics Committees and 
Health Authorities apply. Timely clarification of queries is essential in these instances to 
meet the short regulatory reporting timelines. 
Expedited reporting is also required for SUSARs that have arisen in other clinical studies 
of the same Sponsor and with the same medicinal product, and that could have 
consequences for the safety of the subjects involved in the current clinical study that was 
assessed by the Ethics Committees and Health Authorities. 
The CRO is responsible for unexpected suspected adverse reaction reporting to the 
authorities (Ethics Committees and Health/Competent Authorities).  
The CRO will prepare submissions and submit to the authorities by email, fax, courier, 
local country officer, or hand-carried submission as required by country or local 
regulations. The Sponsor will perform electronic submissions to E2B to the EMA. 
The CRO is responsible for unexpected suspected adverse reaction reporting to ethics 
committees according to local legislation. The CRO will distribute safety letters to 
Central Ethics Committees and Institutional Review Boards (IRBs) as required by 
country or local regulations.  
The CRO will ensure that all relevant information about SUSARs that are fatal or 
life-threatening is recorded and reported as soon as possible to the competent authorities 
in all the Member States concerned, and to the Ethics Committee and in any case no later 
than 7 days after knowledge by the Sponsor of such a case, and that relevant follow-up 
information is subsequently communicated within an additional 8 days.  
All other SUSARs shall be reported to the competent authorities concerned and to the 
Ethics Committee concerned as soon as possible but within a maximum of 15 days of 
first knowledge by the CRO (in accordance with Article 17(1)(a), (b), and (d) of 
European Directive 2001/20/EC). 
The CRO is responsible for unexpected suspected adverse reaction reporting to the 
Investigators according to local legislation. The CRO will distribute safety letters to sites 
as required by country or local regulations. 
8.4.4 
Pregnancy and In Utero Drug Exposure 
The study population includes postmenopausal women and, therefore, no pregnancies are 
expected. In the event of pregnancy, the procedures described below should be followed: 
Only pregnancies considered by the Investigator to be related to study treatment (for 
example, resulting from a drug interaction with a contraceptive medication) qualify as an 
AE. However, all pregnancies with an estimated conception date during participation in 
the study must be recorded by convention in the AE page/section of the eCRF. The 
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Investigator must notify the Sponsor or designee in an expedited manner of any 
pregnancy using the Pregnancy Report Form, which must be transmitted according to the 
same process as described for SAE reporting. 
Investigators must actively follow up, document, and report the outcome of all 
pregnancies, even if the subjects are withdrawn from the study. 
The Investigator must notify the Sponsor or designee of these outcomes using the paper 
Pregnancy Report Form. If an abnormal outcome occurs, the SAE Report Form will be 
used if the subject sustains an event and the Parent-Child/Fetus Adverse Event Report 
Form if the child/fetus sustains an event. 
Any abnormal outcome must be reported in an expedited manner as described for SAE, 
while normal outcomes must be reported within 45 days after delivery. 
If a participant becomes pregnant the IP must be discontinued immediately. The Sponsor 
or designee must be notified without delay and the subject must be followed as 
mentioned above. 
8.5 
Safety Reporting to Health Authorities, Independent Ethics Committees/ 
Institutional Review Boards, and Investigators 
The Sponsor or designee will send appropriate safety notifications to Health Authorities 
in accordance with applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to 
the reporting of SAEs (particularly deaths) involving study subjects to the Independent 
Ethics Committee (IEC)/IRB that approved the study. 
In accordance with International Council for Harmonisation (ICH) GCP, the Sponsor or 
designee will inform the Investigator of “findings that could adversely affect the safety of 
subjects, impact the conduct of the study or alter the IEC’s/IRB’s approval/favorable 
opinion to continue the study.” In accordance with regulations, the Sponsor or designee 
will inform the Investigator of AEs that are both serious and unexpected and are 
considered to be related to the administered product (SUSARs). The Investigator should 
place copies of Safety Reports in the Investigator Site File. National regulations 
concerning Safety Report notifications to Investigators must be met. 
When specifically required by regulations and guidelines, the Sponsor/designee will 
provide appropriate Safety Reports directly to the concerned lead IEC/IRB and will 
maintain records of these notifications. When direct reporting is not clearly defined by 
national or site-specific regulations, the Investigator will be responsible for promptly 
notifying the concerned IEC/IRB of any Safety Reports provided by the 
Sponsor/designee and of filing copies of all related correspondence in the Investigator 
Site File. 
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For clinical studies covered by Directive 2001/20/EC, the Sponsor’s responsibilities 
concerning the reporting of SAEs/SUSARs/Safety Issues will be carried out accordingly 
and in line with the related Detailed Guidance documents. 
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9 STATISTICS 
9.1 
General Procedures 
All personnel involved with the analysis of the study will remain blinded until the study 
database lock, which will occur after the Week 78 data are available and protocol 
deviations are identified. Analyses will be performed using SAS® software Version 9.4 or 
higher (SAS Institute, Cary, NC, US). 
The Statistical Analysis Plan (SAP) will be approved prior to any lock of the study 
database and unblinding of the study data. The SAP will provide a detailed description of 
the statistical methods and expand on the details provided in the protocol. 
Descriptive statistics (number of observations, mean, standard deviation [SD], median, 
minimum, and maximum) will be provided for continuous variables, and counts and 
percentages will be presented for categorical variables. 
If not otherwise specified: 
• Data collected before and analyzed at the end of the Core Treatment Period will be 
summarized per initial treatment group (FKS518 or US-Prolia). 
• Data collected or analyzed after the re-randomization during the Transition Period 
will be summarized for the following 3 treatment groups: FKS518 during the 
complete study duration, US-Prolia during the complete study duration, and switch 
from US-Prolia to FKS518. 
Baseline is defined as the last nonmissing measurement before the first administration of 
IP. 
9.2 
Analysis Populations 
The Enrolled Analysis Set will include all subjects who provide informed consent. This 
analysis set will be used to report disposition and screening failures. 
The Intention-to-Treat (ITT) Analysis Set will include all randomized subjects. Subjects 
will be analyzed according to their randomized treatment. This analysis set will be the 
primary set used for analyses/summaries of the primary efficacy endpoint, as well as for 
the co-primary efficacy endpoint (for MAA in the EU and EEA only), all secondary 
efficacy and other efficacy endpoints.  
The Per Protocol (PP) Analysis Set will include all randomized and treated subjects who 
do not have a clinically important protocol deviation that could affect the assessment of 
the primary efficacy endpoint (ie, use of prohibited medications during the study). The 
protocol deviations that could affect the primary endpoint will be defined and agreed 
upon before unblinding. This analysis set will also be used for the co-primary efficacy 
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(For MAA in the EU and EEA only): For the co-primary endpoint AUEC(0-W26) of 
serum CTX,  based on simulated population PK/PD data with equivalence margins of 
[0.89, 1.12], assuming that the reference population and test population are identical, an 
analysis of covariance (ANCOVA) of the natural logarithm (log) transformed AUEC 
(derived in WinNonlin from simulated PD data) controlling for the natural log of the 
baseline serum CTX, demonstrated that a sample size of n=223 per arm is considered 
adequate to guarantee >99% power to show equivalence between FKS518 and US-Prolia.  
A total of 446 subjects will provide >89% power to demonstrate equivalence between 
treatments for both the primary endpoint LS-BMD and co-primary endpoint 
AUEC(0-W26) of serum CTX with a conservative assumption of independence between 
endpoints. 
To calculate suitable equivalence margins for the AUEC(0-W26) of serum CTX, a 
population PD model for CTX based on a baseline Imax (inhibitory maximum plasma 
concentration of an inhibitor) model with an IC50 (half-maximal inhibitory 
concentration) of 0.784 ng/mL (Zheng, 2015), and the PK concentrations resulting from a 
60-mg denosumab dose, based on the published target mediated drug disposition model 
for denosumab (Sutjandra, 2011), with consideration of intra- and intersubject variability, 
was employed. Based on the considerations presented therein, an equivalence interval of 
[0.89, 1.12] is proposed for the PD variable AUEC(0-W26) of serum CTX to demonstrate 
equivalence between FKS518 and US-Prolia.  
9.4 
Statistical Methods 
9.4.1 
Primary Efficacy Analyses 
9.4.1.1 
Percent Change from Baseline in LS-BMD by DXA at Week 52  
The primary efficacy objective is to demonstrate equivalence of FKS518 to US-Prolia 
based on LS-BMD. 
The 5 attributes of the primary estimand are defined as follows: 
1. Treatment of interest: Treatment (FKS518 or US-Prolia, 60 mg every 26 weeks) as 
randomized. 
2. Population of interest: Women with PMO who were randomized. 
3. Primary variable/endpoint of interest: LS-BMD percent change from baseline at 
Week 52. 
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4. Potential intercurrent events and strategy to address:  
A treatment policy strategy will be applied for all categories: 
○ Permitted concomitant medications with the potential to impact the endpoint of 
interest. 
○ Protocol deviations (prohibited medications, randomization errors, departures 
from visit windows, etc) with the potential to impact the endpoint of interest. 
○ Treatment discontinuation. 
5. Population-level summary: Mean difference between the 2 treatment arms in terms of 
the primary endpoint. 
The primary estimator will be the least squares (LS) mean difference between FKS518 
and US-Prolia, with its 95% CI, estimated within an ANCOVA framework as described 
below. 
Percent change from baseline at Week 52 in LS-BMD will be analyzed using an 
ANCOVA with treatment, age (<65 years; ≥65 years) and prior bisphosphonates therapy 
(Yes/No) as fixed effects, and baseline LS-BMD as a covariate. The difference between 
treatments will be estimated by the LS mean difference between FKS518 and US-Prolia, 
with its 95% CI. 
FKS518 will be considered equivalent to US-Prolia if the 95% CI for the difference in 
mean percent change from baseline to Week 52 in LS-BMD lies entirely within the 
equivalence interval of [-1.45%, 1.45%]. 
Supportive Estimand (Per Protocol Analysis Set) 
The 5 attributes of the supportive estimand are defined as follows: 
1. Treatments under evaluation: Treatment (FKS518 or US-Prolia, 60 mg every 
26 weeks) as administered. 
2. Population of interest: Women with PMO included in the PP Analysis Set. 
3. Primary variable/endpoint of interest: LS-BMD percent change from baseline at 
Week 52. 
4. Potential intercurrent events and strategy to address: None, by definition of the 
population. 
5. Population-level summary: Mean difference between the 2 treatment arms in terms of 
the primary endpoint. 
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Further supportive estimands will be specified in the SAP. 
9.4.1.2 
AUEC of Serum CTX up to Week 26 (for MAA in the EU and EEA only) 
The co-primary objective is to demonstrate equivalence of FKS518 to US-Prolia based on 
AUEC(0-W26) of serum CTX. 
The 5 main attributes of the co-primary estimand are defined as follows: 
1. Treatment of interest: Treatments (FKS518 or US-Prolia, 60 mg every 26 weeks) as 
randomized.  
2. Population of interest: Women with PMO. 
3. Variable/endpoint of interest: AUEC(0-W26) of serum CTX. 
4. Potential intercurrent events and strategy to address:  
A treatment policy strategy will be applied for all categories: 
○ Permitted concomitant medications with the potential to impact the endpoint of 
interest. 
○ Protocol deviation (prohibited medications, randomization errors, departures from 
visit windows, etc) with the potential to impact the endpoint of interest. 
○ Treatment discontinuation. 
5. Population-level summary measure: Mean difference between the 2 treatment arms in 
terms of the endpoint of interest. 
The co-primary estimator will be the LS mean difference between FKS518 and US-Prolia 
with its 95% CI, estimated within an ANCOVA framework as described below. 
The natural log transformed AUEC(0-W26) of serum CTX will be analyzed on the 
PD Analysis Set using an ANCOVA with treatment, age (<65 years; ≥65 years), and 
prior bisphosphonates therapy (Yes/No) as fixed effects, and the natural log of baseline 
serum CTX concentration as a covariate.  
The difference between treatments will be estimated by the LS mean difference between 
FKS518 and US-Prolia, with its 95% CI. The point estimate and the limits of the 95% CI 
will be back transformed on the original scale. FKS518 will be considered equivalent to 
US-Prolia on CTX if the 95% CI for the ratio of means of AUEC(0-W26) lies entirely 
within the equivalence interval of [0.89, 1.12]. 
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Supportive Estimand (Per Protocol Analysis Set) 
The 5 attributes of the supportive estimand are defined as follows: 
1. Treatments under evaluation: Treatment (FKS518 or US-Prolia, 60 mg every 
26 weeks) as administered. 
2. Population of interest: Women with PMO included in the PP Analysis Set. 
3. Variable/endpoint of interest: AUEC(0-W26) of serum CTX. 
4. Potential intercurrent events and strategy to address: None, by definition of the 
population. 
5. Population-level summary: Mean difference between the 2 treatment arms in terms of 
the endpoint of interest. 
9.4.2 
Secondary Efficacy Analyses 
Secondary efficacy endpoints will be analyzed on the ITT and PP Analysis Sets. 
The secondary efficacy estimands are based on BMD in the femoral neck and total hip. 
Percent change from baseline at Week 52 in BMD at femoral neck and total hip by DXA 
will be analyzed using an ANCOVA with study drug, age, and prior bisphosphonates 
therapy as fixed effects, and baseline BMD at femoral neck and total hip by DXA as a 
covariate. The difference between treatments will be estimated by the LS mean difference 
between FKS518 and US-Prolia, with its 95% CI. 
9.4.3 
Secondary Pharmacodynamic Analyses  
The PD estimands are based on CTX and P1NP. The percent change from baseline at 
Week 52 in CTX and P1NP will be analyzed on the PD Analysis Set using an ANCOVA 
with treatment, age, and prior bisphosphonates therapy as fixed effects and baseline CTX 
and P1NP as covariates. The difference between treatments will be estimated by the 
LS mean difference between FKS518 and US-Prolia, with its 95% CI.  
9.4.4 
Other Efficacy Analyses 
Other efficacy analyses will be outlined in the SAP. 
9.4.5 
Safety Analyses 
The Safety Analysis Set will be used for the analysis of safety data (AEs, ISRs, exposure 
to the IP, clinical laboratory, physical examination, vital signs, and ECG). Safety data 
will be summarized for the Core Treatment Period, Transition Period, and overall. 
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10 ETHICS AND RESPONSIBILITIES 
10.1 
Good Clinical Practice 
This study will be conducted in compliance with the accepted version of the Declaration 
of Helsinki and/or all relevant regulations, in compliance with ICH GCP E6(R2) 
Guidelines and according to the appropriate regulatory requirements in the countries 
where the study will be conducted, eg Title 21 of the US Code of Federal Regulations, 
EU Directives 2001/20/EC, EU Directive 2005/28/EC, and EU Regulation 536/2014. 
In addition, this study will adhere to all local regulatory requirements and requirements 
for data protection. 
As per Regulation (EU) No 536/2014 of the European Parliament and of the Council of 
16 April 2014 on Clinical Trials on Medicinal Products for Human use, and repealing 
Directive 2001/20/EU, Article 52, a ‘serious breach’ means a breach likely to affect to a 
significant degree the safety and rights of a subject or the reliability and robustness of the 
data generated in the clinical trial. 
The Sponsor will identify, investigate, and report Serious Breach as required by 
applicable regulation 
FKSBS who is the Sponsor of a clinical trial shall notify in writing the relevant 
regulatory authority of any serious breach identified during the course of the study within 
7 days of becoming aware of that breach.  
During a clinical trial, when the Sponsor may become aware of serious breaches of the 
rules for the conduct of that clinical trial, the Sponsor will report to the Member States 
concerned in order for action to be taken by those Member States, where necessary. 
10.2 
Institutional Review Board/Independent Ethics Committee 
The conduct of the study is conditioned by an appropriately constituted IRB/IEC 
approval. 
Before initiating a study and enrolling any subject, the Investigator/institution must have 
written and dated approval/favorable opinion from the IRB/IEC for the Clinical Study 
Protocol/amendment(s), ICF and subsequent consent form updates, subject recruitment 
materials (eg, advertisements), Investigational Brochure, and any written information to 
be provided to subject. 
The Investigator must obtain a statement from the IRB/IEC that they comply with GCP 
requirements. The IRB/IEC approval must identify the protocol version as well as the 
documents reviewed. 
If required by local regulations, the study should be re-approved by the IEC annually. 
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10.3 
Informed Consent 
An unconditional prerequisite for a subject’s participation in the study is her written 
informed consent which must be given before any study-related activities are carried out 
in compliance with ICH GCP requirements. 
The subject will sign the ICF that contains information about the objectives of the study, 
the procedures followed during the study, and the risks and restrictions of the study, with 
special reference to possible side effects of the medication and potential interactions. 
In addition to providing this written information to a potential subject, the Investigator or 
designee will inform the subject verbally of all pertinent aspects of the study. The 
language used in doing so must be chosen so that the information can be fully and readily 
understood by lay persons. The ICF must be signed and personally dated by the subject 
and the Investigator (or Sub-investigator[s] to whom this was delegated). 
A separate Information Sheet (containing important information about COVID-19, 
clinical research study participation, and subject consent) will be provided to and signed 
by each subject to provide information on the general risks of study participation related 
to COVID-19 and to document that it is understood by the subject. 
Both the subject and the Investigator or designee will sign an original copy of the ICF. A 
copy of the signed and dated ICF will remain at the Investigator’s site and must be safely 
archived by the Investigator so that it can be retrieved at any time for monitoring, 
auditing, and inspection purposes. Another copy of the signed and dated ICF should be 
provided to the subject prior to participation. Whenever important new information that 
may be relevant to the subject’s consent becomes available, the written ICF and any other 
written information provided to subjects will be revised by the Sponsor FKSBS or 
designee (CRO) and be submitted again to the IRB/IEC for review and favorable opinion. 
The agreed, revised information will be provided to each subject in the study for signing 
and dating. The Investigator or designee will explain the changes from the previous 
version to all subjects in the study prior to re-consent. 
The Principal Investigator/Investigator(s) at each center will: 
• Confirm that each subject is given full and adequate oral and written information 
about the nature, purpose, possible risk, and benefit of the study. 
• Confirm that each subject is notified that she is free to discontinue from the study at 
any time. 
• Confirm that each subject is given the opportunity to ask questions and allowed time 
to consider the information provided. 
• Confirm that each subject provides signed and dated informed consent before 
conducting any procedure specifically for the study. 
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• Confirm that a copy of the signed ICF is given to the subject. 
• Confirm that any incentives for subject who participate in the study as well as any 
provisions for subject harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC. 
If the ICF is revised, the revised ICF must have received the IRB/IEC’s 
approval/favorable opinion in advance of its use. Subjects must be informed of the 
changes to the ICF and must re-consent to the most current version during their 
participation in the study. The subject or the subject’s legally acceptable representative 
should be informed in a timely manner if new information becomes available that may be 
relevant to the subject’s willingness to continue participation in the study. The 
communication of this information should be documented. 
10.4 
Financing and Insurance 
10.4.1 
Study Agreement 
The Investigator (and/or, as appropriate, the hospital administrative representative) and 
the Sponsor will sign a Clinical Study Agreement prior to the start of the study, outlining 
overall Sponsor and Investigator responsibilities in relation to the study. The contract 
should describe whether costs for pharmacy, laboratory, and other protocol-required 
services are being paid directly or indirectly. 
The Principal Investigator at each investigational site should comply with all the terms, 
conditions, and obligations of the Clinical Study Agreement, or equivalent, for this study. 
In the event of any inconsistency between this Clinical Study Protocol and the Clinical 
Study Agreement, the terms of Clinical Study Protocol shall prevail with respect to the 
conduct of the study and the treatment of subjects and in all other respects, not relating to 
study conduct or treatment of subjects, the terms of the Clinical Study Agreement shall 
prevail. 
Agreements between the Sponsor FKSBS/CRO and the Principal Investigator should be 
in place before any study-related procedures can take place, or subjects are enrolled. 
10.4.2 
Insurance, Indemnity, and Compensation 
The Sponsor will maintain an appropriate clinical study insurance policy. 
10.4.3 
Financial Disclosure 
Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
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11 RECORDS MANAGEMENT 
All clinical study information should be recorded, handled, and stored in a way that 
allows its accurate reporting, interpretation, and verification. This principle applies to all 
records referenced in this protocol, irrespective of the type of media used. 
During each study visit, a physician participating in the study will maintain progress 
notes in the subject’s medical records to document all significant observations. At a 
minimum, these notes are to contain: 
• The date of the visit and the corresponding day or visit in the study schedule. 
• General condition and status remarks by the subject, including any significant 
medical findings. The severity, frequency, duration, and resolution of any reported 
AE, and the Investigator's assessment as to whether or not the reported AE is related 
to IP. 
• Changes (including dosages) in concomitant medications/therapies (including 
medical foods) or procedures. 
• A general reference to the procedures completed. 
• The signature or initials of all physicians making an entry in the medical record 
(progress notes). 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information is to also be documented in the medical record (progress 
notes), as described above. 
Information from the medical records (progress notes) and other source documents is to 
be promptly entered into the appropriate section of the eCRF. 
Changes to information in the medical record (progress notes) and other source 
documents are to be initialed and dated on the day the change is made by the Investigator 
(or designee). If the reason for the change is not apparent, a brief explanation for the 
change is to be written adjacent to the change. Changes to the eCRF will be electronically 
tracked. 
The 
 will write a data management plan, which will be 
finalized prior to performing any data validation. 
11.1 
Source Documentation 
Source documents contain the results of original observations and activities of a clinical 
investigation. They are the original records in which raw data are first recorded. Source 
documents include, but are not limited to, medical records (progress notes), ECG and 
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computer printouts, screening logs, completed scales, quality of life questionnaires, and 
recorded data from automated instruments. 
The Investigator or designee will record data, derived from the subject source documents, 
into the eCRF, after having received training both on the electronic data capture (EDC) 
system and the eCRFs.  
The Investigator should complete and maintain all source documents in accordance with 
the ALCOAC principles (Attributable, Legible, Contemporaneous, Original, Accurate 
and Complete) in compliance with ICH GCP E6 R2. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, 
via an audit trail). 
All data derived from the study will remain the property of the Sponsor FKSBS. 
Records must be retained in accordance with the current ICH GCP E6 R2 Guidelines. All 
essential study documents including records of subject, source documents, eCRFs, and IP 
inventory must be kept on file at the investigational site. 
The Investigator should confirm the accuracy, completeness, legibility, and timeliness of 
the data reported to the Sponsor in the eCRFs and in all required reports. 
The Investigator must maintain source documents for each subject in the study. Data 
reported on the eCRF, that are derived from source documents, should be consistent with 
the source documents or the discrepancies should be explained. 
Blood samples for PD (bone biomarkers), 
 and immunogenicity analyses will be sent 
to the designated qualified laboratory(ies) for processing per the laboratory manual and 
the results will be transferred electronically according to the data transfer agreement with 
the CRO. 
Blood samples for safety analyses will be sent to the designated laboratory for processing 
per the laboratory manual and the results will be sent to the Investigator and transferred 
electronically according to the data transfer agreement with the CRO. The Investigator 
will maintain the safety laboratory results as part of the subject’s source documents. 
The EDC system includes password protection and internal quality checks, such as 
automatic edit checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
In addition, CRO staff will monitor the data entered in the eCRFs for completeness and 
accuracy. Designated investigational site study staff is required to respond to the query 
and confirm or correct the data in a timely manner. 
The data collected by vendors will be electronically transferred to the CRO through 
datasets. Consistency of these data with the data recorded in the eCRF will be reconciled 
by the CRO. The CRO will send to the relevant investigational site, the central 
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laboratory, and the bioanalytical laboratory (or third-party vendor) a request for 
clarification of data using an electronic data query. All data discrepancies will be 
resolved prior to database lock. 
Concomitant medications entered into the database will be coded using the most current 
World Health Organization (WHO) Drug Dictionary, which employs the Anatomical 
Therapeutic Chemical classification system.  
Medical history and AEs will be coded using the most current MedDRA dictionary. 
All source documents from this study are to be maintained by the Investigator and made 
available for inspection by authorized persons. The Investigator will provide direct access 
to source documents/data for study-related monitoring, audits, IRB/IEC review, and 
regulatory inspections. The Sponsor or designee should verify that each subject has 
consented, in writing, to direct access to her original medical records for study-related 
monitoring, audit, IRB/IEC review, and regulatory inspection. 
11.2 
Case Report Form Completion and Data Management 
An eCRF will be used to store and transmit subject information. The file structure and 
format for the eCRF will be provided by the Sponsor or its representative and should be 
handled in accordance with the instructions provided. 
The eCRF must be reviewed and electronically signed and dated by the Investigator. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by authorized 
site personnel (eg, Investigators and the study coordinator). The eCRF must be completed 
as soon as possible after any subject evaluation or communication. If data are to be 
changed due to erroneous input or other reason, an electronic audit trail will track the 
changes. The eCRFs and computers that store them must be accessible to study monitors 
and other regulatory auditors. Changes to the eCRF will be electronically tracked. 
Data will be entered/loaded into a validated electronic database using a clinical data 
management system. Computerized data cleaning checks will be used in addition to 
manual review to check for discrepancies and to ensure consistency of the data. 
11.3 
Study Files and Record Retention 
All data derived from the study will remain the property of the Sponsor. The Sponsor 
assumes accountability for actions delegated to other individuals, eg, the CRO. 
Records must be retained in accordance with the current ICH Guidelines on GCP. All 
essential study documents, including records of subjects, source documents, eCRFs, and 
the IP inventory, must be kept on file. 
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Essential study documents should be retained 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 until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the proposed 
biosimilar to denosumab FKS518, but for at least 25 years after the end of the clinical 
study in line with the requirements set by EU Regulation 536/2014. However, essential 
study documents may be retained for a longer period if required by the applicable 
regulatory requirements or by agreement with the Sponsor. The Sponsor is responsible 
for informing the Investigator when these documents need no longer be retained. 
After database lock, the Investigator will receive electronic copies of the subject data for 
archiving at the study site. The Investigator is not to dispose of any records relevant to 
this study without written permission from the Sponsor and is to provide the Sponsor the 
opportunity to collect such records. The Investigator shall take responsibility for 
maintaining adequate and accurate hard copy source documents of all observations and 
data generated during this study. Such documentation is subject to inspection by the 
Sponsor, its representatives, and regulatory authorities. 
If an Investigator moves, withdraws from a study, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept 
responsibility. Notice of transfer must be made to and agreed by the Sponsor. 
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12 AUDITING AND MONITORING 
12.1 
Monitoring 
The CRO will perform the monitoring of the study according to CRO’s monitoring plan 
and applicable Standard Operating Procedures to review that the study is conducted and 
documented properly in compliance with the protocol, ICH GCP, and all applicable 
regulatory requirements. 
During the study, a CRO representative will have regular contacts with the study site, 
including remote and on-site visits to: 
• Provide study information and support to the Investigator(s). 
• Confirm that facilities remain fit for purpose and that the site has appropriate 
resources available to conduct the study in compliance with the Clinical Study 
Protocol and are able to collaborate with the CRO monitoring team. 
• Confirm that the investigational team is adhering to the Clinical Study Protocol 
requirements, that data are being recorded in the eCRF in an accurate and timely 
manner, that biological samples are handled in accordance with the laboratory 
manual, and that study IP accountability checks are being performed.  
• Perform direct source data verification by comparing eCRF data with the subject’s 
source document at the investigational site including verification of informed consent 
of participating subject.  
• Discuss with the Investigator any deviation from the Clinical Study Protocol and 
other study instruction, and review that there are timely and completely reported 
accordingly. 
• Review with the Investigator any safety events for timely and complete reporting. 
• Work closely with the Investigator and site staff to facilitate effective management of 
the study in compliance with the Clinical Study Protocol, ICH GCP Guidelines, and 
applicable regulatory requirements. 
The CRO representative will be available between visits if the Investigator(s) or other 
staff at the center needs information and advice about the study conduct. 
12.2 
Audits and Inspections 
Authorized representatives of the Sponsor FKSBS/CRO, a regulatory authority, or an 
IRB/IEC may perform audits or inspections at the center, including source data 
verification. The purpose of an audit or inspection is to systematically and independently 
examine all study-related activities and documents, to determine whether these activities 
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were conducted, and data were recorded, analyzed, and accurately reported according to 
the protocol, GCP, current ICH guidelines, and any applicable regulatory requirements.  
If an inspection of the clinical site is requested by a regulatory authority, the Investigator 
must inform the Sponsor or designee immediately that this request has been made. 
12.3 
Deviation from Study Protocol 
The Investigator should conduct the study and perform procedures as defined in the 
protocol, and collect and record data as instructed by the eCRF completion guidelines. 
Under no circumstances should an Investigator collect additional data or conduct any 
additional procedures for any research-related purpose involving any of the study 
interventions and/or the study IP. 
Protocol deviations will be discussed with the Investigator.  
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13 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by the Sponsor. A protocol change intended to eliminate an apparent 
immediate hazard to subjects should be implemented immediately. 
Any permanent change to the protocol must be handled as a protocol amendment. 
Substantial protocol amendments will be submitted to the regulatory authorities and/or 
IRB/IEC as appropriate, and the Investigator must await approval before implementing 
the changes.  
The current version of the ICF will require similar modification if the IRB/IEC, 
Investigator, and/or Sponsor, judge the amendment to the protocol to substantially change 
the study design and/or increase the potential risk to the subject and/or impact the 
subject's involvement as a study subject. In such cases, the ICF will be renewed for 
enrolled subjects before their continued participation in the study. 
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14 STUDY REPORT AND PUBLICATIONS 
A CSR will be prepared after final database lock.  
The Sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with the CSR according to the applicable regulatory requirements. The 
Sponsor should ensure that the CSR meets the standards of the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). 
The publication policy of the Sponsor is discussed in the Investigator’s Clinical Research 
Agreement.  
The designated Coordinating Investigator will sign the CSR. 
The posting of FKSBS-sponsored study information and tabular study results on the 
respective public registry and as required any national accessible websites will be done 
by the CRO. 
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15 STUDY START AND TERMINATION 
The study start date is the date on which the first subject provides informed consent. 
The end of the study is defined as the date of the last visit or last procedure of the last 
subject in the study.  
The Sponsor FKSBS may terminate the study at an individual investigational site if 
recruitment is poor or if it becomes unjustifiable for medical or ethical reasons. 
The Sponsor FKSBS or the CRO will inform Health Authorities and IECs/IRBs about the 
discontinuation of the study at an individual site and the reasons for discontinuation in 
accordance with applicable regulations. 
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16 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from the Sponsor FKSBS. However, authorized representatives from 
regulatory authorities, IRB/IEC, the Sponsor FKSBS and the CRO are allowed full access 
to the study records including subjects’ source documents (EU General Data Protection 
Regulation). 
 
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17 REFERENCES 
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. 
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Cummings SR, San Martin J, McClung MR, et al. FREEDOM Trial. Denosumab for 
prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 
2009;361(8):756-65. 
EMA Guideline on similar biological medicinal products containing monoclonal 
antibodies – non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010), 
May 2012. 
EMA Prolia EPAR Product Information, last update 08/09/2020. 
EMA Xgeva EPAR Product Information, last update 07/08/2020. 
EU General Data Protection Regulation (https://ec.europa.eu/info/law/law-topic/data-
protection_en). 
McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women 
with low bone mineral density. N Engl J Med. 2006;354(8):821-31. 
Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of 
denosumab in healthy subjects and postmenopausal women with osteopenia or 
osteoporosis. Clin Pharmacokinet. 2011;50(12):793-807. 
US Food and Drug Administration, Guidance for Industry. Clinical Pharmacology Data 
to Support a Demonstration of Biosimilarity to a Reference Product. 2016. 
US Food and Drug Administration, Prolia prescribing information, revised 07/2019. 
US Food and Drug Administration, Xgeva prescribing information, revised 05/2019. 
Vasikaran S, Cooper C, Eastell R, et al. International Osteoporosis Foundation and 
International Federation of Clinical Chemistry and Laboratory Medicine position on bone 
marker standards in osteoporosis. Clin Chem Lab Med. 2011;49(8):1271-4.  
Zheng J, van Schaick E, Wu LS, et al. Using early biomarker data to predict long-term 
bone mineral density: application of semi-mechanistic bone cycle model on denosumab 
data. J Pharmacokinet Pharmacodyn. 2015;42(4):333-47. 
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